Submitted on April 1, 2004
Accepted on June 10, 2004
Pathophysiological plasma ET-1 levels antagonize 
-adrenergic dilation of coronary resistance vessels in conscious dogs
Masaki Okajima1, Robert Parent1, Eric Thorin2, and Michel Lavallee3*
1 Research Center, Institut de Cardiologie de Montreal, Montreal, PQ, Canada
2 Research Center, Institut de Cardiologie de Montreal, Montreal, PQ, Canada; Department of Surgery, Universite de Montreal, Montreal, PQ, Canada
3 Research Center, Institut de Cardiologie de Montreal, Montreal, PQ, Canada; Department of Physiology, Universite de Montreal, Montreal, PQ, Canada
* To whom correspondence should be addressed. E-mail: lavallem{at}icm.umontreal.ca.
On the basis of in vitro experiments showing that endothelin-1 (ET-1) interferes with smooth
muscle KATP channels opening, 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 iv doses of dobutamine caused the expected inotropic responses. As myocardial O2 consumption (MVO2) 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 iv infusions, to reach
pathophysiological plasma levels, reduced the slopes of the pO2/MVO2 and the CBF/MVO2
relationships. In contrast, LV dP/dt responses to dobutamine were not impaired during ET-1 delivery. Clazosentan, an ETA receptor blocker, prevented the reduction of slope of the pO2/MVO2 and the CBF/MVO2 relationships. After ganglionic blockade to exclude reflex
influences, ET-1 still reduced the slopes of the pO2/MVO2 and the CBF/MVO2 relationships. To assess the effects of ET-1 on endothelium-dependent and -independent coronary vascular responses, ACh and NTG were given intracoronary (ic) to directly target coronary vessels. CBF responses to ACh and NTG were maintained during ET-1 delivery. In contrast, responses to ic KATP channel-dependent dilators, adenosine and lemakalim, were impaired by ET-1. In conclusion, pathophysiological levels of ET-1 impair -adrenergic dilation of resistance coronary vessels through an ETA receptor-dependent process. In contrast, LV 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 -adrenergic coronary dilation.
