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1.
J Pharmacol Exp Ther ; 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38262743

RESUMO

Ischemia with non-obstructive coronary arteries (INOCA), caused by coronary artery spasm, has gained increasing attention owing to the poor quality of life of impacted patients. Therapeutic options to address INOCA remain limited, and developing new therapeutic agents is desirable. Herein, we examined whether soluble guanylate cyclase (sGC) activators could be beneficial in preventing coronary spasms. In organ chamber experiments with isolated canine coronary arteries, prostaglandin F2α-, endothelin-1-, 5-hydroxytryptamine-, and potassium chloride-induced contractions were suppressed by the sGC activator BAY 60-2770 (0.1, 1, and 10 nM). In isolated pig coronary arteries, BAY 60-2770 (0.1, 1, and 10 nM) could prolong the cycle length of phasic contractions induced by 3,4-diaminopyridine, as well as lower the peak and bottom tension of the contraction in a concentration-dependent manner. Additionally, BAY 60-2770 (1 pM‒0.1 µM) evoked a concentration-related relaxation to a greater extent in small (first diagonal branch) coronary arteries than in large (left anterior descending) coronary arteries. In vasopressin-induced angina model rats, pretreatment with BAY 60-2770 (3 µg/kg) suppressed electrocardiogram S-wave depression induced by arginine vasopressin without affecting changes in mean blood pressure and heart rate. These findings suggest that BAY 60-2770 could be valuable in preventing both large and small coronary spasms. Therefore, sGC activators could represent a novel and efficacious therapeutic option for INOCA. Significance Statement The sGC activator BAY 60-2770 exerted antispastic effects on the coronary arteries in animal vasospasm models as proof-of-concept studies. These data can help to support potential clinical development with sGC activators, suitable for human use in patients with vasospastic angina.

2.
Biol Pharm Bull ; 45(4): 522-527, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370278

RESUMO

The accumulation of uremic toxins is known to be one of the causes of cardiovascular disorder related to renal disease. Among the many uremic toxins, we focused on kynurenine (kyn), whose levels have been shown to be positively correlated with vascular endothelial dysfunction markers, and directly evaluated the influence of kyn on the rat thoracic aorta. Exposure of the endothelium-intact aorta to kyn markedly attenuated the acetylcholine (ACh)-induced relaxation and significantly increased superoxide anion (O2·-) production. These effects were ameliorated by pretreatment with ascorbic acid, an antioxidant, and CH223191, an aryl hydrocarbon receptor (AhR) inhibitor, but not by apocynin, a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor. In the endothelium-denuded aorta, kyn significantly attenuated the nitric oxide (NO) donor sodium nitroprusside (SNP)-induced vasorelaxation and increased the O2·- production. Ascorbic acid treatment significantly ameliorated these effects, whereas CH223191 and apocynin treatments did not. Kyn had no influence on the vasorelaxant response to BAY 41-2272, a soluble guanylate cyclase stimulator. This suggested that kyn attenuates the NO-mediated vasorelaxation response by promoting O2·- production in thoracic aorta to inactivate NO. O2·- production is likely stimulated in both vascular endothelium and smooth muscle, the former of which may be mediated by AhR activation.


Assuntos
Cinurenina , Superóxidos , Animais , Aorta Torácica , Endotélio Vascular , Cinurenina/farmacologia , Ratos , Vasodilatação
3.
Pharmacology ; 107(3-4): 235-240, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34929695

RESUMO

Soluble guanylate cyclase (sGC) plays an important role in nitric oxide (NO)-mediated regulation of vascular tone; however, NO bioavailability is often reduced in diseased blood vessels. Accumulating evidence suggests that a shift of sGC from the NO-sensitive form to the NO-insensitive form could be an underlying cause contributing to this reduction. Herein, we investigated the impact of renovascular hypertension on NO-sensitive and NO-insensitive sGC-mediated relaxation in rat aortas. Renovascular hypertension was induced by partially clipping the left renal artery (2-kidneys, 1-clip; 2K1C) for 10 weeks. Systolic, diastolic, and mean arterial pressures were significantly increased in the 2K1C group when compared with the sham group. In addition, plasma thiobarbituric acid reactive substances and aortic superoxide generation were significantly enhanced in the 2K1C group when compared with those in the sham group. The vasorelaxant response of isolated aortas to the sGC stimulator BAY 41-2272 (NO-sensitive sGC agonist) was comparable between the sham and 2K1C groups. Likewise, the sGC activator BAY 60-2770 (NO-insensitive sGC agonist)-induced relaxation did not differ between the sham and 2K1C groups. In addition, the cGMP mimetic 8-Br-cGMP (protein kinase G agonist) induced similar relaxation in both groups. Furthermore, there were no differences in BAY 41-2272-stimulated and BAY 60-2770-stimulated cGMP generation between the groups. These findings suggest that the balance between NO-sensitive and NO-insensitive forms of sGC is maintained during renovascular hypertension. Therefore, sGC might not be responsible for the reduced NO bioavailability observed during renovascular hypertension.


Assuntos
Guanilato Ciclase , Hipertensão Renovascular , Animais , Aorta , GMP Cíclico , Óxido Nítrico , Ratos , Guanilil Ciclase Solúvel
4.
J Vasc Res ; 56(3): 109-116, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31085923

RESUMO

BACKGROUND/AIMS: Soluble guanylate cyclase (sGC) exists as reduced, oxidized, and heme-free forms. Currently, it is unclear whether endovascular mechanical stenosis has an impact on vascular tone control by drugs targeting sGC, namely cGMP generators. METHODS: Pharmacological responses to acidified sodium nitrite (reduced sGC stimulant) and BAY 60-2770 (oxidized/heme-free sGC stimulant) were studied in balloon-injured rat carotid arteries at several time points. In addition, sGC expression was detected by immunohistochemistry. RESULTS: At 1 day after injury, acidified sodium nitrite-induced relaxation was attenuated in the injured artery, whereas BAY 60-2770-induced relaxation was augmented. Similar attenuation of response to acidified sodium nitrite was seen at 7 and 14 days after injury. On the other hand, the augmentation of response to BAY 60-2770 disappeared at 7 and 14 days after injury. At 1 day after injury, the immunohistochemical expression pattern of sGC in the smooth muscle layer of the injured artery was not different from that of the uninjured artery. However, in the injured artery, the intensity of sGC staining was weak at 7 and 14 days after injury. CONCLUSION: Balloon injury alters vascular responsiveness to cGMP generators, which seems to be associated with the form and/or expression of sGC.


Assuntos
Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Lesões das Artérias Carótidas/tratamento farmacológico , GMP Cíclico/metabolismo , Ativadores de Enzimas/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Nitrito de Sódio/farmacologia , Guanilil Ciclase Solúvel/metabolismo , Vasodilatação/efeitos dos fármacos , Angioplastia com Balão , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/enzimologia , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/enzimologia , Lesões das Artérias Carótidas/patologia , Modelos Animais de Doenças , Ativação Enzimática , Masculino , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Ratos Sprague-Dawley , Sistemas do Segundo Mensageiro , Fatores de Tempo
5.
J Pharmacol Sci ; 140(1): 43-47, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31036520

RESUMO

This study investigated the effects of thiol and heme oxidants on responsiveness to cGMP generators in isolated rat aorta and pulmonary artery using an organ chamber. The nitric oxide (NO) donor sodium nitroprusside (SNP)-induced relaxation was impaired by exposure to the thiol oxidant diamide in both the aorta and the pulmonary artery, whereas the soluble guanylate cyclase (sGC) stimulator BAY 41-2272- or the sGC activator BAY 60-2770-induced relaxation was not affected. The impairment by diamide of SNP-induced aortic and pulmonary arterial relaxation was completely restored by post-treatment with the thiol reductant dithiothreitol. However, regardless of the vessel type, the relaxant response to SNP or BAY 41-2272 was impaired by exposure to the heme oxidant ODQ, whereas the response to BAY 60-2770 was enhanced. The ODQ-induced effects were reversed partially by post-treatment with the heme reductant dithionite. These findings indicate that thiol oxidation attenuates only the vascular responsiveness to NO donors and that heme oxidation attenuates the responsiveness to NO donors and sGC stimulators but augments that to sGC activators. Therefore, under oxidative stress, the order of usability of the vasodilators is suggested to be: NO donors < sGC stimulators < sGC activators.


Assuntos
Aorta/efeitos dos fármacos , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , GMP Cíclico/metabolismo , Diamida/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Doadores de Óxido Nítrico/farmacologia , Nitroprussiato/farmacologia , Oxidantes/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Pirazóis/farmacologia , Piridinas/farmacologia , Compostos de Sulfidrila/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Ditiotreitol/farmacologia , Técnicas In Vitro , Masculino , Estresse Oxidativo , Ratos Wistar , Guanilil Ciclase Solúvel/metabolismo
6.
Biol Pharm Bull ; 42(11): 1947-1952, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31685777

RESUMO

GGsTop is a highly potent and specific, and irreversible γ-glutamyl transpeptidase (GGT) inhibitor without any influence on glutamine amidotransferases. The aim of the present study was to investigate the involvement of GGT in ischemia/reperfusion-induced cardiac dysfunction by assessing the effects of a treatment with GGsTop. Using a Langendorff apparatus, excised rat hearts underwent 40 min of global ischemia without irrigation and then 30 min of reperfusion. GGT activity was markedly increased in cardiac tissues exposed to ischemia, and was inhibited by the treatment with GGsTop. Exacerbation of cardiac functional parameters caused by ischemia and reperfusion, namely the reduction of left ventricular (LV) developed pressure and the maximum and negative minimum values of the first derivative of LV pressure, and the increment in LV end-diastolic pressure was significantly attenuated by GGsTop treatment. The treatment with GGsTop suppressed excessive norepinephrine release in the coronary perfusate, a marker for myocardial dysfunction, after ischemia/reperfusion. In addition, oxidative stress indicators in myocardium, including superoxide and malondialdehyde, after ischemia/reperfusion were significantly low in the presence of GGsTop. These observations demonstrate that enhanced GGT activity contributes to cardiac damage after myocardial ischemia/reperfusion, possibly via increased oxidative stress and subsequent norepinephrine overflow. GGT inhibitors have potential as a therapeutic strategy to prevent myocardial ischemia/reperfusion injury in vivo.


Assuntos
Aminobutiratos/farmacologia , Isquemia Miocárdica/fisiopatologia , Organofosfonatos/farmacologia , gama-Glutamiltransferase/antagonistas & inibidores , gama-Glutamiltransferase/fisiologia , Animais , Coração/fisiopatologia , Masculino , Malondialdeído/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo , gama-Glutamiltransferase/metabolismo
7.
Circ J ; 82(3): 914-918, 2018 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-29238009

RESUMO

BACKGROUND: The gastroepiploic artery (GEA) plays an important role in the era of multiple arterial revascularization, but spasm is a major matter of concern. The internal thoracic artery has been shown to have a strong tendency to spasm in its distal bifurcating part, whereas the segmental difference in vasoreactivity of the GEA has never been performed.Methods and Results:The full length of the GEA obtained from 21 patients undergoing a total gastrectomy was divided into 3 sections: proximal (5 cm from the origin), middle, and distal (5 cm from the end). Concentration-response curves for vasoconstrictors (phenylephrine, prostaglandin F2α, and endothelin-1) and vasodilators (carperitide, nitroglycerin, and nifedipine) were then established using organ baths. All the vasoconstrictors and vasodilators produced concentration-dependent responses in each section. As the concentration of the vasoconstrictors increased, segments at the distal section showed a significantly greater contraction than those at the middle and proximal sections regardless of the type of vasoconstrictor. The effective concentration of drugs that caused 50% of the maximal response for endothelin-1 was significantly greater in the distal section than that in the proximal sections. No significant difference was found in vasodilators-induced relaxation. CONCLUSIONS: The contractility increases toward to the end of the GEA. Clinically, the distal portion of the GEA should be trimmed off and not be used as an anastomotic site wherever possible.


Assuntos
Artéria Gastroepiploica/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Dinoprosta/farmacologia , Relação Dose-Resposta a Droga , Endotelina-1/farmacologia , Humanos , Fenilefrina/farmacologia , Vasoconstrição/fisiologia
8.
Heart Vessels ; 33(6): 682-687, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29230572

RESUMO

Nitroglycerin is commonly used as an antispasmodic for treating spasm of coronary artery bypass grafts. This study investigated whether the presence of renal failure affects reactivity to nitroglycerin in internal thoracic arteries obtained from patients undergoing coronary bypass surgery. The patients were divided into three groups according to estimated glomerular filtration rate (eGFR, mL/min/1.73 m2): without renal failure (60 ≤ eGFR, n = 13), with moderate renal failure (30 ≤ eGFR < 60, n = 10), and with severe renal failure (eGFR < 30, n = 10). Organ chamber technique was used to evaluate concentration-related responses of isolated internal thoracic arteries to vasodilators. Nitroglycerin induced a concentration-dependent relaxation, which was significantly augmented in patients with severe but not moderate renal failure than in those without renal failure. In addition, there was a negative correlation between eGFR and the relaxant efficacy of nitroglycerin (P = 0.016). On the other hand, relaxant responses to BAY 60-2770 (which enhances cGMP generation as with nitroglycerin) were similar among three grades of renal function. An inverse relationship of eGFR to the relaxant efficacy of BAY 60-2770 was not observed, either (P = 0.314). These findings suggest that severe renal failure specifically potentiates nitroglycerin-induced relaxation in internal thoracic artery grafts.


Assuntos
Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Artéria Torácica Interna/fisiopatologia , Nitroglicerina/farmacologia , Insuficiência Renal/complicações , Vasodilatação/efeitos dos fármacos , Idoso , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/fisiopatologia , Feminino , Taxa de Filtração Glomerular , Humanos , Período Intraoperatório , Masculino , Artéria Torácica Interna/efeitos dos fármacos , Insuficiência Renal/fisiopatologia , Vasodilatadores/farmacologia
9.
Pharmacology ; 99(5-6): 275-280, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28249288

RESUMO

BACKGROUND/AIMS: Nitroglycerin is widely used as a coronary vasodilator in the treatment of ischemic heart diseases. This study investigated the influence of hypoxia on nitroglycerin-induced relaxation in endothelium-intact and -denuded rabbit, monkey, and porcine coronary arteries. METHODS: Helically cut strips of coronary arteries were suspended in organ chambers, and isometric tension was recorded. RESULTS: Nitroglycerin concentration dependently relaxed endothelium-intact rabbit coronary arteries, which were not different under normoxic and hypoxic conditions. On the other hand, nitroglycerin-induced relaxation of endothelium-denuded arteries was significantly attenuated by hypoxia. Similarly, the relaxant response of endothelium-intact monkey coronary arteries to nitroglycerin was not affected by hypoxia, whereas that of endothelium-denuded arteries was impaired. As is the case with rabbit and monkey coronary arteries, exposure to hypoxia resulted in impaired relaxation by nitroglycerin in endothelium-denuded but not endothelium-intact porcine coronary arteries. CONCLUSION: These findings suggest that coronary endothelium plays a pivotal role in preventing the hypoxia-induced impairment of nitroglycerin responsiveness, regardless of the animal species.


Assuntos
Vasos Coronários/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Hipóxia/fisiopatologia , Nitroglicerina/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Animais , Relação Dose-Resposta a Droga , Feminino , Técnicas In Vitro , Macaca , Masculino , Coelhos , Suínos
10.
Biochem Biophys Res Commun ; 468(1-2): 208-13, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26519878

RESUMO

Mitochondrial oxidative capacity in skeletal muscle is known to decrease in diabetic patients, and sarcopenia is a risk factor for diabetes, particularly in elderly people. We previously revealed that microRNA (miR)-494 inhibits mitochondrial biogenesis during myogenic differentiation in murine C2C12 cells and others reported that exercise regulates miR-494 levels in obese sedentary individuals with increased risk of type 2 diabetes. In this study, to investigate the therapeutic potential of miR-494, we first investigated the role of miR-494 during human skeletal myogenesis. Using human induced pluripotent stem (hiPS) cells stably transfected with the Tet/ON-myogenic differentiation 1(MYOD1) gene (MyoD-hiPS cells), we found that miR-494 expression transiently increased and was downregulated after myogenic induction. In miR-494 transfected MyoD-hiPS cells, the level of high oxidative fiber (type IIa) marker proteins specifically decreased, while no change in the total number of cells was observed. In contrast, the expression of both type I and type IIx markers was unaffected by miR-494 overexpression. Furthermore, miR-494 overexpression suppressed basal oxygen consumption rate concomitant with the inhibition of myotube formation and without significant effects on the mitochondrial content. These results suggest that miR-494 plays a novel role in the fiber type-specific skeletal myogenesis in MyoD-hiPS cells, distinct from murine C2C12 myogenesis.


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , MicroRNAs/genética , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/crescimento & desenvolvimento , Linhagem Celular , Regulação para Baixo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , MicroRNAs/metabolismo , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/citologia , Músculo Esquelético/metabolismo , Regulação para Cima
11.
J Cardiovasc Pharmacol ; 65(2): 160-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25329747

RESUMO

Superoxide production is increased in diseased blood vessels, which is considered to lead to impairment of the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP pathway. To investigate the respective influence of extracellular and intracellular superoxide on vascular function through the NO/sGC/cGMP pathway, mechanical responses of rat external iliac arteries without endothelium were studied under exposure to a superoxide-generating agent, pyrogallol, or menadione. Exposure to pyrogallol impaired the relaxation induced by acidified NaNO2 (exogenous NO) but not that by nitroglycerin (organic nitrate), BAY 41-2272 (sGC stimulator), BAY 60-2770 (sGC activator), or 8-Br-cGMP (cGMP analog). Superoxide dismutase (SOD) and tempol restored the impaired relaxation by acidified NaNO2. Superoxide production in the bathing solution, but not in artery segments, was significantly increased by exposure to pyrogallol, which was abolished in the presence of SOD or tempol. However, exposure to menadione impaired the relaxant response to acidified NaNO2, nitroglycerin, or BAY 41-2272, whereas it augmented that to BAY 60-2770. Also, this exposure had no effect on the 8-Br-cGMP-induced vasorelxation. Superoxide production in artery segments was dramatically enhanced by exposure to menadione, whereas that in the bathing solution was not affected. This increase in vascular superoxide production was normalized by tempol but not by SOD. These findings suggest that extracellular superoxide reacts with NO only outside the cell, whereas intracellular superoxide not only scavenges NO inside the cell but also shifts the sGC redox equilibrium.


Assuntos
GMP Cíclico/metabolismo , Guanilato Ciclase/metabolismo , Relaxamento Muscular , Músculo Liso Vascular , Óxido Nítrico/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Superóxidos/metabolismo , Animais , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Hidrocarbonetos Fluorados/farmacologia , Artéria Ilíaca , Masculino , Relaxamento Muscular/efeitos dos fármacos , Relaxamento Muscular/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Pirazóis/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Guanilil Ciclase Solúvel , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
12.
J Vasc Res ; 51(6): 439-46, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25634663

RESUMO

BACKGROUND/AIMS: The present study investigated the mechanism by which peroxynitrite impairs vascular function through the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP pathway. METHODS: Mechanical responses of rat external iliac arteries without endothelium were studied under exposure to peroxynitrite. cGMP concentrations were determined by enzyme immunoassay. RESULTS: Relaxation induced by BAY 41-2272 (sGC stimulator) was impaired under exposure to peroxynitrite, whereas that by BAY 60-2770 (sGC activator) was enhanced. These responses were correlated with tissue levels of cGMP. Effects of peroxynitrite on the relaxant responses to BAY compounds were also observed in the presence of superoxide dismutase (SOD) or tempol, both of which scavenge a certain kind of reactive molecules other than peroxynitrite. As is the case with the relaxant response to BAY 41-2272, acidified NaNO2- and nitroglycerin-induced relaxations were markedly attenuated by exposing the arteries to peroxynitrite, which was not abolished by preincubation with SOD or tempol. On the other hand, peroxynitrite exposure had no effect on the 8-Br-cGMP-induced vasorelxation. CONCLUSION: These findings suggest that peroxynitrite interferes with the NO/sGC/cGMP pathway by altering the redox state of sGC. It is likely that peroxynitrite can shift the sGC redox equilibrium to the NO-insensitive state in the vasculature.


Assuntos
GMP Cíclico/metabolismo , Guanilato Ciclase/metabolismo , Artéria Ilíaca/efeitos dos fármacos , Óxido Nítrico/metabolismo , Ácido Peroxinitroso/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática , Ativadores de Enzimas/farmacologia , Artéria Ilíaca/enzimologia , Masculino , Oxirredução , Ratos Sprague-Dawley , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Guanilil Ciclase Solúvel , Vasodilatadores/farmacologia
13.
J Pharmacol Sci ; 125(2): 169-75, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24859780

RESUMO

Hypoxia or hypoxia/reoxygenation impairs nitric oxide (NO)-mediated relaxation through the increase in superoxide generation in monkey coronary arteries. Soluble guanylate cyclase (sGC), the target enzyme of NO, has been shown to change from the NO-sensitive reduced form to the NO-insensitive oxidized/heme-free form under substantial oxidative stress, so the present study investigated whether hypoxia or hypoxia/reoxygenation influences sGC redox equilibrium. In isolated monkey coronary arteries without endothelium, the relaxation caused by the sGC stimulator BAY 41-2272 (Emax: 93.3% ± 2.2%) was somewhat impaired under hypoxia (Emax: 86.3% ± 2.6%) or hypoxia/reoxygenation (Emax: 86.1% ± 3.2%), whereas that by the sGC activator BAY 60-2770 (Emax: 86.0% ± 3.2%) was significantly augmented under hypoxia (Emax: 94.4% ± 1.3%) or hypoxia/reoxygenation (Emax: 95.5% ± 1.1%). In addition, cGMP formation in response to BAY 41-2272 and BAY 60-2770 was inhibited and stimulated, respectively, under hypoxia or hypoxia/reoxygenation. The effects of hypoxia or hypoxia/reoxygenation on BAY 41-2272- and BAY 60-2770-induced vasorelaxation were completely canceled by the treatment with the superoxide dismutase mimetic tempol. These findings suggest that sGC redox equilibrium in the coronary artery is shifted towards the NO-insensitive form under hypoxia or hypoxia/reoxygenation and that superoxide seems to play an important role in this shift.


Assuntos
Vasos Coronários/enzimologia , Vasos Coronários/fisiopatologia , Guanilato Ciclase/metabolismo , Hipóxia/enzimologia , Hipóxia/fisiopatologia , Superóxidos/metabolismo , Vasodilatação , Animais , Benzoatos/antagonistas & inibidores , Benzoatos/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/farmacologia , Vasos Coronários/metabolismo , GMP Cíclico/metabolismo , Feminino , Hidrocarbonetos Fluorados/antagonistas & inibidores , Hidrocarbonetos Fluorados/farmacologia , Hipóxia/metabolismo , Técnicas In Vitro , Macaca , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico/fisiologia , Oxirredução , Estresse Oxidativo , Pirazóis/antagonistas & inibidores , Pirazóis/farmacologia , Piridinas/antagonistas & inibidores , Piridinas/farmacologia , Solubilidade , Superóxido Dismutase/farmacologia , Vasodilatação/efeitos dos fármacos
14.
J Pharmacol Sci ; 124(1): 76-85, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24389820

RESUMO

Deficiency of tetrahydrobiopterin (BH4) in the vascular tissue contributes to endothelial dysfunction through reduced eNOS activity and increased superoxide anion (O2(-)) generation in the insulin-resistant state. We investigated the effects of atorvastatin, a 3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor; amlodipine, a calcium antagonist; and their combination on blood pressure, arterial relaxation and contraction, and vascular oxidative stress in aortas of high fructose-fed rats. Oral administration of atorvastatin for 8 weeks did not significantly lower blood pressure, but normalized angiotensin II-induced vasoconstriction and endothelial function in the fructose-fed rats. Atorvastatin treatment of fructose-fed rats increased vascular BH4 content, which was associated with an increase in endothelial NO synthase activity as well as a reduction in endothelial O2(-) production. On the other hand, administration of amlodipine did not affect the angiotensin II-induced vasoconstriction and endothelial function, but normalized the elevated blood pressure in the fructose-fed rats. The combined treatment did not show synergistic but additive beneficial effects. The present study suggests that combined therapy of HMG-CoA reductase inhibitors and calcium antagonists prevents functional vascular disorders in the insulin-resistant state, possibly resulting in the protection against or delay of development of hypertension, vascular dysfunction in diabetes, and thereafter atherosclerosis.


Assuntos
Anlodipino/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/fisiopatologia , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Resistência à Insulina , Pirróis/farmacologia , Animais , Atorvastatina , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Biopterinas/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Modelos Animais de Doenças , Quimioterapia Combinada , Endotélio Vascular/efeitos dos fármacos , Frutose/administração & dosagem , Frutose/efeitos adversos , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
15.
J Pharmacol Sci ; 126(2): 168-71, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25242170

RESUMO

Metabolic syndrome (MetS) induces serious complications; therefore, we developed a noninvasive MetS model using an extremely small minipig, the Microminipig. For 8 weeks, Microminipigs were administrated a high-fat and high-cholesterol diet (HFCD) for atherosclerosis and N(G)-nitro-l-arginine methyl ester (l-NAME) for inhibiting nitric oxide synthase. HFCD significantly increased serum low-density lipoprotein levels, l-NAME increased blood pressure and cardiac hypertrophy, and HFCD-induced aortal arteriosclerosis was accelerated by l-NAME administration. Endothelium-dependent relaxation of the coronary artery was remarkably decreased by l-NAME administration. This model may be useful for elucidating the mechanisms of MetS and developing new therapeutic medicines for its treatment.


Assuntos
Colesterol na Dieta/administração & dosagem , Dieta Hiperlipídica , Modelos Animais de Doenças , Síndrome Metabólica , Porco Miniatura , Animais , Aterosclerose/etiologia , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/induzido quimicamente , Colesterol na Dieta/efeitos adversos , Vasos Coronários/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Descoberta de Drogas , Endotélio Vascular/fisiologia , Lipoproteínas LDL/sangue , Masculino , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/administração & dosagem , NG-Nitroarginina Metil Éster/efeitos adversos , Óxido Nítrico Sintase/antagonistas & inibidores , Suínos
16.
Pharmacology ; 91(5-6): 322-30, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23797011

RESUMO

Individual vascular beds exhibit differences in vascular reactivity. The present study examined the influence of hypoxia on endothelium-dependent, especially nitric oxide (NO)-mediated, relaxation in the isolated rat common carotid, superior mesenteric and external iliac arteries. Hypoxia for 1 and 3 h had no effects on the relaxations caused by acetylcholine (ACh) and sodium nitroprusside (SNP) in common carotid and external iliac arteries. In addition, NO synthase inhibitor N(G)-nitro-L-arginine (L-NA, 10 µmol/l)-resistant, endothelium-dependent relaxations by ACh were also unaffected by hypoxia in these arteries. On the other hand, ACh-induced relaxation in superior mesenteric arteries was significantly impaired by exposure to hypoxia, while this condition did not affect the relaxation induced by SNP or ACh in the presence of L-NA. This impairment was partially prevented by treatment with tempol (3 mmol/l), a superoxide scavenger. These findings demonstrate a marked heterogeneity in response to hypoxia in rat arteries. Briefly, acute hypoxia induces impairment of endothelium-derived NO-mediated relaxation through the decrease in its bioavailability in the superior mesenteric, but not in common carotid or external iliac, arteries. Furthermore, superoxide seems to be one causal factor responsible for the undesirable effect of hypoxia.


Assuntos
Artérias Carótidas/fisiopatologia , Hipóxia/fisiopatologia , Artéria Ilíaca/fisiopatologia , Artérias Mesentéricas/fisiopatologia , Óxido Nítrico/fisiologia , Animais , Técnicas In Vitro , Masculino , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo , Vasodilatação/fisiologia
17.
Physiol Rep ; 11(12): e15755, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37340325

RESUMO

This study investigated whether beetroot juice (BRJ) ingestion ameliorates aging-induced functional and structural changes in vasculature. Aged mice (98-100 weeks old) were supplemented with BRJ (nitrate: 3.5 mmol/L) or drinking water for 4 weeks and compared with young mice (12-15 weeks old). The vasorelaxant response of isolated aortas to acetylcholine was markedly weaker in aged mice than in young mice, but the attenuated relaxation was significantly improved in BRJ-supplemented aged mice. The acetylcholine-induced relaxation was completely abolished by Nω -nitro-l-arginine methyl ester in all groups. Additionally, the response to sodium nitroprusside was comparable among the three groups. The aortic medial thickness was significantly greater in aged mice than in young mice, and BRJ supplementation did not suppress this thickening. Plasma nitrate levels were significantly higher in BRJ-supplemented aged mice than in non-supplemented aged mice. Conversely, non-supplemented aged mice had high plasma levels of thiobarbituric acid-reactive substances, but the levels were suppressed in BRJ-supplemented aged mice. These findings suggest that BRJ ingestion improves vascular endothelial dysfunction associated with aging, at least in part, by enhancing nitric oxide bioavailability and reducing oxidative stress. Therefore, beetroot ingestion may be a highly useful self-medication option to prevent vascular aging.


Assuntos
Nitratos , Doenças Vasculares , Camundongos , Animais , Acetilcolina , Antioxidantes , Suplementos Nutricionais
18.
J Cardiovasc Pharmacol ; 60(3): 269-75, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22635075

RESUMO

The purpose of this study is to elucidate the relationship between sex difference and norepinephrine (NE) release in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. Isolated male and female rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. Compared with male hearts, I/R-induced cardiac dysfunction, such as decreased left ventricular developed pressure and dP/dtmax and increased left ventricular end diastolic pressure, was significantly attenuated in female hearts. An excessive NE overflow in the coronary effluent from the postischemic heart in females was much less than that in males. These sex differences were abolished by ovariectomy, but in vivo treatment with 17ß-estradiol recovered it. This ameliorating effect of 17ß-estradiol was not observed in the presence of nitric oxide (NO) synthase inhibitor N-nitro-L-arginine. When NOx (NO2/NO3) levels in the coronary effluent after onset of reperfusion were measured, reversed correlated relationships between NOx production and I/R-induced cardiac dysfunction, and NE overflow, were observed. These findings suggest that sex differences in the postischemic cardiac dysfunction are closely related to the NE overflow from the postischemic heart and that estrogen plays a key role in the cardioprotective effect against I/R injury in female rats, by suppressing NE release via the enhancement of NO production.


Assuntos
Estrogênios/fisiologia , Coração/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico/fisiologia , Norepinefrina/metabolismo , Caracteres Sexuais , Animais , Feminino , Coração/fisiologia , Masculino , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/patologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley
19.
J Cardiovasc Pharmacol ; 60(1): 55-60, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22494993

RESUMO

Angiotensin type 1 receptor (AT1R) antagonist and endothelin type A receptor (ET(A)R) antagonist were compared as regards their effects on ischemia-induced exocytotic or carrier-mediated norepinephrine (NE) release from cardiac sympathetic nerve endings. According to the Langendorff technique, isolated rat hearts were subjected to 20-minute or 40-minute global ischemia followed by 30-minute reperfusion. Candesartan (selective AT1R antagonist) and ABT-627 (selective ET(A)R antagonist) were perfused, beginning 15 minutes before ischemia. Candesartan (10 and 100 nM) and ABT-627 (3 µM) suppressed excessive NE overflow (exocytotic release) in the coronary effluent from the heart exposed to 20-minute ischemia. In addition, these agents improved postischemic cardiac dysfunction. On the other hand, the beneficial effects of ABT-627 (1 and 3 µM) on NE overflow (carrier-mediated release) and cardiac dysfunction were also observed in 40-minute ischemia, whereas those were not improved by treatment with candesartan (10 and 100 nM and 1 µM). These findings suggest that both AT1R antagonist and ET(A)R antagonist have ability to inhibit the exocytotic NE release, but the carrier-mediated NE release induced by prolonged ischemia cannot be avoided by AT1R antagonist. Thus, ET(A)R antagonist may be more useful than AT1R antagonist in the clinical settings of ischemic heart disease.


Assuntos
Benzimidazóis/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Pirrolidinas/farmacologia , Tetrazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Atrasentana , Benzimidazóis/administração & dosagem , Compostos de Bifenilo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Antagonistas do Receptor de Endotelina A , Masculino , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Norepinefrina/metabolismo , Pirrolidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Tetrazóis/administração & dosagem , Fatores de Tempo
20.
J Pharmacol Sci ; 119(4): 302-13, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22863667

RESUMO

Endothelin (ET)-1 derived from endothelial cells has a much more important role in cardiovascular system regulation than the ET-2 and ET-3 isoforms. Numerous lines of evidence indicate that ET-1 possesses a number of biological activities leading to cardiovascular diseases (CVD) including hypertension and atherosclerosis. Physiological and pathophysiological responses to ET-1 in various tissues are mediated by interactions with ET(A)- and ET(B)-receptor subtypes. Both subtypes on vascular smooth muscle cells mediate vasoconstriction, whereas the ET(B)-receptor subtype on endothelial cells contributes to vasodilatation and ET-1 clearance. Although selective ET(A)- or nonselective ET(A)/ET(B)-receptor antagonisms have been assumed as potential strategies for the treatment of several CVD based on clinical and animal experiments, it remains unclear which antagonisms are suitable for individuals with CVD because upregulation of the nitric oxide system via the ET(B) receptor is responsible for vasoprotective effects such as vasodilatation and anti-cell proliferation. In this review, we have summarized the current understanding regarding the role of ET receptors, especially the ET(B) receptor, in CVD.


Assuntos
Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Receptores de Endotelina/fisiologia , Animais , Endotelina-1/fisiologia , Humanos
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