title: Pathophysiological plasma ET-1 levels antagonize beta-adrenergic dilation of coronary resistance vessels in conscious dogs.
abstract: On the basis of in vitro experiments showing that endothelin (ET)-1 interferes with smooth muscle ATP-sensitive K(+) (K(ATP)) channel opening, which is pivotal in beta-adrenergic coronary dilation, we hypothesized that pathophysiological plasma ET-1 levels impair beta-adrenergic dilation of resistance coronary vessels. In conscious instrumented dogs, graded intravenous doses of dobutamine caused the expected inotropic responses. As myocardial O(2) consumption (MVo(2)) increased, the disproportionate rise in coronary sinus (CS) Po(2) indicates that increases in coronary blood flow (CBF) exceeded metabolic requirements, consistent with beta-adrenergic dilation. ET-1 intravenous infusions, to reach pathophysiological plasma levels, reduced slopes of the Po(2)-MVo(2) and CBF-MVo(2) relations. In contrast, the first derivative of left ventricular pressure over time responses to dobutamine were not impaired during ET-1 delivery. Clazosentan, an ET(A) receptor blocker, prevented reduction of the slope of Po(2)-MVo(2) and CBF-MVo(2) relations. After ganglionic blockade to exclude reflex influences, ET-1 still reduced slopes of Po(2)-MVo(2) and CBF-MVo(2) relations. To assess effects of ET-1 on endothelium-dependent and -independent coronary vascular responses, intracoronary ACh and nitroglycerin were given to directly target coronary vessels. CBF responses to ACh and nitroglycerin were maintained during ET-1 delivery. In contrast, responses to intracoronary K(ATP) channel-dependent dilators adenosine and lemakalim were impaired by ET-1. In conclusion, pathophysiological levels of ET-1 impaired beta-adrenergic dilation of resistance coronary vessels through an ET(A) receptor-dependent process. In contrast, left ventricular inotropic responses to dobutamine were not impaired during ET-1 delivery. Our data suggest that ET-1 may interfere with smooth muscle K(ATP) channels to impair beta-adrenergic coronary dilation.
authors.affiliation: Institut de Cardiologie de Montréal, Centre de Recherche, 5000 Bélanger East, Montréal, Quebec, Canada H1T 1C8.
authors.forename: Masaki
authors.initials: M
authors.lastname: Okajima
authors.forename: Robert
authors.initials: R
authors.lastname: Parent
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
authors.forename: Michel
authors.initials: M
authors.lastname: Lavallée
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D003243:Consciousness; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D019806:Cromakalim / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood* / Q000494:pharmacology; D005730:Ganglionic Blockers / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D044022:Receptor, Endothelin A / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D005730:Ganglionic Blockers; D044022:Receptor, Endothelin A; D011943:Receptors, Adrenergic, beta; D014665:Vasodilator Agents; D019806:Cromakalim; D009569:Nitric Oxide; D004280:Dobutamine; D000241:Adenosine