Role of endogenous endothelin in normal hemodynamic status of anesthetized dogs.
Endothelin (ET) is a potent vasoconstrictor that may be involved in a number of cardiovascular disorders, although its role in normal hemodynamics remains unclear. Twenty-two anesthetized open-chest dogs were instrumented for measurement of systemic and pulmonary hemodynamics, cardiac output, coronary blood flow, and cardiac contractility. Big ET induced peripheral and coronary vasoconstriction, which occurred before significant elevations in plasma ET and which was nearly completely blocked by bosentan, a new nonpeptidic mixed (ETA and ETB) ET receptor antagonist. Bosentan also prevented the peripheral dilatation caused by the specific ETB receptor agonist, sarafotoxin S6c, but did not prevent the peripheral vasoconstriction induced by angiotensin II. Bosentan alone had no significant hemodynamic effect in the normal anesthetized dog, although it did induce a reactive increase in the plasma level of ET-1 and ET-3. This study demonstrates that, despite blocking both ETA and ETB receptors, bosentan alone had no hemodynamic effect, suggesting that ET does not play a major role in the normal hemodynamic status of anesthetized dogs.
Department of Medicine, University of California Medical Center, San Francisco 94143-0124.
J R
JR
Teerlink
J P
JP
Carteaux
U
U
Sprecher
B M
BM
Löffler
M
M
Clozel
J P
JP
Clozel
D000704:Analysis of Variance; D000768:Anesthesia, General; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D002302:Cardiac Output / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D011498:Protein Precursors / Q000494:pharmacology; D011863:Radioimmunoassay; D013449:Sulfonamides / Q000494:pharmacology; D013599:Systole; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D000077300:Bosentan