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Potent vasoconstriction mediated by endothelin ETB receptors in canine coronary arteries
J R Teerlink1, V Breu, U Sprecher
1Pharma Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Insights
Endothelin ETB receptors in dog coronary arteries mediate both vasodilation and vasoconstriction. This finding is crucial for understanding ET
Area of Science:
- Cardiovascular Pharmacology
- Endothelin Receptor Research
Background:
- Endothelin (ET)-1 is a potent coronary vasoconstrictor implicated in coronary artery disease.
- The specific ET receptor subtypes mediating vasoconstriction in coronary arteries remain incompletely understood.
Purpose of the Study:
- To characterize ET receptor subtypes in canine coronary arteries.
- To investigate the in vivo functional roles of ETB receptors in the coronary vasculature.
Main Methods:
- Competition binding assays using radiolabeled ET-1, ET-1, ET-3, ETA antagonist BQ-123, and ETB agonist sarafotoxin S6c.
- In vivo administration of sarafotoxin S6c in a canine coronary artery perfusion model.
Main Results:
- Canine coronary arteries exhibit ETA, high-affinity ETB, and low-affinity ETB binding sites.
- ETB receptor stimulation with sarafotoxin S6c induced dose-dependent coronary vasodilation and vasoconstriction.
- Sarafotoxin S6c-induced effects were not blocked by the ETA antagonist BQ-123.
Conclusions:
- Canine coronary arteries possess functional ETB receptors capable of mediating both vasodilation and vasoconstriction.
- These findings highlight the complex role of ETB receptors in coronary hemodynamics.
- Understanding ETB receptor function is vital for developing targeted ET antagonists for cardiovascular diseases.
Abstract:
Endothelin (ET) 1 is a powerful vasoconstrictor of coronary arteries and may play a role in coronary spasm, atherosclerosis, and myocardial infarction. Previous studies have demonstrated that intracoronary ET caused marked vasoconstriction of the coronary circulation; however, it remains unclear which ET receptor types are present and which of these receptors mediate this vasoconstriction. To characterize the ET receptors present in dog coronary arteries, competition binding assays with radiolabeled ET-1 using ET-1, ET-3, ETA receptor antagonist BQ-123, and sarafotoxin S6c were performed. Three binding sites were apparent in the left circumflex coronary artery: an ETA receptor, a high-affinity ETB receptor, and a lower-affinity ETB receptor. To investigate the in vivo effects of ETB receptor stimulation, intracoronary sarafotoxin S6c, a highly selective ETB agonist, was administered in anesthetized open-chest dogs in a constant-pressure coronary artery perfusion model. Sarafotoxin S6c doses of 0.1 and 0.3 microgram caused a transient pronounced decrease in coronary resistance. Doses of 1.0 and 3.0 micrograms caused marked decreases in coronary diameter and blood flow, as well as myocardial segmental shortening. These effects of sarafotoxin S6c were not inhibited by constant infusion of BQ-123. The present study demonstrates the presence of ETB receptors in the canine coronary circulation that can mediate both vasodilation and vasoconstriction. These findings have important implications for an understanding of the pathophysiological function of ET in the coronary vasculature and for the development of therapeutically effective ET antagonists.