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 F1 alpha 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 alpha 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.[1]References
- Dose-dependent effect of endothelin-1 on blood flow to normal and collateral-dependent myocardium. Traverse, J.H., Judd, D., Bache, R.J. Circulation (1996) [Pubmed]
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