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Dose-dependent effect of endothelin-1 on blood flow to normal and collateral-dependent myocardium
J H Traverse1, D Judd, R J Bache
1Department of Medicine, University of Minnesota Medical School, Minneapolis 55455, USA.
Insights
Endothelin-1 (ET-1) initially boosts myocardial blood flow (MBF) but impairs it at high levels. Coronary prostacyclin release blunts ET-1
Area of Science:
- Cardiovascular Physiology
- Endocrinology
- Pharmacology
Background:
- Plasma endothelin-1 (ET-1) levels rise during ischemia, potentially impairing myocardial blood flow (MBF).
- Collateral vessels may be especially sensitive to ET-1 due to enhanced vasoconstrictor responsiveness.
Purpose of the Study:
- To investigate the effects of ET-1 on MBF in normal and collateral-dependent myocardium.
- To determine the role of prostacyclin in mediating ET-1's vascular effects.
Main Methods:
- Studies in 13 dogs with collateral vessels induced by embolization.
- Measurement of MBF using radioactive microspheres during ET-1 infusions.
- Quantification of ET-1 and 6-keto-prostaglandin F1 alpha levels.
- Assessment of prostacyclin's role after cyclooxygenase blockade with indomethacin.
Main Results:
- Moderate ET-1 (10 ng/min) increased MBF in normal myocardium but not in collateral zones.
- High ET-1 (100 ng/min) decreased MBF in both normal and collateral zones.
- ET-1 dose-dependently increased prostacyclin levels.
- Indomethacin abolished ET-1-induced vasodilation and increased collateral vascular resistance.
Conclusions:
- Moderate ET-1 increases MBF in normal myocardium; collateral flow remains unchanged.
- Significantly elevated ET-1 impairs MBF in both normal and collateral-dependent areas.
- Coronary prostacyclin production is crucial for blunting ET-1's vasoconstrictive effects, particularly in collateral vessels.
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.