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(Circulation. 1996;93:558-566.)
© 1996 American Heart Association, Inc.

Articles

Dose-Dependent Effect of Endothelin-1 on Blood Flow to Normal and Collateral-Dependent Myocardium

Jay H. Traverse, MD; Dianne Judd, BS; Robert J. Bache, MD

From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis.

Correspondence to Robert J. Bache, MD, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455.

Background Plasma levels of endothelin-1 (ET-1) increase during ischemia and could potentially contribute to impairment of myocardial blood flow (MBF). Because collateral vessels demonstrate enhanced responsiveness to certain vasoconstrictors, blood flow to collateral-dependent myocardium could be particularly sensitive to increases in ET-1 levels.

Methods and Results Studies were performed in 13 dogs in which collateral vessel development was produced by fluoroscopic embolization of the midleft anterior descending coronary artery with a hollow plug 4 to 6 weeks before the study. MBF was measured with radioactive microspheres at baseline and during 30-minute infusions of ET-1 (1, 10, and 100 ng/min) into the left main coronary artery. Because ET-1 stimulates endothelial prostacyclin release, aortic and coronary sinus levels of ET-1 and 6-keto–prostaglandin F₁ were measured at the end of each infusion. ET-1 increased MBF from 0.82 mL·min^-1·g^-1 at baseline to 0.92 mL·min^-1·g^-1 at 10 ng/min (P<.05), which corresponded to a coronary plasma concentration of 73±16 pg/mL. Blood flow in the collateral zone was less (0.74 mL·min^-1·g^-1) than in the normal zone (P<.05) and did not increase at an ET-1 dose of 10 ng/min. MBF in the normal and collateral zones significantly decreased when ET-1 was increased to 100 ng/min, corresponding to a coronary sinus concentration of 175±45 pg/mL (P<.05). ET-1 produced dose-related increases in aortic and coronary sinus 6-keto–prostaglandin F₁ and the transcoronary difference (P<.05). To assess the importance of prostacyclin in opposing the vasoconstriction produced by ET-1, additional studies were performed after cyclooxygenase blockade with indomethacin. After indomethacin administration, ET-1 (10 ng/min) caused a 120±23% increase in collateral vascular resistance (P<.05) and abolished the vasodilation that this dose produced in the normal zone.

Conclusions Blood flow to normal myocardium is increased at moderate plasma elevations of ET-1, whereas collateral blood flow is unchanged. Only at significantly elevated plasma concentrations of ET-1 is blood flow to normal and collateral-dependent myocardium impaired. Coronary endothelial production of prostacyclin in response to increasing concentrations of ET-1 represents an important means of blunting the vasoconstrictor properties of ET-1 in the canine coronary circulation. Coronary collateral vessels demonstrate a much greater dependence on prostacyclin production in blunting the vasoconstrictor properties of ET-1.

Key Words: vasoconstriction • prostaglandins • vasodilation • microspheres • endothelium

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