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This Article Full Text Full Text (PDF) All Versions of this Article: 287/4/H1476    most recent 00297.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Okajima, M. Articles by Lavallée, M. Search for Related Content PubMed PubMed Citation Articles by Okajima, M. Articles by Lavallée, M.

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

¹Institut de Cardiologie de Montréal and Departments of ²Physiology and ³Surgery, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada H1T 1C8

Submitted 1 April 2004 ; accepted in final form 10 June 2004

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 -adrenergic coronary dilation, we hypothesized that pathophysiological plasma ET-1 levels impair -adrenergic dilation of resistance coronary vessels. In conscious instrumented dogs, graded intravenous doses of dobutamine caused the expected inotropic responses. As myocardial O₂ consumption (MO₂) increased, the disproportionate rise in coronary sinus (CS) PO₂ indicates that increases in coronary blood flow (CBF) exceeded metabolic requirements, consistent with -adrenergic dilation. ET-1 intravenous infusions, to reach pathophysiological plasma levels, reduced slopes of the PO₂-MO₂ and CBF-MO₂ 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 PO₂-MO₂ and CBF-MO₂ relations. After ganglionic blockade to exclude reflex influences, ET-1 still reduced slopes of PO₂-MO₂ and CBF-MO₂ 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 -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 -adrenergic coronary dilation.

endothelin-1; coronary blood flow; dobutamine; ATP-dependent potassium channels; myocardial oxygen consumption