bq-123 and Cardiovascular-Diseases

Topics: Amino Acid Sequence; Animals; Azepines; Cardiovascular Diseases; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Indans; Indoles; Molecular Sequence Data; Peptides, Cyclic; Pyrimidines; Receptors, Endothelin; Sulfonamides; Vasoconstriction

Topics: Animals; Aspartic Acid Endopeptidases; Bosentan; Cardiovascular Diseases; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Hemodynamics; Humans; Metalloendopeptidases; Organophosphonates; Peptides, Cyclic; Quinazolines; Receptors, Endothelin; Sulfonamides; Sulfonylurea Compounds; Tetracyclines; Tetrazoles

Topics: Animals; Cardiovascular Diseases; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; GTP-Binding Proteins; Humans; Oligopeptides; Peptides, Cyclic; Piperidines; Receptors, Endothelin; Signal Transduction

Endothelin (ET) -1 is a potent vasoconstrictor and promitogenic peptide produced by the vascular endothelium. The ET system is activated in atherosclerosis and in most cardiovascular conditions associated with increased vascular tone and remodelling. There are two ET-receptor (ET-R) subtypes: the ETA-Rs mediate smooth muscle vasoconstriction and proliferation, and the more complex ETB-Rs have antagonistic actions - they serve a dual role of clearance and vasodilation in the endothelium, while in smooth muscle cells they also provoke vasoconstriction. Selective ETA-R and nonselective ETA/B-R antagonists are entering the clinical development phase. These agents have shown their effectiveness in the therapy of various models of heart failure, pulmonary hypertension, systemic hypertension and ischemia-reperfusion and in the prevention of restenosis. In patients with congestive heart failure, short term ET-antagonist (ET-R) therapy provides hemodynamic and symptomatic improvement. Because of the dual role of the ETB-R, nonselective antagonists may provide greater or fewer benefits than selective ETA-R antagonists: a lack of direct comparison of the two categories of agents, however, does not allow this distinction at present. In the evaluation of this new class of therapeutic agents, particular attention should be paid to potency and receptor selectivity of a compound, the alterations in ETA-R and ETB-R activity brought on by pathological conditions, the proportions of ETA versus ETB-R of the target system, and finally, the net importance of the possible protective role of the endothelial ETB versus the deleterious effects of the smooth muscle ETB-R.

Topics: Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Evaluation; Endothelin Receptor Antagonists; Humans; Oligopeptides; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Treatment Outcome; Vasoconstriction

Topics: Animals; Antihypertensive Agents; Bosentan; Cardiovascular Diseases; Endothelin Receptor Antagonists; Humans; Peptides, Cyclic; Receptors, Endothelin; Sulfonamides

The experimental aim of this study was to determine whether ET-1-mediated vasoconstrictor tone is elevated in adult humans with impaired fasting blood glucose concentrations, independent of other cardiovascular risk factors.. Forearm blood flow (FBF: plethysmography) responses to intra-arterial infusion of selective ETA receptor blockade (BQ-123: 100 nmol/min for 60 min) and non-selective ETA/B blockade (BQ-123 + BQ-788: 50 nmol/min for 60 min) were determined in 28 middle-aged, sedentary adults (17 M/11 F): 14 with normal fasting blood glucose (age: 57 ± 2 yr; 6 F/8 M; BMI: 29.2 ± 0.9 kg/m(2); glucose: 4.9 ± 0.1 mmol/L) and 14 impaired fasting blood glucose (58 ± 1 yr; 5 F/9 M; 29.6 ± 1.1 kg/m(2); 5.8 ± 0.1 mmol/L) concentrations.. Selective ETA receptor blockade elicited a significantly greater (∼20%) increase in FBF in the impaired fasting glucose adults compared with the normoglycemia controls. ETA/B blockade resulted in a further 2-fold increase (P < 0.05) in FBF above that elicited by ETA receptor antagonism in the impaired fasting glucose but not normal fasting glucose adults. There was a positive correlation between fasting blood glucose levels and the peak vascular responses to ETA (r = 0.44; P < 0.05) and ETA/B (r = 0.62; P < 0.05) blockade. No other anthropometric, hemodynamic or metabolic variable was correlated with the blood flow responses to ET-1 receptor blockade.. ET-1-mediated vasoconstrictor tone is elevated in adults with impaired fasting blood glucose concentrations, independent of other cardiometabolic risk factors. Enhanced ET-1 system activity may underlie endothelial vasomotor dysfunction and increased cardiovascular risk in adults with impaired fasting blood glucose concentrations.

Topics: Antihypertensive Agents; Blood Glucose; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Fasting; Female; Glucose Intolerance; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Plethysmography; Risk Factors; Sedentary Behavior; Vasoconstriction

Non-Hispanic black (BL) individuals have the greatest prevalence of cardiovascular disease (CVD), relative to other racial/ethnic groups (e.g., non-Hispanic white population; WH), which may be secondary to blunted vascular function. Although women typically present with reduced CVD relative to men of the same racial/ethnic group, the prevalence is similar between BL women and men though the mechanisms differ. This study hypothesized that reduced microvascular function in young, BL women is associated with endothelin-1 (ET-1) overactivity or insufficient l-arginine bioavailability. Nine BL and nine WH women participated (age: 20 ± 2 vs. 22 ± 2 yr). Cutaneous microvascular function was assessed during 39°C local heating, whereas lactated Ringer's (control), BQ-123 (ET-1 receptor type A antagonist), BQ-788 (ET-1 receptor type B antagonist), or l-arginine were infused via intradermal microdialysis to modify cutaneous vascular conductance (CVC). Subsequent infusion of

Topics: Arginine; Black or African American; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelins; Female; Humans; Microvessels; Nitric Oxide; Peptides, Cyclic; Receptors, Endothelin; Vasodilation; Young Adult

Elevated levels of endothelin-1 (ET-1) were recorded in sera of scorpion sting patients. However, no studies focused on the mechanism of ET-1 involvement in the pathogenesis of scorpion envenomation, particularly in the cardiovascular system which is seriously affected in severe cases of scorpion stings. Inflammation induced by

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Diseases; Cardiovascular System; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Inflammation; Inflammation Mediators; Male; Mice; Peptides, Cyclic; Receptor, Endothelin A; Scorpion Stings; Scorpion Venoms; Signal Transduction

The current study addressed the hypothesis that the local decrease in endothelin-1 (ET-1) bioavailability during sustained flow increases contributes to endothelium-dependent, flow-mediated dilatation (FMD) of conduit arteries and is altered in presence of cardiovascular risk factors.. In nine young healthy individuals, the decrease in local ET-1 plasma levels and radial artery FMD in response to hand skin heating (from 34 to 44 °C) was not affected by endothelin type A (ETA) receptor blockade, achieved using the brachial infusion of BQ-123 (100 nmol/min per l of forearm), as compared with physiological saline (0.9% NaCl) infusion. In contrast, endothelin type B (ETB) receptor blockade with BQ-788 (10 nmol/min per l) suppressed the decrease in plasma ET-1 during heating and reduced FMD, without altering nitric oxide release. The coinfusion of BQ-123 did not affect the inhibitory effect of ETB receptor blockade on the decrease in ET-1 plasma levels during heating but prevented the reduction in FMD. Basal radial artery parameters, systemic hemodynamics, and endothelium-independent dilatation to glyceryl trinitrate were not modified by ETA and/or ETB blockade. In a general population of 40 participants without treatment or major cardiovascular diseases, including the nine healthy individuals, the reduction in endothelin-1 level during heating was correlated with FMD (r = -0.55, P < 0.001) and decreased with increased age (r = 0.49, P = 0.001), mean arterial blood pressure (r = 0.48, P = 0.002), and total cholesterol level (r = 0.37, P = 0.024).. The uptake of endothelin-1 by ETB receptors contributes to conduit artery FMD, preventing its vasoconstrictor action mediated by ETA receptors. The alteration of this mechanism by cardiovascular risk factors may contribute to endothelial dysfunction.

Topics: Adult; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Female; Hemodynamics; Humans; Male; Nitric Oxide; Oligopeptides; Peptides, Cyclic; Piperidines; Risk Factors; Vasodilation; Young Adult

Healthy middle-aged postmenopausal women have higher endothelium-dependent dilation and lower vasoconstrictor activity of endothelin-1 than men. Whether these sex-specific differences extend to patients with cardiovascular risk factors has not been investigated. The current study aimed to determine whether, in patients with cardiovascular risk factors, sex-specific differences exist in endothelium-dependent dilation and endothelin-1 activity.. Forearm blood flow responses were measured by strain-gauge plethysmography during the intra-arterial infusion of acetylcholine, sodium nitroprusside, and the selective endothelin type A receptor blocker BQ-123 in 50 women and 64 men with cardiovascular risk factors.. Acetylcholine and sodium nitroprusside induced a significant vasodilation in women and men alike (p < 0.01 for both). Also BQ-123 caused a significant vasodilation (p < 0.001) in both groups. The vasodilator response to acetylcholine was greater in women compared to men; however there were no differences in the response to sodium nitroprusside and BQ-123 (p = NS for both) between the two sex groups.. Middle-aged women with cardiovascular risk factors have significantly higher endothelium-dependent dilation than middle-aged men; however, vascular endothelin 1 activity is similar in the two groups. These findings suggest that the presence of cardiovascular risk factors is associated with sex-specific effects on endothelium-dependent dilation but not on endothelin 1 activity. Further study is needed to confirm our findings and to characterize the mechanisms underlying this sex-specific regulation of endothelial function.

Topics: Acetylcholine; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Forearm; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Nitroprusside; Peptides, Cyclic; Regional Blood Flow; Risk Factors; Sex Characteristics; Vasodilation; Vasodilator Agents

Endothelin-1 is elevated in women with polycystic ovary syndrome (PCOS), and may play a role in the endothelial dysfunction associated with PCOS. Endothelin-1 binds two receptor subtypes, endothelin A (ET-A) and endothelin B (ET-B). We hypothesized that ET-A mediates vasoconstriction in the cutaneous microvasculature in women with and without PCOS. We further hypothesized that while the ET-B receptors mediate vasodilatation in both groups of women, this response would be blunted in women with PCOS. During local skin warming, we used laser Doppler flowmetry combined with intradermal microdialysis to measure skin blood flow (SkBF) during graded ET-A (BQ-123) and ET-B (BQ-788) antagonist infusions in women with (n = 6) and without (n = 8) PCOS. In both groups, SkBF increased during local heating. The percentage of maximal SkBF-[BQ123] sigmoidal dose-response curve indicated a vasodilatory response as the concentration of the antagonist increased (Hill slope 4.96 ± 4.77, 4.74 ± 5.01; logED(50) 2.53 ± 0.09, 2.49 ± 0.09 nm, for PCOS and Control, respectively). In contrast, the % max SkBF-[BQ788] curve indicated a vasoconstrictive response (Hill slope -4.69 ± 3.85, -4.03 ± 3.85; logED(50), 2.56 ± 0.09, 2.41 ± 0.12 nm, in PCOS and Control). Moreover, the SkBF-[BQ788] curve shifted to the right in women with PCOS, suggesting attenuated ET-B receptor mediated vasodilatation during local skin warming compared to Controls. Thus, the endothelium located ET-B receptors function similarly in women with and without PCOS, although with blunted responsiveness in women with PCOS. Our studies suggest that the lower ET-B receptor responsiveness associated with PCOS may reflect lower endothelial-mediated vasodilatation independent of generally lower vascular reactivity.

Topics: Adult; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelium, Vascular; Female; Humans; Microcirculation; Microvessels; Oligopeptides; Peptides, Cyclic; Piperidines; Polycystic Ovary Syndrome; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; Skin; Vasoconstriction; Vasodilation; Young Adult

The contribution of endothelin-1 (ET-1) to vascular hyper-reactivity associated with chronic ethanol intake, a major risk factor in several cardiovascular diseases, remains to be investigated.. The biphasic haemodynamic responses to ET-1 (0.01-0.1 nmol kg(-1), i.v.) or to the selective ETB agonist, IRL1620 (0.001-1.0 nmol kg(-1), i.v.), with or without ETA or ETB antagonists (BQ123 (c(DTrp-Dasp-Pro-Dval-Leu)) at 1 and 2.5 mg kg(-1) and BQ788 (N-cis-2,6-dimethyl-piperidinocarbonyl-L-gamma-methylleucyl1-D-1methoxycarbonyltryptophanyl-D-norleucine) at 0.25 mg kg(-1), respectively) were tested in anaesthetized rats, after 2 weeks' chronic ethanol treatment. Hepatic parameters and ET receptor protein levels were also determined.. The initial hypotensive responses to ET-1 or IRL1620 were unaffected by chronic ethanol intake, whereas the subsequent pressor effects induced by ET-1, but not by IRL1620, were potentiated. BQ123 at 2.5 but not 1 mg kg(-1) reduced the pressor responses to ET-1 in ethanol-treated rats. Conversely, BQ788 (0.25 mg kg(-1)) potentiated ET-1-induced increases in mean arterial blood pressure in control as well as in ethanol-treated rats. Interestingly, in the latter group, increases in heart rate, induced by ET-1 at a dose of 0.025 mg kg(-1) were enhanced following ETB receptor blockade. Finally, we observed higher levels of ETA receptor in the heart and mesenteric artery and a reduction of ETB receptor protein levels in the aorta and kidney from rats chronically treated with ethanol.. Increased vascular reactivity to ET-1 and altered protein levels of ETA and ETB receptors could play a role in the pathogenesis of cardiovascular complications associated with chronic ethanol consumption.

Topics: Acetylcholine; Alcohol Drinking; Animals; Aorta; Blood Pressure; Cardiovascular Diseases; Endothelin-1; Endothelins; Ethanol; Heart Rate; Kidney; Liver; Male; Mesenteric Arteries; Myocardium; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Phenylephrine; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Self Administration; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents