Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs

Author:

Okajima Masaki,Parent Robert,Thorin Eric,Lavallée Michel

Abstract

On the basis of in vitro experiments showing that endothelin (ET)-1 interferes with smooth muscle ATP-sensitive K+ (KATP) channel opening, which is pivotal in β-adrenergic coronary dilation, we hypothesized that pathophysiological plasma ET-1 levels impair β-adrenergic dilation of resistance coronary vessels. In conscious instrumented dogs, graded intravenous doses of dobutamine caused the expected inotropic responses. As myocardial O2 consumption (MV̇o2) increased, the disproportionate rise in coronary sinus (CS) Po2 indicates that increases in coronary blood flow (CBF) exceeded metabolic requirements, consistent with β-adrenergic dilation. ET-1 intravenous infusions, to reach pathophysiological plasma levels, reduced slopes of the Po2-MV̇o2 and CBF-MV̇o2 relations. In contrast, the first derivative of left ventricular pressure over time responses to dobutamine were not impaired during ET-1 delivery. Clazosentan, an ETA receptor blocker, prevented reduction of the slope of Po2-MV̇o2 and CBF-MV̇o2 relations. After ganglionic blockade to exclude reflex influences, ET-1 still reduced slopes of Po2-MV̇o2 and CBF-MV̇o2 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 KATP channel-dependent dilators adenosine and lemakalim were impaired by ET-1. In conclusion, pathophysiological levels of ET-1 impaired β-adrenergic dilation of resistance coronary vessels through an ETA 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 KATP channels to impair β-adrenergic coronary dilation.

Publisher

American Physiological Society

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

Cited by 4 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Adenosine induced coronary vasospasm during Rubidium PET myocardial perfusion scan in a patient with Takayasu’s Arteritis;Journal of Nuclear Cardiology;2016-06-20

2. Endothelium-derived endothelin-1;Pflügers Archiv - European Journal of Physiology;2009-12-05

3. Effects of Endothelin-1 on the Relaxation of Rat Coronary Arteries;Journal of Cardiovascular Pharmacology;2009-11

4. Q‐T interval (QTC) in patients with cirrhosis: relation to vasoactive peptides and heart rate;Scandinavian Journal of Clinical and Laboratory Investigation;2007-01

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