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1.
Int J Mol Sci ; 22(19)2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34639181

RESUMO

The antidiabetic drug empagliflozin is reported to produce a range of cardiovascular effects, including a reduction in systemic blood pressure. However, whether empagliflozin directly modulates the contractility of resistance-size mesenteric arteries remains unclear. Here, we sought to investigate if empagliflozin could relax resistance-size rat mesenteric arteries and the associated underlying molecular mechanisms. We found that acute empagliflozin application produces a concentration-dependent vasodilation in myogenic, depolarized and phenylephrine (PE)-preconstricted mesenteric arteries. Selective inhibition of smooth muscle cell voltage-gated K+ channels KV1.5 and KV7 abolished empagliflozin-induced vasodilation. In contrast, pharmacological inhibition of large-conductance Ca2+-activated K+ (BKCa) channels and ATP-sensitive (KATP) channels did not abolish vasodilation. Inhibition of the vasodilatory signaling axis involving endothelial nitric oxide (NO), smooth muscle cell soluble guanylyl cyclase (sGC) and protein kinase G (PKG) did not abolish empagliflozin-evoked vasodilation. Inhibition of the endothelium-derived vasodilatory molecule prostacyclin (PGI2) had no effect on the vasodilation. Consistently, empagliflozin-evoked vasodilation remained unaltered by endothelium denudation. Overall, our data suggest that empagliflozin stimulates smooth muscle cell KV channels KV1.5 and KV7, resulting in vasodilation in resistance-size mesenteric arteries. This study demonstrates for the first time a novel mechanism whereby empagliflozin regulates arterial contractility, resulting in vasodilation. Due to known antihypertensive properties, treatment with empagliflozin may complement conventional antihypertensive therapy.


Assuntos
Compostos Benzidrílicos/farmacologia , Endotélio Vascular/fisiologia , Glucosídeos/farmacologia , Artérias Mesentéricas/fisiologia , Músculo Liso Vascular/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Vasodilatação , Vasodilatadores/farmacologia , Animais , Endotélio Vascular/efeitos dos fármacos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
2.
Int Heart J ; 62(5): 962-969, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34544970

RESUMO

Fractional flow reserve (FFR) is considered the standard for assessment of the physiological significance of coronary artery stenosis. Intracoronary papaverine (PAP) is the most potent vasodilator used for the achievement of maximal hyperemia. However, its use can provoke ventricular tachycardia (VT) due to excessive QT prolongation. We evaluated the clinical efficacy and safety of the administration of PAP after nicorandil (NIC), a potassium channel opener that prevents VT, for optimal FFR measurement.A total of 127 patients with 178 stenoses were enrolled. The FFR values were measured using NIC (NIC-FFR) and PAP (PAP-FFR). We administered PAP following NIC (NIC-PAP). Changes in the FFR and electrogram parameters (baseline versus NIC versus PAP) were assessed and the incidence of arrhythmias after PAP was evaluated. In addition, we analyzed another 41 patients with 51 stenoses by assessing the FFR using PAP before NIC (PAP-NIC). After propensity score matching, the electrogram parameters between 2 groups were compared.The mean PAP-FFR was significantly lower than the mean NIC-FFR (0.82 ± 0.11 versus 0.81 ± 0.11, P < 0.05). The mean baseline-QTc, NIC-QTc, and PAP-QTc values were 425 ± 37 ms1/2, 424 ± 41 ms1/2, and 483 ± 54 ms1/2, respectively. VT occurred in only 1 patient (0.6%). Although PAP induced QTc prolongation (P < 0.05), the PAP-QTc duration was significantly shorter in NIC-PAP compared to PAP-NIC (P < 0.05).The administration of PAP with NIC may induce sufficient hyperemia and prevent fatal arrhythmia through reductions in the PAP-induced QTc prolongation during FFR measurement.


Assuntos
Arritmias Cardíacas/epidemiologia , Estenose Coronária/tratamento farmacológico , Reserva Fracionada de Fluxo Miocárdico/efeitos dos fármacos , Nicorandil/farmacologia , Papaverina/farmacologia , Taquicardia Ventricular/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/fisiopatologia , Estudos de Casos e Controles , Angiografia Coronária/métodos , Angiografia Coronária/estatística & dados numéricos , Estenose Coronária/diagnóstico , Estenose Coronária/fisiopatologia , Quimioterapia Combinada , Eletrocardiografia/métodos , Feminino , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Hiperemia/induzido quimicamente , Hiperemia/fisiopatologia , Incidência , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nicorandil/administração & dosagem , Nicorandil/uso terapêutico , Papaverina/administração & dosagem , Papaverina/efeitos adversos , Papaverina/uso terapêutico , Estudos Retrospectivos , Segurança , Taquicardia Ventricular/induzido quimicamente , Taquicardia Ventricular/fisiopatologia , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico
3.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502308

RESUMO

Rutaecarpine (RUT) is a bioactive alkaloid isolated from the fruit of Evodia rutaecarpa that exerts a cellular protective effect. However, its protective effects on endothelial cells and its mechanism of action are still unclear. In this study, we demonstrated the effects of RUT on nitric oxide (NO) synthesis via endothelial nitric oxide synthase (eNOS) phosphorylation in endothelial cells and the underlying molecular mechanisms. RUT treatment promoted NO generation by increasing eNOS phosphorylation. Additionally, RUT induced an increase in intracellular Ca2+ concentration and phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase ß (CaMKKß), AMP-activated protein kinase (AMPK), and Ca2+/calmodulin-dependent kinase II (CaMKII). Inhibition of transient receptor potential vanilloid type 1 (TRPV1) attenuated RUT-induced intracellular Ca2+ concentration and phosphorylation of CaMKII, CaMKKß, AMPK, and eNOS. Treatment with KN-62 (a CaMKII inhibitor), Compound C (an AMPK inhibitor), and STO-609 (a CaMKKß inhibitor) suppressed RUT-induced eNOS phosphorylation and NO generation. Interestingly, RUT attenuated the expression of ICAM-1 and VCAM-1 induced by TNF-α and inhibited the inflammation-related NF-κB signaling pathway. Taken together, these results suggest that RUT promotes NO synthesis and eNOS phosphorylation via the Ca2+/CaMKII and CaM/CaMKKß/AMPK signaling pathways through TRPV1. These findings provide evidence that RUT prevents endothelial dysfunction and benefit cardiovascular health.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Endotélio Vascular/metabolismo , Alcaloides Indólicos/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Quinazolinas/farmacologia , Canais de Cátion TRPV/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Endotélio Vascular/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , Óxido Nítrico Sintase Tipo III/genética , Fosforilação , Transdução de Sinais , Canais de Cátion TRPV/genética , Vasodilatadores/farmacologia
4.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576086

RESUMO

The cysteine-rich LIM-only protein 4 (CRP4), a LIM-domain and zinc finger containing adapter protein, has been implicated as a downstream effector of the second messenger 3',5'-cyclic guanosine monophosphate (cGMP) pathway in multiple cell types, including vascular smooth muscle cells (VSMCs). VSMCs and nitric oxide (NO)-induced cGMP signaling through cGMP-dependent protein kinase type I (cGKI) play fundamental roles in the physiological regulation of vascular tone and arterial blood pressure (BP). However, it remains unclear whether the vasorelaxant actions attributed to the NO/cGMP axis require CRP4. This study uses mice with a targeted deletion of the CRP4 gene (CRP4 KO) to elucidate whether cGMP-elevating agents, which are well known for their vasorelaxant properties, affect vessel tone, and thus, BP through CRP4. Cinaciguat, a NO- and heme-independent activator of the NO-sensitive (soluble) guanylyl cyclase (NO-GC) and NO-releasing agents, relaxed both CRP4-proficient and -deficient aortic ring segments pre-contracted with prostaglandin F2α. However, the magnitude of relaxation was slightly, but significantly, increased in vessels lacking CRP4. Accordingly, CRP4 KO mice presented with hypotonia at baseline, as well as a greater drop in systolic BP in response to the acute administration of cinaciguat, sodium nitroprusside, and carbachol. Mechanistically, loss of CRP4 in VSMCs reduced the Ca2+-sensitivity of the contractile apparatus, possibly involving regulatory proteins, such as myosin phosphatase targeting subunit 1 (MYPT1) and the regulatory light chain of myosin (RLC). In conclusion, the present findings confirm that the adapter protein CRP4 interacts with the NO-GC/cGMP/cGKI pathway in the vasculature. CRP4 seems to be part of a negative feedback loop that eventually fine-tunes the NO-GC/cGMP axis in VSMCs to increase myofilament Ca2+ desensitization and thereby the maximal vasorelaxant effects attained by (selected) cGMP-elevating agents.


Assuntos
Pressão Sanguínea , Vasos Sanguíneos/fisiologia , GMP Cíclico/metabolismo , Proteínas com Domínio LIM/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Feminino , Masculino , Camundongos Knockout , Modelos Biológicos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Norepinefrina/farmacologia , Transdução de Sinais , Guanilil Ciclase Solúvel/metabolismo , Vasodilatadores/farmacologia
5.
Int J Mol Sci ; 22(18)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34575925

RESUMO

Protein kinase C (PKC) activation can evoke vasoconstriction and contribute to coronary disease. However, it is unclear whether PKC activation, without activating the contractile machinery, can lead to coronary arteriolar dysfunction. The vasoconstriction induced by the PKC activator phorbol 12,13-dibutyrate (PDBu) was examined in isolated porcine coronary arterioles. The PDBu-evoked vasoconstriction was sensitive to a broad-spectrum PKC inhibitor but not affected by inhibiting PKCß2 or Rho kinase. After exposure of the vessels to a sub-vasomotor concentration of PDBu (1 nmol/L, 60 min), the endothelium-dependent nitric oxide (NO)-mediated dilations in response to serotonin and adenosine were compromised but the dilation induced by the NO donor sodium nitroprusside was unaltered. PDBu elevated superoxide production, which was blocked by the superoxide scavenger Tempol. The impaired NO-mediated vasodilations were reversed by Tempol or inhibition of PKCß2, xanthine oxidase, c-Jun N-terminal kinase (JNK) and Rho kinase but were not affected by a hydrogen peroxide scavenger or inhibitors of NAD(P)H oxidase and p38 kinase. The PKCß2 protein was detected in the arteriolar wall and co-localized with endothelial NO synthase. In conclusion, activation of PKCß2 appears to compromise NO-mediated vasodilation via Rho kinase-mediated JNK signaling and superoxide production from xanthine oxidase, independent of the activation of the smooth muscle contractile machinery.


Assuntos
Vasos Coronários/metabolismo , Endotélio Vascular/metabolismo , Óxido Nítrico/metabolismo , Proteína Quinase C beta/metabolismo , Vasodilatação , Animais , Imuno-Histoquímica , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Dibutirato de 12,13-Forbol/farmacologia , Proteína Quinase C beta/genética , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Suínos , Vasodilatação/genética , Vasodilatadores/farmacologia , Xantina Oxidase/metabolismo
6.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445661

RESUMO

Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.


Assuntos
Adenosina/farmacologia , Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Membrana Sinovial/efeitos dos fármacos , Sinoviócitos/efeitos dos fármacos , Vasodilatadores/farmacologia , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/metabolismo , Osteoartrite/patologia , Sinoviócitos/metabolismo , Sinoviócitos/patologia
7.
J Am Heart Assoc ; 10(16): e020498, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34350775

RESUMO

Background The vascular pharmacodynamics of anthocyanins is only partially understood. To examine whether the anthocyanin-induced vasorelaxation is related to membrane estrogen receptor activity, the role of ERα or GPER antagonism was ascertained on anthocyanins or 17-ß estradiol-(E2) induced vasodilatations and NO production. Methods and Results The rat arterial mesenteric bed was perfused with either anthocyanins or corresponding 3-O-glycosides, or E2, to examine rapid concentration-dependent vasorelaxations. The luminally accessible fraction of NO in mesenteric perfusates before and after anthocyanins or E2 administration was quantified. Likewise, NO-DAF signal detected NO production in primary endothelial cells cultures incubated with anthocyanins or E2 in the absence and presence of ERα (ICI 182,780) or GPER (G-36) selective antagonists. Anthocyanins or corresponding glycosides elicited, within minutes, vasodilation with nanomolar potencies; half maximal anthocyanin response reached 50% to 60% efficacy, in contrast to acetylcholine. The vasorelaxation is of rapid onset and exclusively endothelium-dependent; NOS inhibition annulled the vasorelaxation. The delphinidin vascular response was not modified by 100 nmol/L atropine but significantly attenuated by joint application of ICI plus G-36 (52±4.6 versus 8.5±1.5%), revealing the role of membrane estrogen receptors. Moreover, the anthocyanin or E2-induced NO production was antagonized up to 70% by these antagonists. NO-DAF signal elicited by anthocyanins was annulled by NOS inhibition or by ICI plus G-36 addition. Conclusions The biomedical effect of anthocyanins or 3-O-glycosylates derivatives contained in naturally purple-colored foods or berries is due to increased NO production, and not to the phytochemical's antioxidant potential, highlighting the nutraceutical role of natural products in cardiovascular diseases.


Assuntos
Antocianinas/farmacologia , Receptor alfa de Estrogênio/agonistas , Artéria Mesentérica Superior/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fitoestrógenos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Masculino , Artéria Mesentérica Superior/metabolismo , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais
8.
Chem Biol Interact ; 348: 109620, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34411564

RESUMO

Naringenin is a naturally occurring flavanone (flavonoid) known to have bioactive effects on human health. It has been reported to show cardiovascular effects. This study aimed to investigate the possible vasorelaxant effect of naringenin and the mechanism behind it by using a Sprague Dawley rat aortic ring assay model. Naringenin caused significant vasorelaxation of endothelium-intact aortic rings precontracted with phenylephrine (pD2 = 4.27 ± 0.05; Rmax = 121.70 ± 4.04%) or potassium chloride (pD2 = 4.00 ± 0.04; Rmax = 103.40 ± 3.82%). The vasorelaxant effect decreased in the absence of an endothelium (pD2 = 3.34 ± 0.10; Rmax = 62.29 ± 2.73%). The mechanisms of the vasorelaxant effect of naringenin in the presence of antagonists were also investigated. Indomethacin, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, atropine, 4-aminopyridine, Nω-nitro-l-arginine methyl ester, glibenclamide and propranolol significantly reduced the relaxation stimulated by naringenin in the presence of endothelium. Besides that, the effect of naringenin on the voltage-operated calcium channel (VOCC) in the endothelium-intact aortic ring was studied, as was intracellular Ca2+ release from the sarcoplasmic reticulum (SR) in the endothelium-denuded aortic ring. The results showed that naringenin also significantly blocked the entry of Ca2+ via the VOCC, SERCA/SOCC and suppressed the release of Ca2+ from the SR. Thus, the vasorelaxant effect shown by naringenin mostly involve the COX pathway, the endothelium-dependent pathway via NO/sGC/prostaglandin, calcium and potassium channels.


Assuntos
Aorta Torácica/efeitos dos fármacos , Canais de Cálcio/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Flavanonas/farmacologia , Canais de Potássio/metabolismo , Vasodilatadores/farmacologia , Animais , Aorta Torácica/citologia , Aorta Torácica/metabolismo , Aorta Torácica/fisiologia , Relação Dose-Resposta a Droga , Ratos , Ratos Sprague-Dawley
9.
J Appl Physiol (1985) ; 131(4): 1311-1327, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34435510

RESUMO

Cardiovascular lability is common after cardiac arrest. We investigated whether altered endothelial function is present in cerebral and mesenteric arteries 2 and 4 h after resuscitation. Male Sprague-Dawley rats were anesthetized, intubated, ventilated, and intravascularly catheterized whereupon rats were randomized into four groups. Following 7 min of asphyxial cardiac arrest and subsequent resuscitation, cardiac arrest and sham rats were observed for either 2 or 4 h. Neuron-specific enolase levels were measured in blood samples. Middle cerebral artery segments and small mesenteric arteries were isolated and examined in microvascular myographs. qPCR and immunofluorescence analysis were performed on cerebral arteries. In cerebral arteries, bradykinin-induced vasodilation was inhibited in the presence of either calcium-activated K+ channel blockers (UCL1684 and senicapoc) or the nitric oxide (NO) synthase inhibitor, Nω-nitro-L-arginine methyl ester hydrochloride (l-NAME), whereas the combination abolished bradykinin-induced vasodilation across groups. Neuron-specific enolase levels were significantly increased in cardiac arrest rats. Cerebral vasodilation was comparable between the 2-h groups, but markedly enhanced in response to bradykinin, NS309 (an opener of small and intermediate calcium-activated K+ channels), and sodium nitroprusside 4 h after cardiac arrest. Endothelial NO synthase and guanylyl cyclase subunit α-1 mRNA expression was unaltered after 2 h, but significantly decreased 4 h after resuscitation. In mesenteric arteries, the endothelium-dependent vasodilation was comparable between corresponding groups at both 2 and 4 h. Our findings show enhanced cerebral endothelium-dependent vasodilation 4 h after cardiac arrest mediated by potentiated endothelial-derived hyperpolarization and NO pathways. Altered cerebral endothelium-dependent vasodilation may contribute to disturbed cerebral perfusion after cardiac arrest.NEW & NOTEWORTHY This is the first study, to our knowledge, to demonstrate enhanced endothelium-dependent vasodilation in middle cerebral arteries in a cardiac arrest rat model. The increased endothelium-dependent vasodilation was a result of potentiated endothelium-derived hyperpolarization and endothelial nitric oxide pathways. Immunofluorescence microscopy confirmed the presence of relevant receptors and eNOS in cerebral arteries, whereas qPCR showed altered expression of genes related to guanylyl cyclase and eNOS. Altered endothelium-dependent vasoregulation may contribute to disturbed cerebral blood flow in the postcardiac arrest period.


Assuntos
Endotélio Vascular , Vasodilatação , Animais , Artérias Cerebrais , Masculino , Artérias Mesentéricas , Óxido Nítrico/farmacologia , Ratos , Ratos Sprague-Dawley , Vasodilatadores/farmacologia
10.
Mol Pharmacol ; 100(5): 428-455, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34452975

RESUMO

Vascular pathology is increased in diabetes because of reactive-oxygen-species (ROS)-induced endothelial cell damage. We found that in vitro and in a streptozotocin diabetes model in vivo, metformin at diabetes-therapeutic concentrations (1-50 µM) protects tissue-intact and cultured vascular endothelial cells from hyperglycemia/ROS-induced dysfunction typified by reduced agonist-stimulated endothelium-dependent, nitric oxide-mediated vasorelaxation in response to muscarinic or proteinase-activated-receptor 2 agonists. Metformin not only attenuated hyperglycemia-induced ROS production in aorta-derived endothelial cell cultures but also prevented hyperglycemia-induced endothelial mitochondrial dysfunction (reduced oxygen consumption rate). These endothelium-protective effects of metformin were absent in orphan-nuclear-receptor Nr4a1-null murine aorta tissues in accord with our observing a direct metformin-Nr4a1 interaction. Using in silico modeling of metformin-NR4A1 interactions, Nr4a1-mutagenesis, and a transfected human embryonic kidney 293T cell functional assay for metformin-activated Nr4a1, we identified two Nr4a1 prolines, P505/P549 (mouse sequences corresponding to human P501/P546), as key residues for enabling metformin to affect mitochondrial function. Our data indicate a critical role for Nr4a1 in metformin's endothelial-protective effects observed at micromolar concentrations, which activate AMPKinase but do not affect mitochondrial complex-I or complex-III oxygen consumption rates, as does 0.5 mM metformin. Thus, therapeutic metformin concentrations requiring the expression of Nr4a1 protect the vasculature from hyperglycemia-induced dysfunction in addition to metformin's action to enhance insulin action in patients with diabetes. SIGNIFICANCE STATEMENT: Metformin improves diabetic vasodilator function, having cardioprotective effects beyond glycemic control, but its mechanism to do so is unknown. We found that metformin at therapeutic concentrations (1-50µM) prevents hyperglycemia-induced endothelial dysfunction by attenuating reactive oxygen species-induced damage, whereas high metformin (>250 µM) impairs vascular function. However, metformin's action requires the expression of the orphan nuclear receptor NR4A1/Nur77. Our data reveal a novel mechanism whereby metformin preserves diabetic vascular endothelial function, with implications for developing new metformin-related therapeutic agents.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Células HEK293 , Humanos , Hiperglicemia/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , Estresse Oxidativo/fisiologia , Vasodilatadores/farmacologia
11.
Sci Rep ; 11(1): 15855, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349211

RESUMO

Polyols are effective against caries-causing streptococci but the effect on oropharynx-derived pyogenic streptococci is not well characterised. We aimed to study the effect of erythritol (ERY) and xylitol (XYL) against Streptococcus pyogenes isolated from peritonsillar abscesses (PTA). We used 31 clinical isolates and 5 throat culture collection strains. Inhibition of bacterial growth by polyols at 2.5%, 5% and 10% concentrations was studied and the results were scored. Amylase levels in PTA pus were compared to polyol effectivity scores (PES). Growth curves of four S. pyogenes isolates were analysed. Our study showed that XYL was more effective than ERY inhibiting 71-97% and 48-84% of isolates, respectively, depending of concentrations. 48% of clinical and all throat strains were inhibited by polyols in all concentrations (PES 3). PES was negative or zero in 26% of the isolates in the presence of ERY and in 19% of XYL. ERY enhanced the growth of S. pyogenes isolated from pus with high amylase levels. Polyols in all concentrations inhibited the growth in exponential phase. In conclusion, ERY and XYL are potent growth inhibitors of S. pyogenes isolated from PTA. Therefore, ERY and XYL may have potential in preventing PTA in the patients with frequent tonsillitis episodes.


Assuntos
Eritritol/farmacologia , Abscesso Peritonsilar/patologia , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus pyogenes/crescimento & desenvolvimento , Streptococcus pyogenes/isolamento & purificação , Xilitol/farmacologia , Humanos , Abscesso Peritonsilar/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/efeitos dos fármacos , Edulcorantes/farmacologia , Vasodilatadores/farmacologia
12.
Int J Cardiol ; 342: 7-14, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34358553

RESUMO

OBJECTIVES: Adenosine hyperemia is an integral component of the physiological assessment of obstructive coronary artery disease in patients with chronic coronary syndrome (CCS). The aim of this study was to compare systemic, coronary and microcirculatory hemodynamics between intravenous (IV) adenosine hyperemia versus physical exercise stress in patients with CCS and coronary stenosis. METHODS: Twenty-three patients (mean age, 60.6 ± 8.1 years) with CCS and single-vessel coronary stenosis underwent cardiac catheterization. Continuous trans-stenotic coronary pressure-flow measurements were performed during: i) IV adenosine hyperemia, and ii) physical exercise using a catheter-table-mounted supine ergometer. Systemic, coronary and microcirculatory hemodynamic responses were compared between IV adenosine and exercise stimuli. RESULTS: Mean stenosis diameter was 74.6% ± 10.4. Median (interquartile range) FFR was 0.54 (0.44-0.72). At adenosine hyperemia versus exercise stress, mean aortic pressure (Pa, 91 ± 16 mmHg vs 99 ± 15 mmHg, p < 0.0001), distal coronary pressure (Pd, 58 ± 21 mmHg vs 69 ± 24 mmHg, p < 0.0001), trans-stenotic pressure ratio (Pd/Pa, 0.63 ± 0.18 vs 0.69 ± 0.19, p < 0.0001), microvascular resistance (MR, 2.9 ± 2.2 mmHg.cm-1.sec-1 vs 4.2 ± 1.7 mmHg.cm-1.sec-1, p = 0.001), heart rate (HR, 80 ± 15 bpm vs 85 ± 21 bpm, p = 0.02) and rate-pressure product (RPP, 7522 ± 2335 vs 9077 ± 3200, p = 0.0001) were all lower. Conversely, coronary flow velocity (APV, 23.7 ± 9.5 cm/s vs 18.5 ± 6.8 cm/s, p = 0.02) was higher. Additionally, temporal changes in Pa, Pd, Pd/Pa, MR, HR, RPP and APV during IV adenosine hyperemia versus exercise were all significantly different (p < 0.05 for all). CONCLUSIONS: In patients with CCS and coronary stenosis, invasive hemodynamic responses differed markedly between IV adenosine hyperemia versus physical exercise stress. These differences were observed across systemic, coronary and microcirculatory hemodynamics.


Assuntos
Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Hiperemia , Adenosina/farmacologia , Idoso , Cateterismo Cardíaco , Estenose Coronária/diagnóstico por imagem , Vasos Coronários , Exercício Físico , Hemodinâmica , Humanos , Microcirculação , Pessoa de Meia-Idade , Síndrome , Vasodilatadores/farmacologia
13.
Nutrients ; 13(5)2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063322

RESUMO

Preservation of vascular endothelium integrity and functionality represents an unmet medical need. Indeed, endothelial dysfunction leads to decreased nitric oxide biosynthesis, which is prodromic of hypertension and hypercoagulability. In this panorama, the nutraceutical supplement Taurisolo®, a polyphenolic extract from Aglianico cultivar grape, rich in catechin and procyanidins, was evaluated as a vasoprotective, vasorelaxing, anti-hypertensive and anti-coagulant agent in: cell lines, isolated vessels, in vivo models of chronic hypertension and hypercoagulability, and in clinical tests of endothelial reactivity. Taurisolo® demonstrated to fully protect vascular cell viability from oxidative stimulus at 100 µg/mL and evoke vasorelaxing effects (Emax = 80.6% ± 1.9 and pEC50 = 1.19 ± 0.03) by activation of the Sirtuins-AMPK-pathway. Moreover, Taurisolo®, chronically administered at 20 mg/Kg/die in in vivo experiments, inhibited the onset of cardiac hypertrophy (heart weight/rat weight = 3.96 ± 0.09 vs. 4.30 ± 0.03), hypercoagulability (decrease of fibrinogen vs. control: p < 0.01) and hypertension (mean of Psys: 200 ± 2 vs. control 234 ± 2 mmHg) and improved endothelial function (Emax = 88.9% ± 1.5 vs. control 59.6% ± 3.6; flow-mediated dilation in healthy volunteers after 400 mg twice daily for 8 weeks vs. baseline: p = 0.019). In conclusion, Taurisolo® preserves the vascular function against ox-inflamm-ageing process and the consequent cardiovascular accidents.


Assuntos
Suplementos Nutricionais , Endotélio Vascular/efeitos dos fármacos , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Vitis/química , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Anticoagulantes/farmacologia , Anti-Hipertensivos/farmacologia , Catequina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Humanos , Hipertensão/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Proantocianidinas/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/metabolismo , Trombofilia/tratamento farmacológico , Vasodilatadores/farmacologia
14.
Arch Virol ; 166(9): 2387-2397, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34114139

RESUMO

Influenza is an acute viral respiratory disease that can also cause gastroenteritis-like symptoms, such as abdominal pain, nausea, vomiting, and diarrhea. Immune dysfunction of adipose tissue is involved in the occurrence and prognosis of influenza viral pneumonia. In this study, we analyzed intestinal and adipose immune responses in mice infected with influenza virus and found that the impairment of intestinal and adipose immunity to influenza virus infection could be reversed by treatment with puerarin, a medicinal compound isolated from Pueraria lobata (called "gegen" in Chinese). We found that the lungs, small intestines (duodenum, ileum, jejunum) and large intestines (colon and rectum) of infected mice showed obvious inflammatory lesions, with significantly increased levels of virus, inflammatory cytokines (interleukin [IL]-6, IL-17, and tumor necrosis factor-α), Toll-like receptors 3, 4, and 9, and integrin αvß3 and α4, and a decreased level of secreted IgA compared to the normal control group (NC) (P < 0.05-0.001). Influenza virus infected mesenteric lymph nodes and adipose tissue, and adipokines (leptin, visfatin, "chemerin", and adiponectin) of lung and mesenteric adipose tissue were dysregulated. Puerarin treatment reversed the impairment of the intestinal and adipose immune responses in mice infected with influenza virus. Our findings suggest that influenza virus can infect adipose tissue and lead to intestinal adipose immune dysfunction in normal-weight mice and that the impairment of the intestinal and adipose immune response to influenza virus infection can be reversed by puerarin treatment.


Assuntos
Tecido Adiposo/imunologia , Imunidade/efeitos dos fármacos , Intestinos/imunologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/imunologia , Vasodilatadores/farmacologia , Animais , Citocinas/metabolismo , Feminino , Humanos , Imunoglobulina A Secretora , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/imunologia , Intestinos/patologia , Intestinos/virologia , Isoflavonas , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nicotinamida Fosforribosiltransferase , Pneumonia , Pueraria/química , RNA Viral , Carga Viral
15.
Crit Care ; 25(1): 207, 2021 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-34118980

RESUMO

BACKGROUND: Acute kidney injury (AKI) is a common and serious complication after cardiac surgery, and current strategies aimed at treating AKI have proven ineffective. Levosimendan, an inodilatating agent, has been shown to increase renal blood flow and glomerular filtration rate in uncomplicated postoperative patients and in patients with the cardiorenal syndrome. We hypothesized that levosimendan through its specific effects on renal vasculature, a preferential vasodilating effect on preglomerular resistance vessels, could improve renal function in AKI-patients with who did not have clinical indication for inotropic support. METHODS: In this single-center, double-blind, randomized controlled study, adult patients with postoperative AKI within 2 days after cardiac surgery, who were hemodynamically stable with a central venous oxygen saturation (ScvO2) ≥ 60% without inotropic support were eligible for inclusion. After randomization, study drug infusions, levosimendan (n = 16) or placebo (n = 13) were given for 5 h. A bolus infusion of levosimendan (12 µg/kg), were given for 30 min followed by 0.1 µg/kg/min for 5 h. Renal blood flow and glomerular filtration rate were measured using infusion clearance of para-aminohippuric acid and a filtration marker, respectively. As a safety issue, norepinephrine was administered to maintain mean arterial pressure between 70-80 mmHg. Intra-group differences were tested by Mann-Whitney U-tests, and a linear mixed model was used to test time and group interaction. RESULTS: Twenty-nine patients completed the study. At inclusion, the mean serum creatinine was higher in the patients randomized to levosimendan (148 ± 29 vs 127 ± 22 µmol/L, p = 0.030), and the estimated GFR was lower (46 ± 12 vs 57 ± 11 ml/min/1.73 m2, p = 0.025). Levosimendan induced a significantly (p = 0.011) more pronounced increase in renal blood flow (15%) compared placebo (3%) and a more pronounced decrease in renal vascular resistance (- 18% vs. - 4%, respectively, p = 0.043). There was a trend for a minor increase in glomerular filtration rate with levosimendan (4.5%, p = 0.079), which did differ significantly from the placebo group (p = 0.440). The mean norepinephrine dose was increased by 82% in the levosimedan group and decreased by 29% in the placebo group (p = 0.012). CONCLUSIONS: In hemodynamically stable patients with AKI after cardiac surgery, levosimendan increases renal blood flow through renal vasodilatation. Trial registration NCT02531724, prospectly registered on 08/20/2015. https://clinicaltrials.gov/ct2/show/NCT02531724?cond=AKI&cntry=SE&age=1&draw=2&rank=1.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Circulação Renal/efeitos dos fármacos , Simendana/farmacologia , Injúria Renal Aguda/fisiopatologia , Adulto , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/métodos , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Simendana/efeitos adversos , Estatísticas não Paramétricas , Suécia , Vasodilatadores/efeitos adversos , Vasodilatadores/farmacologia
16.
Am J Physiol Heart Circ Physiol ; 321(2): H353-H368, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34142887

RESUMO

Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study, Ephx2 (the gene encodes sEH enzyme) null (Ephx2-/-) mice and wild-type (WT) littermate mice were infused with or without nicotine and administered with or without nicotinamide [NAM, sirtuin-1 (SIRT1) inhibitor] simultaneously for 4 wk. Nicotine treatment increased sEH expression and activity in the aortas of WT mice. Nicotine infusion significantly induced vascular remodeling, arterial stiffness, and SIRT1 deactivation in WT mice, which was attenuated in Ephx2 knockout mice (Ephx2-/- mice) without NAM treatment. However, the arterial protective effects were gone in Ephx2-/- mice with NAM treatment. In vitro, 11,12-EET treatment attenuated nicotine-induced matrix metalloproteinase 2 (MMP2) upregulation via SIRT1-mediated yes-associated protein (YAP) deacetylation. In conclusion, sEH knockout attenuated nicotine-induced arterial stiffness and vascular remodeling via SIRT1-induced YAP deacetylation.NEW & NOTEWORTHY We presently show that sEH knockout repressed nicotine-induced arterial stiffness and extracellular matrix remodeling via SIRT1-induced YAP deacetylation, which highlights that sEH is a potential therapeutic target in smoking-induced arterial stiffness and vascular remodeling.


Assuntos
Aorta/efeitos dos fármacos , Epóxido Hidrolases/genética , Niacinamida/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Sirtuína 1/metabolismo , Rigidez Vascular/efeitos dos fármacos , Complexo Vitamínico B/farmacologia , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Aorta/metabolismo , Aorta/fisiopatologia , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/genética , Camundongos , Camundongos Knockout , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/efeitos dos fármacos , Rigidez Vascular/genética , Vasodilatadores/farmacologia
17.
Am J Physiol Heart Circ Physiol ; 321(2): H339-H352, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34170194

RESUMO

Electronic cigarettes (E-cigs) have been promoted as harm-free or less risky than smoking, even for women during pregnancy. These claims are made largely on E-cig aerosol having fewer number of toxic chemicals compared with cigarette smoke. Given that even low levels of smoking are found to produce adverse birth outcomes, we sought to test the hypothesis that vaping during pregnancy (with or without nicotine) would not be harm-free and would result in vascular dysfunction that would be evident in offspring during adolescent and/or adult life. Pregnant female Sprague Dawley rats were exposed to E-cig aerosol (1 h/day, 5 days/wk, starting on gestational day 2 until pups were weaned) using e-liquid with 0 mg/mL (E-cig0) or 18 mg/mL nicotine (E-cig18) and compared with ambient air-exposed controls. Body mass at birth and at weaning were not different between groups. Assessment of middle cerebral artery (MCA) reactivity revealed a 51%-56% reduction in endothelial-dependent dilation response to acetylcholine (ACh) for both E-cig0 and E-cig18 in 1-mo, 3-mo (adolescent), and 7-mo-old (adult) offspring (P < 0.05 compared with air, all time points). MCA responses to sodium nitroprusside (SNP) and myogenic tone were not different across groups, suggesting that endothelial-independent responses were not altered. The MCA vasoconstrictor response (5-hydroxytryptamine, 5-HT) was also not different across treatment and age groups. These data demonstrate that maternal vaping during pregnancy is not harm-free and confers significant cerebrovascular health risk/dysfunction to offspring that persists into adult life. NEW & NOTEWORTHY These data established that vaping electronic cigarettes during pregnancy, with or without nicotine, is not safe and confers significant risk potential to the cerebrovascular health of offspring in early and adult life. A key finding is that vaping without nicotine does not protect offspring from cerebrovascular dysfunction and results in the same level of cerebrovascular dysfunction (compared with maternal vaping with nicotine), indicating that the physical and/or chemical properties from the base solution (other than nicotine) are responsible for the cerebrovascular dysfunction that we observed. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/maternal-vaping-impairs-vascular-function-in-theoffspring/.


Assuntos
Vapor do Cigarro Eletrônico/farmacologia , Artéria Cerebral Média/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Vaping , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Acetilcolina/farmacologia , Aerossóis , Animais , Sistemas Eletrônicos de Liberação de Nicotina , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Artéria Cerebral Média/fisiopatologia , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Nitroprussiato/farmacologia , Gravidez , Ratos , Serotonina/farmacologia , Vasoconstrição/fisiologia , Vasoconstritores/farmacologia , Vasodilatação/fisiologia , Vasodilatadores/farmacologia
18.
Biomed Res Int ; 2021: 5565748, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34095301

RESUMO

Gentiopicroside (GPS), a main active secoiridoid glucoside derived from the roots of perennial herbs in the Gentianaceae family, has antispasmodic and relaxant effects. However, the vasorelaxant effects of GPS on aortic rings and the molecular mechanisms involved in these effects are not yet clear. Therefore, we investigated whether GPS inhibits phenylephrine- (PE-) or KCl-induced contractions in isolated rat thoracic aortic rings. The present study found that GPS produced a dose-dependent relaxation in aortic rings precontracted with PE or KCl and significantly reduced CaCl2-, narciclasine- (Rho-kinase activator-), and phorbol-12,13-diacetate- (PKC activator-) induced vasocontractions. Pretreatment with NG-Nitroarginine methyl ester hydrochloride (L-NAME, NOS inhibitor), methylene blue (sGC inhibitor), indomethacin (COX inhibitor), 4-aminopyridine (KV channel inhibitor), and glibenclamide (KATP channel inhibitor) had no influence on the vasorelaxant effect of GPS, while BaCl2 (Kir channel inhibitor), tetraethylammonium chloride (KCa channel inhibitor), ruthenium red (RYR inhibitor), and heparin (IP3R inhibitor) significantly reduced GPS-induced vasorelaxation. Moreover, GPS pretreatment remarkably inhibited the influx of Ca2+ in vascular smooth muscle cells stimulated using KCl or PE-containing CaCl2 solution. Western blot analysis confirmed that GPS treatment inhibited PE-induced increases in the protein levels of p-Akt, p-myosin light chain (MLC), and p-myosin-binding subunit of myosin phosphatase 1 (MYPT1) in the aortic rings. Additionally, the vasorelaxation activity of GPS was attenuated upon pretreatment with LY294002 (PI3K/Akt inhibitor), Y27632 (Rho-kinase inhibitor), and verapamil (L-type Ca2+ channel inhibitor). These findings demonstrate that GPS exhibits endothelium-independent vasorelaxant effects through inhibition of voltage-dependent, receptor-operated, and inositol triphosphate receptor (IP3R)/ryanodine receptor- (RYR-) mediated Ca2+ channels as well as the PI3K/Akt/Rho-kinase signaling pathway.


Assuntos
Aorta Torácica/metabolismo , Glucosídeos Iridoides/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , China , Endotélio Vascular/metabolismo , Receptores de Inositol 1,4,5-Trifosfato , Glucosídeos Iridoides/metabolismo , Masculino , Miócitos de Músculo Liso/metabolismo , Fenilefrina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Cloreto de Potássio/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Transdução de Sinais/fisiologia , Vasodilatação/fisiologia , Vasodilatadores/farmacologia , Quinases Associadas a rho/metabolismo
19.
Rev. bras. med. esporte ; 27(2): 134-137, Apr.-June 2021. graf
Artigo em Inglês | LILACS | ID: biblio-1280057

RESUMO

ABSTRACT Introduction: The use of substances to enhance sports performance among professional and amateur athletes is increasing. Such substances may either be included in the group of dietary supplements or fall into pharmacological classes. Every substance used for this purpose is called an ergogenic agent. The number of ergogenic options available increases every day, favoring overuse and use without proper guidance. Among the dietary supplements, we highlight the use of creatine, a substance widespread in sports. Among the pharmacological groups, many drugs are used. Recently the use of sildenafil citrate by professional athletes from various predominantly aerobic sports modalities was reported in the media. Objective: To compare and demonstrate the responses caused by physical training associated with the use of creatine and sildenafil citrate in mice. Methods: A swim training protocol was applied and then an electrophysiograph was used in order to obtain parameters related to contraction intensity, the area under the curve and the percentage drop. Results: The responses obtained demonstrated the ergogenic action of creatine because it altered the parameters used for measurement. The use of sildenafil citrate did not yield satisfactory results to frame the drug as an ergogenic agent. Conclusion: Creatine has an ergogenic effect, reducing the percentage drop after 10 seconds, while sildenafil demonstrated no ergogenic potential and, interestingly, resulted in weaker responses when compared to the exercise groups. Evidence level II; Comparative prospective study .


RESUMEN Introducción: El uso de sustancias con el objetivo de aumentar el rendimiento deportivo entre atletas profesionales y amateurs es creciente. Tales sustancias pueden formar parte del grupo de suplementos alimentarios o integrar clases farmacológicas. Toda sustancia empleada para ese fin es denominada agente ergogénico. El número de opciones entre los agentes ergogénicos aumenta cada día, favoreciendo así su uso excesivo y sin la debida orientación. Entre los suplementos alimentarios, se destaca el uso de creatina, sustancia muy difundida en el medio deportivo. Ya entre los grupos farmacológicos, muchas sustancias son usadas. Recientemente, fue divulgado entre los medios de comunicación el uso de citrato de sildenafil por atletas profesionales, de varias modalidades deportivas, predominantemente las aeróbicas. Objetivos: Comparar y demostrar las respuestas ocasionadas por el entrenamiento físico, asociadas al uso de creatina y citrato de sildenafil en ratones. Métodos: Se aplicó un protocolo de entrenamiento de natación y, a continuación, se usó un electrofisiógrafo con el objetivo de obtener parámetros referentes a la intensidad de contracción, al área bajo la curva y a la caída porcentual. Resultados: Las respuestas obtenidas demuestran acción ergogénica de la creatina, visto que alteraron los parámetros empleados para la medición. Ya el uso de citrato de sildenafil no presentó resultados satisfactorios para encuadrar al fármaco como agente ergogénico. Conclusión: La creatina presenta efecto ergogénico porque reduce la caída porcentual después de 10 segundos, mientras que el sildenafil no presentó potencial ergogénico y, curiosamente, demostró respuestas inferiores cuando comparado a los grupos de ejercicio. Nivel de evidencia II; Estudio prospectivo comparativo .


RESUMO Introdução: O uso de substâncias com o objetivo de aumentar o rendimento esportivo entre atletas profissionais e amadores é crescente. Tais substâncias podem fazer parte do grupo de suplementos alimentares ou integrar classes farmacológicas. Toda substância empregada para esse fim é denominada de agente ergogênico. O número de opções entre os agentes ergogênicos aumenta a cada dia, favorecendo assim o uso em demasia e sem a devida orientação. Entre os suplementos alimentares, salientamos a utilização de creatina, substância muito difundida no meio esportivo. Já entre os grupos farmacológicos, muitas substâncias são utilizadas. Recentemente, foi divulgado entre os meios de comunicação o uso de citrato de sildenafila por atletas profissionais de várias modalidades esportivas, predominantemente as aeróbicas. Objetivos: Comparar e demonstrar as repostas ocasionadas pelo treinamento físico, associadas ao uso de creatina e citrato de sildenafila em camundongos. Métodos: Aplicou-se um protocolo de treinamento de natação e, a seguir, empregou-se um eletrofisiógrafo com objetivo de obter parâmetros referentes à intensidade de contração, à área sob a curva e à queda percentual. Resultados: As respostas obtidas demonstram ação ergogênica da creatina, visto que alteraram os parâmetros empregados para a mensuração. Já a utilização de citrato de sildenafila não apresentou resultados satisfatórios para enquadrar o fármaco como agente ergogênico. Conclusão: A creatina apresenta efeito ergogênico porque reduz a queda percentual após 10 segundos, já a sildenafila não apresentou potencial ergogênico e, curiosamente, demonstrou respostas inferiores quando comparado aos grupos de exercício. Nível de evidência II; Estudo prospectivo comparativo .


Assuntos
Animais , Masculino , Camundongos , Natação , Vasodilatadores/farmacologia , Fadiga Muscular/efeitos dos fármacos , Creatina/farmacologia , Citrato de Sildenafila/farmacologia , Desempenho Físico Funcional , Nervo Isquiático/cirurgia , Tendões/cirurgia , Modelos Animais , Eletrofisiologia/instrumentação
20.
J Interv Cardiol ; 2021: 5522707, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007248

RESUMO

Background: The resting full-cycle ratio (RFR) is a novel resting index which in contrast to the gold standard (fractional flow reserve (FFR)) does not require maximum hyperemia induction. The objectives of this study were to evaluate the agreement between RFR and FFR with the currently recommended thresholds and to design a hybrid RFR-FFR ischemia detection strategy, allowing a reduction of coronary vasodilator use. Materials and Methods: Patients subjected to invasive physiological study in 9 Spanish centers were prospectively recruited between April 2019 and March 2020. Sensitivity and specificity studies were made to assess diagnostic accuracy between the recommended levels of RFR ≤0.89 and FFR ≤0.80 (primary objective) and to determine the RFR "grey zone" in order to define a hybrid strategy with FFR affording 95% global agreement compared with FFR alone (secondary objective). Results: A total of 380 lesions were evaluated in 311 patients. Significant correlation was observed (R 2 = 0.81; P < 0.001) between the two techniques, with 79% agreement between RFR ≤ 0.89 and FFR ≤ 0.80 (positive predictive value, 68%, and negative predictive value, 80%). The hybrid RFR-FFR strategy, administering only adenosine in the "grey zone" (RFR: 0.86 to 0.92), exhibited an agreement of over 95% with FFR, with high predictive values (positive predictive value, 91%, and negative predictive value, 92%), reducing the need for vasodilators by 58%. Conclusions: Dichotomous agreement between RFR and FFR with the recommended thresholds is significant but limited. The adoption of a hybrid RFR-FFR strategy affords very high agreement, with minimization of vasodilator use.


Assuntos
Adenosina/farmacologia , Angiografia Coronária/métodos , Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Hiperemia , Isquemia Miocárdica , Idoso , Circulação Coronária/efeitos dos fármacos , Estenose Coronária/diagnóstico , Estenose Coronária/epidemiologia , Estenose Coronária/fisiopatologia , Correlação de Dados , Relação Dose-Resposta a Droga , Feminino , Humanos , Hiperemia/induzido quimicamente , Hiperemia/fisiopatologia , Masculino , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/fisiopatologia , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Espanha/epidemiologia , Vasodilatadores/farmacologia
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