Dose-dependent effect of endothelin-1 on blood flow to normal and collateral-dependent myocardium

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 F(1α) 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 F(1α) 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.