bq-123 and Coronary-Disease

Endothelin (ET) exerts a tonic, stiffening effect on the common carotid artery in rats in vitro. This effect is mediated via the ET(A) receptor. The aim of this study was to examine the acute effects of ET(A) receptor antagonism on coronary artery compliance in humans. We examined 22 patients with stable angina after diagnostic coronary arteriography. Intracoronary BQ-123 (6 micromol), an ET(A) receptor antagonist (14 patients), or saline (8 patients), was infused in an artery without significant lesion over 20 min. The artery lumen area in the proximal arterial segment was measured at end diastole and end systole before and after BQ-123 or saline administration using an intravascular ultrasound catheter. Calculations were made of absolute (in mm(2)/mmHg x 10(3)) and normalized compliance index (in mmHg(-1) x 10(3)). Pulse pressure decreased from 64+/-21 to 61+/-17 mmHg after BQ-123 administration and increased from 59+/-16 to 68+/-20 mmHg after saline administration (F=9.54, P=0.006). The respective changes in absolute compliance index were from 24+/-18 to 39+/-25 and from 19+/-15 to 14+/-17 (F=6.43, P=0.02). Normalized compliance index changed from 2.5+/-2.0 to 3.6+/-2.4 and from 2.7+/-2.6 to 1.6+/-1.8 (F=11.92, P=0.002) respectively, in the two groups. Acute ET(A) receptor antagonism improves coronary artery compliance in coronary artery disease patients.

Topics: Aged; Analysis of Variance; Coronary Disease; Endothelin Receptor Antagonists; Female; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Peptides, Cyclic; Pulse; Receptor, Endothelin A; Vascular Resistance; Vasodilator Agents

Coronary vascular dysfunction has been observed in several models of heart failure (HF). Recent evidence indicates that exercise training is beneficial for patients with HF, but the precise intensity and underlying mechanisms are unknown. Left ventricular (LV) hypertrophy can play a significant role in the development of HF; therefore, the purpose of this study was to assess the effects of low-intensity interval exercise training on coronary vascular function in sedentary (HF) and exercise trained (HF-TR) aortic-banded miniature swine displaying LV hypertrophy. Six months postsurgery, in vivo coronary vascular responses to endothelin-1 (ET-1) and adenosine were measured in the left anterior descending coronary artery. Baseline and maximal coronary vascular conductance were similar between all groups. ET-1-induced reductions in coronary vascular conductance (P < 0.05) were greater in HF vs. sedentary control and HF-TR groups. Pretreatment with the ET type A (ET(A)) receptor blocker BQ-123 prevented ET-1 hypersensitivity in HF animals. Whole cell voltage clamp was used to characterize composite K(+) currents (I(K(+))) in coronary smooth muscle cells. Raising internal Ca(2+) from 200 to 500 nM increased Ca(2+)-sensitive K(+) current in HF-TR and control, but not HF animals. In conclusion, an ET(A)-receptor-mediated hypersensitivity to ET-1, elevated resting LV wall tension, and decreased coronary smooth muscle cell Ca(2+)-sensitive I(K(+)) was found in sedentary animals with LV hypertrophy. Low-intensity interval exercise training preserved normal coronary vascular function and smooth muscle cell Ca(2+)-sensitive I(K(+)), illustrating a potential mechanism underlying coronary vascular dysfunction in a large-animal model of LV hypertrophy. Our results demonstrate the potential clinical impact of exercise on coronary vascular function in HF patients displaying pathological LV hypertrophy.

Topics: Animals; Blood Pressure; Capillaries; Cardiotonic Agents; Coronary Circulation; Coronary Disease; Coronary Vessels; Dobutamine; Endothelin A Receptor Antagonists; Endothelin-1; Heart Rate; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Myocardial Contraction; Peptides, Cyclic; Physical Conditioning, Animal; Potassium Channels, Calcium-Activated; Receptor, Endothelin A; Swine; Swine, Miniature

Endothelin (ET)-1 is a vasoconstrictor and proinflammatory peptide that may inhibit glucose uptake. The objective of the study was to investigate if ET (selective ET(A) and dual ET(A)+ET(B)) receptor blockade improves insulin sensitivity in patients with insulin resistance and coronary artery disease.. Seven patients (aged 58 +/- 2 years) with insulin resistance and coronary artery disease completed three hyperinsulinemic-euglycemic clamp protocols: a control clamp (saline infusion), during ET(A) receptor blockade (BQ123), and during combined ET(A) (BQ123) and ET(B) receptor blockade (BQ788). Splanchnic blood flow (SBF) and renal blood flow (RBF) were determined by infusions of cardiogreen and p-aminohippurate.. Total-body glucose uptake (M) differed between the clamp protocols with the highest value in the BQ123+BQ788 clamp (P < 0.05). The M value corrected by insulin was higher in the BQ123+BQ788 than in the control clamp (P < 0.01) or the BQ123 clamp (P < 0.05). There was no difference between the control clamp and the BQ123 clamp. Mean arterial pressure did not change during the control clamp, whereas it decreased during both the BQ123 (P < 0.01) and BQ123+BQ788 (P < 0.05) clamps. RBF increased and renal vascular resistance decreased in the BQ123+BQ788 clamp (P < 0.05) but not in the BQ123 clamp. There was no change in SBF in either clamp.. Dual ET(A)+ET(B) receptor blockade acutely enhances insulin sensitivity in patients with insulin resistance and coronary artery disease, indicating an important role for endogenous ET-1.

Topics: Antihypertensive Agents; Blood Glucose; Blood Pressure; Coronary Disease; Diabetes Mellitus, Type 2; Endothelin Receptor Antagonists; Glucose Clamp Technique; Glucose Intolerance; Heart Rate; Humans; Insulin; Insulin Resistance; Middle Aged; Obesity; Oligopeptides; Peptides, Cyclic; Piperidines

Previous studies in animal models of angioplasty have suggested a role in neointimal hyperplasia for endothelins (ETs), potent vasoconstricting peptides that also exert growth-promoting effects. The present studies were undertaken to test the hypothesis that endothelin receptor blockade can reduce neointimal thickening in injured porcine coronary arteries.. An ET(A)/ET(B) antagonist, L-749,329, was evaluated as an inhibitor of intimal thickening in a porcine balloon/stent model of coronary artery injury. L-749,329 competitively inhibited [(125)I]ET-1 binding to porcine ET(A) (IC(50) approximately 0.3 nmol/L) or ET(B) (IC(50) approximately 20 nmol/L) receptors and inhibited ET-1-stimulated signaling in cell culture. In anesthetized pigs, big ET-1-stimulated increases in systemic blood pressure were totally inhibited after intravenous infusion of L-749,329 (>/=0.2 mg. kg(-1). h(-1)). In vascular injury studies, pigs were treated with vehicle or L-749,329 (1 mg. kg(-1). h(-1)) beginning 2 days before and continuing 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of an angioplasty balloon wrapped with a coiled metallic stent. After 28 days, mean neointimal thickness in the L-749,329-treated group was reduced by 9.0% compared with vehicle-treated controls, but this effect was not statistically significant (P=0.13).. Blockade of endothelin receptors for 28 days with only a mixed ET(A)/ET(B) receptor antagonist is insufficient to substantially inhibit intimal hyperplasia after balloon/stent coronary artery injury in the pig, in contrast to results with a selective ET(A) antagonist. The effects of selective or mixed ET(A)/ET(B) antagonists in diseased vessels remain to be determined in this model.

Topics: Acetamides; Animals; Binding, Competitive; Blood Pressure; Cell Line; Cells, Cultured; Coronary Disease; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Female; Iodine Radioisotopes; Male; Muscle, Smooth, Vascular; Peptides, Cyclic; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Signal Transduction; Swine; Tunica Intima

Topics: Acetylcholine; Bosentan; Coronary Artery Bypass; Coronary Disease; Endothelin Receptor Antagonists; Endothelium, Vascular; Female; Humans; In Vitro Techniques; Male; Mammary Arteries; Nitric Oxide; Oligopeptides; Peptides, Cyclic; Piperidines; Receptors, Endothelin; Sulfonamides; Vasodilation; Vasodilator Agents

The aim of this work was to investigate the influence of endothelin on myocardial ischemia and reperfusion in anaesthetized dogs. Animals were submitted to left thoracotomy and 120 min of left anterior descending coronary occlusion, followed by 180 min of reperfusion. Arterial blood pressure and electrocardiogram (ECG) were recorded in order to analyze heart rate (HR)-pressure product and production of ectopic beats. Infarcted areas were identified by a macroscopic staining method and infarct size was expressed as percentage of risk zone. To inhibit the effects of endothelin in a group of animals, we administered intravenously an endothelin synthesis inhibitor (phosphoramidon) and in another group, an endothelin-1 A receptor blocker (BQ-123). Phosphoramidon decreased the HR-pressure product during reperfusion period, and both, phosphoramidon and BQ-123 decreased infarct size by 40% and the number of ventricular ectopic beats by 88% and 68%, respectively, as compared to the saline treated dogs. In conclusion, endothelin seems to play a deleterious role on the myocardium submitted to ischemia and reperfusion.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Coronary Disease; Dogs; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Glycopeptides; Injections, Intravenous; Myocardial Infarction; Myocardial Reperfusion; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Endothelin; Ventricular Fibrillation; Ventricular Premature Complexes