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1.
Metabolism ; 114: 154390, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33039407

RESUMO

BACKGROUND: Endothelial dysfunction is an early pathogenic event in the progression of cardiovascular disease in patients with Type 2 Diabetes (T2D). Endothelial KCa2.3 and KCa3.1 K+ channels are important regulators of arterial diameter, and we thus hypothesized that SKA-31, a small molecule activator of KCa2.3 and KCa3.1, would positively influence agonist-evoked dilation in myogenically active resistance arteries in T2D. METHODOLOGY: Arterial pressure myography was utilized to investigate endothelium-dependent vasodilation in isolated cremaster skeletal muscle resistance arteries from 22 to 24 week old T2D Goto-Kakizaki rats, age-matched Wistar controls, and small human intra-thoracic resistance arteries from T2D subjects. Agonist stimulated changes in cytosolic free Ca2+ in acutely isolated, single endothelial cells from Wistar and T2D Goto-Kakizaki cremaster and cerebral arteries were examined using Fura-2 fluorescence imaging. MAIN FINDINGS: Endothelium-dependent vasodilation in response to acetylcholine (ACh) or bradykinin (BK) was significantly impaired in isolated cremaster arteries from T2D Goto-Kakizaki rats compared with Wistar controls, and similar results were observed in human intra-thoracic arteries. In contrast, inhibition of myogenic tone by sodium nitroprusside, a direct smooth muscle relaxant, was unaltered in both rat and human T2D arteries. Treatment with a threshold concentration of SKA-31 (0.3 µM) significantly enhanced vasodilatory responses to ACh and BK in arteries from T2D Goto-Kakizaki rats and human subjects, whereas only modest effects were observed in non-diabetic arteries of both species. Mechanistically, SKA-31 enhancement of evoked dilation was independent of vascular NO synthase and COX activities. Remarkably, SKA-31 treatment improved agonist-stimulated Ca2+ elevation in acutely isolated endothelial cells from T2D Goto-Kakizaki cremaster and cerebral arteries, but not from Wistar control vessels. In contrast, SKA-31 treatment did not affect intracellular Ca2+ release by the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor cyclopiazonic acid. CONCLUSIONS: Collectively, our data demonstrate that KCa channel modulation can acutely restore endothelium-dependent vasodilatory responses in T2D resistance arteries from rats and humans, which appears to involve improved endothelial Ca2+ mobilization.


Assuntos
Artérias/metabolismo , Cálcio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Endotélio Vascular/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Acetilcolina/farmacologia , Animais , Artérias/efeitos dos fármacos , Bradicinina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Músculo Esquelético/irrigação sanguínea , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos
2.
Vascul Pharmacol ; 133-134: 106779, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32814163

RESUMO

Atherosclerosis is a very common macrovascular complication in type 2 diabetes mellitus, and cardiovascular disease is the primary cause of death in diabetes patients. Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are a newly identified class of drugs targeting the renal proximal tubules to increase glucose excretion. Large-scale clinical trials have confirmed the cardiovascular protective effects of SGLT inhibitors in patients with diabetes diagnosed with or at a higher risk of atherosclerotic cardiovascular disease. In addition to its direct effect on glycemic control, the function of SGLT-2i in the alleviation of volume load, renal protection, and reduction of inflammation plays an essential role in its therapeutic effect on atherosclerosis. SGLT-2i are known to decrease the levels of inflammatory factors in circulation and in arteries in situ, inhibit foam cell formation and macrophage infiltration, and sustain plaque stability, ultimately blocking the development and progression of atherosclerosis.


Assuntos
Anti-Infecciosos/uso terapêutico , Artérias/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inflamação/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Anti-Infecciosos/efeitos adversos , Artérias/metabolismo , Artérias/patologia , Aterosclerose/diagnóstico , Aterosclerose/metabolismo , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Humanos , Inflamação/diagnóstico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Placa Aterosclerótica , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
3.
Cardiovasc Pathol ; 49: 107259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692664

RESUMO

Perivascular adipose tissue (PVAT) is a fat tissue deposit that encircles the vasculature. PVAT is traditionally known to protect the vasculature from external stimuli that could cause biological stress. In addition to the protective role of PVAT, it secretes certain biologically active substances known as adipokines that induce paracrine effects on proximate blood vessels. These adipokines influence vascular tones. There are different types of PVAT and they are phenotypically and functionally distinct. These are the white and brown PVATs. Under certain conditions, white PVAT could undergo phenotypic switch to attain a brown PVAT-like phenotype. This type of PVAT is referred to as Beige PVAT. The morphology of adipose tissue is influenced by species, age, and sex. These factors play significant roles in adipose tissue mass, functionality, paracrine activity, and predisposition to vascular diseases. The difficulty that is currently experienced in extrapolating animal models to human physiology could be traceable to these factors. Up till now, the involvement of PVAT in the development of vascular pathology is still not well understood. Brown and white PVAT contribute differently to vascular pathology. Thus, the PVAT could be a therapeutic target in curbing certain vascular diseases. In this review, knowledge would be updated on the multifaceted involvement of PVAT in vascular pathology and also explore its vascular therapeutic potential.


Assuntos
Tecido Adiposo Bege/patologia , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Artérias/patologia , Doenças Vasculares/patologia , Adipocinas/metabolismo , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Bege/fisiopatologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiopatologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiopatologia , Adiposidade , Animais , Artérias/efeitos dos fármacos , Artérias/metabolismo , Artérias/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Hemodinâmica , Humanos , Mediadores da Inflamação/metabolismo , Comunicação Parácrina , Transdução de Sinais , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/metabolismo , Doenças Vasculares/fisiopatologia
4.
J Anim Sci ; 98(7)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32629472

RESUMO

Ergot alkaloids are produced by the fungus Claviceps purpurea and their levels are carefully monitored in animal and human diets due to their harmful effects and widespread contamination of cereal crops. Ergot alkaloids exist in two forms known as the (R)- and (S)-epimers with only the former being monitored in diets in North America. The (S)-epimers of ergot alkaloids are thought to be biologically inactive and, therefore, harmless. A major mechanism by which the (R)-epimers of ergot alkaloids produce their toxic effect is through vasoconstriction. Therefore, the objective of this study was to examine the vasoactivity potential (contractile response) of four (S)-epimers, namely ergocryptinine, ergocristinine, ergocorninine, and ergotaminine utilizing an in vitro arterial tissue bath system. Bovine metatarsal arteries (n = 6, ergocryptinine and ergocorninine; n = 6, ergocristinine and ergotaminine; n = 6 arteries/(S)-epimer, total n = 12) were collected from healthy mixed-breed beef steers immediately after slaughter, cut into 3-mm arterial cross sections, and suspended in a tissue bath with continuously oxygenated Krebs-Henseleit buffer. To assess the contractile response of each (S)-epimer, a cumulative contractile dose-response curve was constructed by incubating arteries with increasing concentrations (1 × 10-11 to 1 × 10-6 M) of that (S)-epimer. Contractile responses were recorded as grams of tension and were normalized to an initial contraction of phenylephrine. Contrary to the widespread belief, all tested (S)-epimers were found vasoactive and produced a concentration-dependent arterial contractile response similar to what has been reported for the (R)-epimers. The arterial contractile response to ergotaminine was strongest and was significantly greater than that of ergocryptinine and ergocristinine at the highest concentration used (P ≤ 0.01). Our results indicate that the (S)-epimers are biologically active and are likely harmful similar to the (R)-epimers. The levels of (S)-epimers should be carefully monitored in human and animal diets worldwide.


Assuntos
Artérias/efeitos dos fármacos , Alcaloides de Claviceps/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Bovinos , Alcaloides de Claviceps/química , Técnicas de Cultura de Tecidos
5.
Arterioscler Thromb Vasc Biol ; 40(9): 1982-1989, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32673526

RESUMO

Atherosclerosis is a systemic disease that involves multiple vascular beds. The pathological characteristics and clinical presentation, however, vary among the different vascular territories. Acute coronary syndrome is a relatively common manifestation of coronary atherosclerotic disease, wherein the thrombosis occurs secondary to disruption (65%-75%) and erosion (25%-35%) of the fibrous caps of atheromatous plaques. The plaques associated with plaque rupture have large necrotic cores and thin and inflamed fibrous caps. However, the pathological manifestations of peripheral artery disease result from thrombosis regardless of the extent of atherosclerosis. Approximately 75% of peripheral arteries with significant stenosis demonstrate presence of thrombi, of which two-thirds have thrombi associated with insignificant atherosclerosis. The presence of obliterative thrombi in peripheral arteries of patients with critical limb ischemia in the absence of coronary artery-like lesions suggests a locally thrombogenic or remotely embolic basis of disease. Extensive calcification of the medial vascular layer is commonly observed. In this review, we have described and compared the pathological basis of coronary and peripheral artery disease in patients with acute coronary syndrome and critical limb ischemia. It is expected that pathogenetic characterization would allow for definition of strategic targets for superior management of peripheral artery disease.


Assuntos
Síndrome Coronariana Aguda/patologia , Artérias/patologia , Doença da Artéria Coronariana/patologia , Isquemia/patologia , Doença Arterial Periférica/patologia , Placa Aterosclerótica , Trombose/patologia , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/epidemiologia , Artérias/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/epidemiologia , Vasos Coronários/patologia , Estado Terminal , Progressão da Doença , Fibrinolíticos/uso terapêutico , Fibrose , Humanos , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/epidemiologia , Prognóstico , Ruptura Espontânea , Trombose/tratamento farmacológico , Trombose/epidemiologia
6.
Am J Physiol Heart Circ Physiol ; 319(1): H162-H170, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502373

RESUMO

Vasodilatory effects of insulin support the delivery of insulin and glucose to skeletal muscle. Concurrently, insulin exerts central effects that increase sympathetic nervous system activity (SNA), which is required for the acute maintenance of blood pressure (BP). Indeed, in a cohort of young healthy adults, herein we show that intravenous infusion of insulin increases muscle SNA while BP is maintained. We next tested the hypothesis that sympathoexcitation evoked by hyperinsulinemia restrains insulin-stimulated peripheral vasodilation and contributes to sustaining BP. To address this, a separate cohort of participants were subjected to 5-s pulses of neck suction (NS) to simulate carotid hypertension and elicit a reflex-mediated reduction in SNA. NS was conducted before and 60 min following intravenous infusion of insulin. Insulin infusion caused an increase in leg vascular conductance and cardiac output (CO; P < 0.050), with maintenance of BP (P = 0.540). As expected, following NS, decreases in BP were greater in the presence of hyperinsulinemia compared with control (P = 0.045). However, the effect of NS on leg vascular conductance did not differ between insulin and control conditions (P = 0.898). Instead, the greater decreases in BP following NS in the setting of insulin infusion paralleled with greater decreases in CO (P = 0.009). These findings support the idea that during hyperinsulinemia, SNA-mediated increase in CO, rather than restraint of leg vascular conductance, is the principal contributor to the maintenance of BP. Demonstration in isolated arteries that insulin suppresses α-adrenergic vasoconstriction suggests that the observed lack of restraint of leg vascular conductance may be attributed to sympatholytic actions of insulin.NEW & NOTEWORTHY We examined the role of sympathetic activation in restraining vasodilatory responses to hyperinsulinemia and sustaining blood pressure in healthy adults. Data are reported from two separate experimental protocols in humans and one experimental protocol in isolated arteries from mice. Contrary to our hypothesis, the present findings support the idea that during hyperinsulinemia, a sympathetically mediated increase in cardiac output, rather than restraint of peripheral vasodilation, is the principal contributor to the maintenance of systemic blood pressure.


Assuntos
Pressão Sanguínea , Débito Cardíaco , Hiperinsulinismo/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Vasodilatação , Adrenérgicos/farmacologia , Adulto , Animais , Artérias/efeitos dos fármacos , Artérias/fisiologia , Feminino , Humanos , Insulina/administração & dosagem , Insulina/farmacologia , Perna (Membro)/irrigação sanguínea , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fluxo Sanguíneo Regional
7.
Am J Physiol Heart Circ Physiol ; 319(1): H203-H212, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502374

RESUMO

High-altitude (>2,500 m) residence increases the incidence of intrauterine growth restriction (IUGR) due, in part, to reduced uterine artery blood flow and impaired myometrial artery (MA) vasodilator response. A role for the AMP-activated protein kinase (AMPK) pathway in protecting against hypoxia-associated IUGR is suggested by genomic and transcriptomic studies in humans and functional studies in mice. AMPK is a hypoxia-sensitive metabolic sensor with vasodilatory properties. Here we hypothesized that AMPK-dependent vasodilation was increased in MAs from high versus low-altitude (<1,700 m) Colorado women with appropriate for gestational age (AGA) pregnancies and reduced in IUGR pregnancies regardless of altitude. Vasoreactivity studies showed that, in AGA pregnancies, MAs from high-altitude women were more sensitive to vasodilation by activation of AMPK with A769662 due chiefly to increased endothelial nitric oxide production, whereas MA responses to AMPK activation in the low-altitude women were endothelium independent. MAs from IUGR compared with AGA pregnancies had blunted vasodilator responses to acetylcholine at high altitude. We concluded that 1) blunted vasodilator responses in IUGR pregnancies confirm the importance of MA vasodilation for normal fetal growth and 2) the increased sensitivity to AMPK activation in AGA pregnancies at high altitude suggests that AMPK activation helped maintain MA vasodilation and fetal growth. These results highlight a novel mechanism for vasodilation of MAs under conditions of chronic hypoxia and suggest that AMPK activation could provide a therapy for increasing uteroplacental blood flow and improving fetal growth in IUGR pregnancies.NEW & NOTEWORTHY Intrauterine growth restriction (IUGR) impairs infant well- being and increases susceptibility to later-in-life diseases for mother and child. Our study reveals a novel role for AMPK in vasodilating the myometrial artery (MA) from women residing at high altitude (>2,500 m) with appropriate for gestational age pregnancies but not in IUGR pregnancies at any altitude.


Assuntos
Doença da Altitude/metabolismo , Artérias/metabolismo , Retardo do Crescimento Fetal/metabolismo , Miométrio/irrigação sanguínea , Proteínas Quinases/metabolismo , Vasodilatação , Adulto , Doença da Altitude/fisiopatologia , Artérias/efeitos dos fármacos , Artérias/fisiopatologia , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Óxido Nítrico/metabolismo , Gravidez , Pironas/farmacologia , Tiofenos/farmacologia
8.
J Vasc Res ; 57(4): 185-194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32526735

RESUMO

Information on the function of transient receptor potential vanilloid 1 (TRPV1) in arteriogenesis is limited. We aimed to verify whether TRPV1 is involved in collateral vessel growth in rat hind limbs and elucidate the possible subcellular action mechanisms. Adult Sprague Dawley rats were chosen to establish the hind limb ischemic model and treatment with capsaicin. Angiographies were performed, and tissue was isolated for immunohistochemistry. In vitro, rat aortic endothelial cells (RAECs) were treated with capsaicin and antagonist capsazepine. The RAEC proliferation was determined, and the protein and mRNA levels of Ca2+-dependent transcription factors were assessed. In vivo, the collateral vessels exhibited positive outward remodeling characterized by enhanced inflammatory cell/macrophage accumulation in the adventitia and activated cell proliferation in all layers of the vascular wall and elevated endothelial NO synthetase expression in the rats with hind limb ligation. In RAECs, TRPV1 activation-induced Ca2+-dependent transcriptional factors, nuclear factor of activated T cells 1, calsenilin and myocyte enhancer factor 2C increase, and augmented RAEC proliferation could be a subcellular mechanism for TRPV1 in endothelial cells and ultimately contribute to collateral vessel growth. TRPV1, a novel candidate, positively regulates arteriogenesis, meriting further studies to unravel the potential therapeutic target leading to improved collateral vessel growth for treating ischemic diseases.


Assuntos
Indutores da Angiogênese/farmacologia , Artérias/efeitos dos fármacos , Capsaicina/farmacologia , Circulação Colateral/efeitos dos fármacos , Isquemia/tratamento farmacológico , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica/efeitos dos fármacos , Canais de Cátion TRPV/agonistas , Animais , Artérias/metabolismo , Artérias/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Membro Posterior , Isquemia/metabolismo , Isquemia/fisiopatologia , Proteínas Interatuantes com Canais de Kv/metabolismo , Fatores de Transcrição MEF2/metabolismo , Fatores de Transcrição NFATC/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional , Transdução de Sinais , Canais de Cátion TRPV/metabolismo
9.
Vasc Med ; 25(3): 226-234, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32539632

RESUMO

Chemotherapy, alone or in association with radiation therapy, has represented the cornerstone of cancer treatment for decades. However, in the last several years, an unprecedented progress in the understanding of cancer biology and the discovery of novel therapeutic targets have led to a paradigm shift in the management of patients with neoplastic diseases. The introduction of tyrosine kinase inhibitors, vascular endothelial growth factor pathway inhibitors, immunomodulatory agents, proteasome inhibitors, immune checkpoint inhibitors, and chimeric antigen receptor T cells, among others, has been associated with prolonged survival in many forms of cancer. A common feature of both chemotherapy and novel cancer treatments is the frequent occurrence of vascular toxicity, mainly mediated by injury to the endothelium. While the mechanisms may vary between agents, the clinical manifestations may overlap and range from hypertension, vasospastic and thrombotic arterial events (myocardial ischemia and infarction, peripheral ischemia, and limb gangrene), venous thromboembolism (deep vein thrombosis and pulmonary embolism) to capillary leak syndrome. Therefore, the effective management of patients with cancer requires a multidisciplinary team approach in which oncologist and cardiovascular medicine specialists work together to prevent, detect, and minimize acute vascular toxicity and long-term consequences of cancer therapy.


Assuntos
Antineoplásicos/efeitos adversos , Artérias/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Doenças Vasculares/induzido quimicamente , Animais , Artérias/patologia , Artérias/fisiopatologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Humanos , Medição de Risco , Fatores de Risco , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologia
10.
Arterioscler Thromb Vasc Biol ; 40(7): e193-e202, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32404005

RESUMO

Vascular calcification is a ubiquitous pathology of aging. Oxidative stress, persistent DNA damage, and senescence are major pathways driving both cellular and tissue aging, and emerging evidence suggests that these pathways are activated, and even accelerated, in patients with vascular calcification. The DNA damage response-a complex signaling platform that maintains genomic integrity-is induced by oxidative stress and is intimately involved in regulating cell death and osteogenic differentiation in both bone and the vasculature. Unexpectedly, a posttranslational modification, PAR (poly[ADP-ribose]), which is a byproduct of the DNA damage response, initiates biomineralization by acting to concentrate calcium into spheroidal structures that can nucleate apatitic mineral on the ECM (extracellular matrix). As we start to dissect the molecular mechanisms driving aging-associated vascular calcification, novel treatment strategies to promote healthy aging and delay pathological change are being unmasked. Drugs targeting the DNA damage response and senolytics may provide new avenues to tackle this detrimental and intractable pathology.


Assuntos
Envelhecimento/patologia , Artérias/patologia , Aterosclerose/patologia , Dano ao DNA , Estresse Oxidativo , Placa Aterosclerótica , Calcificação Vascular/patologia , Fatores Etários , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Apatitas/metabolismo , Artérias/efeitos dos fármacos , Artérias/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Senescência Celular , Dano ao DNA/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Mediadores da Inflamação/metabolismo , Osteogênese , Estresse Oxidativo/efeitos dos fármacos , Poli Adenosina Difosfato Ribose/metabolismo , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/genética , Calcificação Vascular/metabolismo
11.
Am J Physiol Heart Circ Physiol ; 319(1): H123-H132, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32469638

RESUMO

Cold exposure causes cutaneous vasoconstriction via a reflex increase in sympathetic activity and a local effect to augment adrenergic constriction. Local cooling also initiates cutaneous dilatation, which may function to restrain cold-induced constriction. However, the underlying mechanisms and physiological role of cold-induced dilatation have not been defined. Experiments were performed to assess the role of endothelial-derived mediators in this response. In isolated pressurized cutaneous mouse tail arteries, cooling (28°C) did not affect the magnitude of dilatation to acetylcholine in preconstricted arteries. However, inhibition of nitric oxide (NO) [NG-nitro-l-arginine methyl ester (l-NAME)] and prostacyclin (PGI2) (indomethacin) reduced acetylcholine-induced dilatation at 37°C but not at 28°C, suggesting that cooling increased NO/PGI2-independent dilatation. This NO/PGI2-independent dilatation was reduced by inhibition of endothelial SK (UCL1684) and IK (TRAM34) Ca2+-activated K+-channels (KCa), consistent with endothelium-derived hyperpolarization (EDH). Cooling also increased dilatation to direct activation of KCa channels (SKA31, CyPPA) but did not affect dilatation to exogenous NO (DEA-NONOate). This cooling-induced increase in EDH-type dilatations was associated with divergent effects on potential downstream EDH mechanisms: cooling reduced dilatation to K+, which mimics an intercellular K+ cloud, but increased direct communication between endothelial and smooth muscle cells (myoendothelial coupling), assessed by cellular transfer of biocytin. Indeed, inhibition of gap junctions (carbenoxolone) abolished the EDH-type component of dilatation to acetylcholine during cooling but did affect NO-dominated dilatation at 37°C. Cooling also inhibited U46619 constriction that was prevented by inhibition of IK and SK KCa channels or inhibition of gap junctions. The results suggest that cooling dilates cutaneous arteries by increasing myoendothelial communication and amplifying EDH-type dilatation.NEW & NOTEWORTHY Cold causes cutaneous vasoconstriction to restrict heat loss. Although cold also initiates cutaneous dilatation, the mechanisms and role of this dilatation have not been clearly defined. This study demonstrates that cooling increases myoendothelial coupling between smooth muscle and endothelial cells in cutaneous arteries, which is associated with increased endothelium-derived hyperpolarization (EDH)-type dilatation. Dysfunction in this process may contribute to excessive cold-induced constriction and tissue injury.


Assuntos
Artérias/fisiologia , Temperatura Baixa , Endotélio Vascular/fisiologia , Músculo Liso Vascular/fisiologia , Pele/irrigação sanguínea , Vasodilatação , Acetilcolina/farmacologia , Alcanos/farmacologia , Animais , Artérias/efeitos dos fármacos , Carbenoxolona/farmacologia , Endotélio Vascular/metabolismo , Epoprostenol/farmacologia , Indometacina/farmacologia , Masculino , Potenciais da Membrana , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Canais de Potássio Cálcio-Ativados/metabolismo , Pirazóis/farmacologia , Compostos de Quinolínio/farmacologia , Vasoconstrição , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
12.
Arterioscler Thromb Vasc Biol ; 40(7): 1627-1634, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32434408

RESUMO

Peripheral artery disease is a common disorder and a major cause of morbidity and mortality worldwide. Therapy is directed at reducing the risk of major adverse cardiovascular events and at ameliorating symptoms. Medical therapy is effective at reducing the incidence of myocardial infarction and stroke to which these patients are prone but is inadequate in relieving limb-related symptoms, such as intermittent claudication, rest pain, and ischemic ulceration. Limb-related morbidity is best addressed with surgical and endovascular interventions that restore perfusion. Current medical therapies have only modest effects on limb blood flow. Accordingly, there is an opportunity to develop medical approaches to restore limb perfusion. Vascular regeneration to enhance limb blood flow includes methods to enhance angiogenesis, arteriogenesis, and vasculogenesis using angiogenic cytokines and cell therapies. We review the molecular mechanisms of these processes; briefly discuss what we have learned from the clinical trials of angiogenic and cell therapies; and conclude with an overview of a potential new approach based upon transdifferentiation to enhance vascular regeneration in peripheral artery disease.


Assuntos
Indutores da Angiogênese/uso terapêutico , Artérias/efeitos dos fármacos , Citocinas/uso terapêutico , Neovascularização Fisiológica/efeitos dos fármacos , Doença Arterial Periférica/terapia , Regeneração/efeitos dos fármacos , Transplante de Células-Tronco , Animais , Artérias/metabolismo , Artérias/patologia , Artérias/fisiopatologia , Humanos , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/patologia , Doença Arterial Periférica/fisiopatologia , Recuperação de Função Fisiológica , Fluxo Sanguíneo Regional , Resultado do Tratamento
13.
Am J Physiol Heart Circ Physiol ; 319(1): H144-H158, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32442021

RESUMO

Pyridine nucleotides, such as NADPH and NADH, are emerging as critical players in the regulation of heart and vascular function. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, is the primary source and regulator of cellular NADPH. In the current study, we have identified two isoforms of G6PD (slow and fast migrating) and functionally characterized the slow migrating isoform of G6PD (G6PD545) in bovine and human arteries. We found that G6PD545 is eluted in the caveolae fraction of vascular smooth muscle (VSM) and has a higher maximum rate of reaction (Vmax: 1.65-fold) than its fast migrating isoform (G6PD515). Interestingly, caveolae G6PD forms a complex with the pore-forming α1C-subunit of the L-type Ca2+ channel, Cav1.2, as demonstrated by a proximity ligation assay in fixed VSMCs. Additionally, Förster resonance energy transfer (FRET) analysis of HEK293-17T cells cotransfected with red fluorescent protein (RFP)-tagged G6PD545 (C-G6PD545) and green fluorescent protein (GFP)-tagged Cav1.2-(Cav1.2-GFP) demonstrated strong FRET signals as compared with cells cotransfected with Cav1.2-GFP and C-G6PD515. Furthermore, L-type Ca2+ channel conductance was larger and the voltage-independent component of availability (c1) was augmented in C-G6PD545 and Cav1.2-GFP cotransfectants compared with those expressing Cav1.2-GFP alone. Surprisingly, epiandrosterone, a G6PD inhibitor, disrupted the G6PD-Cav1.2 complex, also decreasing the amplitude of L-type Ca2+ currents and window currents, thereby reducing the availability of the c1 component. Moreover, overexpression of adeno-G6PD545-GFP augmented the KCl-induced contraction in coronary arteries compared with control. To determine whether overexpression of G6PD had any clinical implication, we investigated its activity in arteries from patients and rats with metabolic syndrome and found that G6PD activity was high in this disease condition. Interestingly, epiandrosterone treatment reduced elevated mean arterial blood pressure and peripheral vascular resistance in metabolic syndrome rats, suggesting that the increased activity of G6PD augmented vascular contraction and blood pressure in the metabolic syndrome. These data suggest that the novel G6PD-Cav1.2 interaction, in the caveolae fraction, reduces intrinsic voltage-dependent inactivation of the channel and contributes to regulate VSM L-type Ca2+ channel function and Ca2+ signaling, thereby playing a significant role in modulating vascular function in physiological/pathophysiological conditions.NEW & NOTEWORTHY In this study we have identified a novel isozyme of glucose-6-phosphate dehydrogenase (G6PD), a metabolic enzyme, that interacts with and contributes to regulate smooth muscle cell l-type Ca2+ ion channel function, which plays a crucial role in vascular function in physiology and pathophysiology. Furthermore, we demonstrate that expression and activity of this novel G6PD isoform are increased in arteries of individuals with metabolic syndrome and in inhibition of G6PD activity in rats of metabolic syndrome reduced blood pressure.


Assuntos
Artérias/metabolismo , Canais de Cálcio Tipo L/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Potenciais de Ação , Androsterona/farmacologia , Animais , Artérias/efeitos dos fármacos , Artérias/fisiologia , Pressão Sanguínea , Bovinos , Cavéolas/metabolismo , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Glucosefosfato Desidrogenase/antagonistas & inibidores , Células HEK293 , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Masculino , Camundongos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Ligação Proteica , Transporte Proteico , Ratos , Ratos Sprague-Dawley , Vasoconstrição
14.
J Vasc Res ; 57(3): 152-163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32248195

RESUMO

Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB1, CB2, TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequency- and dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoylethanolamide in animals receiving i.v. bolus of the antagonists NIDA41020 (CB1), AM630 (CB2), capsazepine (TRPV1), and/or cannabidiol (GPR55). Palmitoyletha-nolamide (0.1-3.1 µg/kg/min) dose-dependently inhibited the sympathetically induced and noradrenaline-induced vasopressor responses. Both inhibitions were: (i) partially blocked by 100 µg/kg NIDA41020, 100 µg/kg capsazepine, or 31 µg/kg cannabidiol; (ii) unaffected by 310 µg/kg AM630; and (iii) abolished by the combination NIDA41020 + capsazepine + cannabidiol (100, 100, and 31 µg/kg, respectively). The resting blood pressure was decreased by palmitoylethanolamide (effect prevented by NIDA41020, capsazepine or cannabidiol, but not by AM630). These results suggest that: (i) palmitoylethanolamide inhibits the vasopressor responses to sympathetic stimulation and exogenous noradrenaline and that it induces hypotension; and (ii) all these effects are mediated by prejunctional and vascular CB1, TRPV1 and probably GPR55, but not by CB2, receptors.


Assuntos
Artérias/efeitos dos fármacos , Etanolaminas/farmacologia , Ácidos Palmíticos/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Amidas , Animais , Artérias/inervação , Artérias/metabolismo , Estado de Descerebração , Estimulação Elétrica , Masculino , Norepinefrina/farmacologia , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Receptores de Canabinoides/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , Sistema Nervoso Simpático/fisiologia , Simpatomiméticos/farmacologia , Canais de Cátion TRPV/metabolismo
15.
PLoS One ; 15(4): e0231244, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298274

RESUMO

BACKGROUND: Quantifying dose-dependent ultra-early edema and ultrastructural changes in the myocyte after drug delivery is important for the development of new mixed calcium channel blockers (CCBs). MATERIALS AND METHODS: Arterial cannulation was used to measure mean arterial pressure in real time; simultaneously, magnetic resonance imaging proton density mapping was used to quantify edema 5-55 min after the delivery of L-type CCBs, T- and L-type CCBs, and solvent to a spontaneously hypertensive rat model. Transmission electron microscopy was used to show ultrastructural changes in the myocyte. RESULTS: Analysis of variance showed significant differences among the three groups in mean arterial pressure reduction (F = 246.36, P = 5.75E-25), ultra-early level of edema (ULE) (F = 175.49, P = 5.62E-22), and dose-dependent level of edema (DLE) (F = 199.48, P = 4.28E-23). Compared with the solvent's mean arterial pressure reduction (2.65±6.56±1.64), ULE (1.16±0.09±0.02), and DLE (0.0010±0.0001±0.0000), post hoc tests showed that T- and L-type CCBs had better mean arterial pressure reduction (90.67±11.58±2.90, P = 1.06E-24 vs. 68.34±15.19±3.80, P = 1.76E-12), lower ULE (1.53±0.14±0.04, P = 4.74E-9 vs. 2.08±0.18±0.04, P = 2.68E-22), and lower DLE (0.0025±0.0004±0.0001, P = 1.14E-11 vs. 0.0047±0.0008±0.0002, P = 2.10E-11) than L- type CCBs. Transmission electron microscopy showed that T- and L-type CCBs caused fewer ultrastructural changes in the myocytes after drug delivery than L-type CCBs. CONCLUSION: T- and L-type CCBs produced less ultra-early and dose-dependent edema, fewer ultrastructural changes in the myocyte, and a greater antihypertensive effect. Proton density mapping combined with arterial cannulation and transmission electron microscopy allowed for quantification of ultra-early and dose-dependent edema, antihypertensive efficacy, and ultrastructural changes in the myocyte. This is important for the evaluation of induced vasodilatory edema.


Assuntos
Anti-Hipertensivos/farmacologia , Artérias/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Edema/diagnóstico , Hipertensão/tratamento farmacológico , Células Musculares/efeitos dos fármacos , Animais , Anti-Hipertensivos/administração & dosagem , Artérias/fisiopatologia , Bloqueadores dos Canais de Cálcio/administração & dosagem , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo T/metabolismo , Edema/induzido quimicamente , Ratos , Ratos Endogâmicos SHR
16.
Sci Rep ; 10(1): 6422, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286470

RESUMO

Physiological regulation of blood flow in bone marrow is important to maintain oxygen and glucose supplies but also the physiological hypoxic state of the hematopoietic stem cell (HSC) niche. However, regulatory mechanisms underlying microcirculation in the bone marrow (BM) niche remain unclear. Here, we identify vessels functioning in control of blood flow in bone marrow and assess their contractility. To evaluate contractile potential of Alexa Fluor 633 (AF633; an arterial marker)-positive vessels, we performed immunohistochemistry for α-smooth muscle actin (α-SMA) and found it expressed around AF633+ vessels in the femoral and calvarial marrow. To validate AF633+ vessel contractility, we developed a simple system to locally administer vasoactive agents that penetrate BM through transcalvarial vessels. After exposure of the calvarial surface to FITC-dextran (70 kDa), FITC intensity in calvarial bone marrow gradually increased. When we evaluated the effect of transcalvarial administration (TCA) of norepinephrine (NE) on vascular tone of AF633+ arteries and behavior of transplanted blood cells, NE administration decreased artery diameter and transendothelial migration of transplanted cells, suggesting that adrenergic signaling regulates the HSC niche microcirculation and blood cell migration into the BM via effects on BMarteries. We conclude that TCA is a useful tool for bone marrow research.


Assuntos
Medula Óssea/irrigação sanguínea , Medula Óssea/diagnóstico por imagem , Microscopia Intravital , Animais , Artérias/diagnóstico por imagem , Artérias/efeitos dos fármacos , Artérias/fisiologia , Vias de Administração de Medicamentos , Antígenos Comuns de Leucócito/metabolismo , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Norepinefrina/farmacologia , Crânio/diagnóstico por imagem , Bibliotecas de Moléculas Pequenas/administração & dosagem , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Vasoconstrição
17.
Am J Physiol Regul Integr Comp Physiol ; 318(4): R822-R827, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32130026

RESUMO

Profound increases (>15 mmHg) in arterial carbon dioxide (i.e., hypercapnia) reduce renal blood flow. However, a relatively brief and mild hypercapnia can occur in patients with sleep apnea or in those receiving supplemental oxygen therapy during an acute exacerbation of chronic obstructive pulmonary disease. We tested the hypothesis that a brief, mild hypercapnic exposure increases vascular resistance in the renal and segmental arteries. Blood velocity in 14 healthy adults (26 ± 4 yr; 7 women, 7 men) was measured in the renal and segmental arteries with Doppler ultrasound while subjects breathed room air (Air) and while they breathed a 3% CO2, 21% O2, 76% N2 gas mixture for 5 min (CO2). The end-tidal partial pressure of CO2 ([Formula: see text]) was measured via capnography. Mean arterial pressure (MAP) was measured beat to beat via the Penaz method. Vascular resistance in the renal and segmental arteries was calculated as MAP divided by blood velocity. [Formula: see text] increased with CO2 (Air: 45 ± 3, CO2: 48 ± 3 mmHg, P < 0.01), but there were no changes in MAP (P = 0.77). CO2 decreased blood velocity in the renal (Air: 35.2 ± 8.1, CO2: 32.2 ± 7.3 cm/s, P < 0.01) and segmental (Air: 24.2 ± 5.1, CO2: 21.8 ± 4.2 cm/s, P < 0.01) arteries and increased vascular resistance in the renal (Air: 2.7 ± 0.9, CO2: 3.0 ± 0.9 mmHg·cm-1·s, P < 0.01) and segmental (Air: 3.9 ± 1.0, CO2: 4.4 ± 1.0 mmHg·cm-1·s, P < 0.01) arteries. These data provide evidence that the kidneys are hemodynamically responsive to a mild and acute hypercapnic stimulus in healthy humans.


Assuntos
Dióxido de Carbono/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipercapnia/fisiopatologia , Rim/irrigação sanguínea , Resistência Vascular/efeitos dos fármacos , Adulto , Artérias/efeitos dos fármacos , Feminino , Humanos , Masculino , Adulto Jovem
18.
Am J Physiol Heart Circ Physiol ; 318(4): H937-H946, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32142360

RESUMO

The arterial baroreflex has dominant control over multiunit muscle sympathetic nerve activity (MSNA) burst occurrence, but whether this extends to all single units or is influenced by resting blood pressure status is unclear. In 22 men (32 ± 8 yr), we assessed 68 MSNA single units during sequential bolus injections of nitroprusside and phenylephrine (modified Oxford). Sympathetic baroreflex sensitivity (sBRS) was quantified as the weighted negative linear regression slope between diastolic blood pressure (DBP) and single-unit spike firing probability and multiple spike firing. Strong negative linear relationships (r ≥ -0.50) between DBP and spike firing probability were observed in 63/68 (93%) single units (-2.27 ± 1.27%·cardiac cycle-1·mmHg-1 [operating range, 18 ± 8 mmHg]). In contrast, only 45/68 (66%) single units had strong DBP-multiple spike firing relationships (-0.13 ± 0.18 spikes·cardiac cycle-1·mmHg-1 [operating range, 14 ± 7 mmHg]). Participants with higher resting DBP (65 ± 3 vs. 77 ± 3 mmHg, P < 0.001) had similar spike firing probability sBRS (low vs. high, -2.08 ± 1.08 vs. -2.46 ± 1.42%·cardiac cycle-1·mmHg-1, P = 0.33), but a smaller sBRS operating range (20 ± 6 vs. 16 ± 9 mmHg, P = 0.01; 86 ± 24 vs. 52 ± 25% of total range, P < 0.001) and a higher proportion of single units without arterial baroreflex control outside this range [6/31 (19%) vs. 21/32 (66%), P < 0.001]. Participants with higher resting DBP also had fewer single units with arterial baroreflex control of multiple spike firing (79 vs. 53%, P = 0.04). The majority of MSNA single units demonstrate strong arterial baroreflex control over spike firing probability during pharmacological manipulation of blood pressure. Changes in single-unit sBRS operating range and control of multiple spike firing may represent altered sympathetic recruitment patterns associated with the early development of hypertension.NEW & NOTEWORTHY Muscle sympathetic single units can be differentially controlled during stress. In contrast, we demonstrate that 93% of single units maintain strong arterial baroreflex control during pharmacological manipulation of blood pressure. Interestingly, the operating range and proportion of single units that lose arterial baroreflex control outside of this range are influenced by resting blood pressure levels. Altered single unit, but not multiunit, arterial baroreflex control may represent changes in sympathetic recruitment patterns in early stage development of hypertension.


Assuntos
Artérias/fisiologia , Barorreflexo , Pressão Sanguínea , Músculo Liso Vascular/fisiologia , Sistema Nervoso Simpático/fisiologia , Adulto , Artérias/efeitos dos fármacos , Humanos , Masculino , Condução Nervosa , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Vasodilatadores/farmacologia
19.
Arterioscler Thromb Vasc Biol ; 40(5): 1168-1181, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32188275

RESUMO

OBJECTIVE: Intraplaque neovascularization is an important feature of unstable human atherosclerotic plaques. However, its impact on plaque formation and stability is poorly studied. Because proliferating endothelial cells generate up to 85% of their ATP from glycolysis, we investigated whether pharmacological inhibition of glycolytic flux by the small-molecule 3PO (3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one) could have beneficial effects on plaque formation and composition. Approach and Results: ApoE-/- (apolipoprotein E deficient) mice treated with 3PO (50 µg/g, ip; 4×/wk, 4 weeks) showed a metabolic switch toward ketone body formation. Treatment of ApoE-/-Fbn1C1039G+/- mice with 3PO (50 µg/g, ip) either after 4 (preventive, twice/wk, 10 weeks) or 16 weeks of Western diet (curative, 4×/wk, 4 weeks) inhibited intraplaque neovascularization by 50% and 38%, respectively. Plaque formation was significantly reduced in all 3PO-treated animals. This effect was independent of intraplaque neovascularization. In vitro experiments showed that 3PO favors an anti-inflammatory M2 macrophage subtype and suppresses an M1 proinflammatory phenotype. Moreover, 3PO induced autophagy, which in turn impaired NF-κB (nuclear factor-kappa B) signaling and inhibited TNF-α (tumor necrosis factor-alpha)-mediated VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) upregulation. Consistently, a preventive 3PO regimen reduced endothelial VCAM-1 expression in vivo. Furthermore, 3PO improved cardiac function in ApoE-/-Fbn1C1039G+/- mice after 10 weeks of treatment. CONCLUSIONS: Partial inhibition of glycolysis restrained intraplaque angiogenesis without affecting plaque composition. However, less plaques were formed, which was accompanied by downregulation of endothelial adhesion molecules-an event that depends on autophagy induction. Inhibition of coronary plaque formation by 3PO resulted in an overall improved cardiac function.


Assuntos
Artérias/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Glicólise/efeitos dos fármacos , Neovascularização Patológica , Placa Aterosclerótica , Piridinas/farmacologia , Animais , Artérias/metabolismo , Artérias/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Autofagia/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Fibrilina-1/genética , Fibrilina-1/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Knockout para ApoE , NF-kappa B/metabolismo , Fenótipo , Molécula 1 de Adesão de Célula Vascular/metabolismo
20.
PLoS One ; 15(3): e0227316, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32126062

RESUMO

Alpha adrenergic stimulation is known to produce vasoconstriction. We have earlier shown that, in spiral strips of small arteries Phenylephrine (PE) caused vasorelaxation under high nitric oxide (NO) environment. However, on further experimentation it was realized that the PE-induced vasorelaxant response occurred only with longitudinal strips of small arteries even under normal NO environment while circular strips showed contraction with PE even under high NO environment. Such PE-induced vasorelaxation of longitudinal strips was blocked by Phentolamine, an alpha-adrenergic receptor blocker. On delineation of specific receptor subtype, PE-induced relaxation was found to be mediated through alpha 1D receptor. However, this phenomenon is specific to small artery, as longitudinal smooth muscle of aorta showed only contractile response to adrenergic stimulation. There is no prior report of longitudinal smooth muscle in small artery up to our knowledge. The results of this study and histological examination of vessel sections suggest the presence of longitudinal smooth muscle in small artery and their relaxant response to alpha adrenergic stimulation is a novel phenomenon.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Artérias/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Fenilefrina/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Artérias/fisiologia , Cabras , Extremidade Inferior/irrigação sanguínea , Músculo Liso Vascular/fisiologia
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