Endothelin antagonists block alpha(1)-adrenergic constriction of coronary arterioles

We have previously observed that intracoronary administration of the al-adr energic agonist phenylephrine (PE) over a period of minutes induced both an immediate and long-lasting (2h) vasoconstriction of epicardial coronary ar terioles. Because it is unlikely that alpha(1)-adrenergic constriction woul d persist for hours after removal of the agonist, this observation supports the view that another constrictor(s) is released during alpha(1)-adrenergi c activation and induces the prolonged vasoconstriction. Therefore, we hypo thesized that the prolonged microvascular constriction after PE is due to t he production of endothelin (ET). We focused on ET not only because this pe ptide produces potent vasoconstriction but also because its vasoconstrictor action is characterized by a long duration. To test this hypothesis, the d iameters of coronary arterioles (< 222 mu m) in the beating heart of pentob arbital-anesthetized dogs with stroboscopic intravital microscopy were meas ured during a 15-min intracoronary infusion of PE (1 mu g.kg(-1).min(-1)) a nd at 15-min intervals for a total of 120 min. All experiments were perform ed in the presence of beta-adrenergic blockade with propranolol. At 120 min , arterioles in the PE group were constricted (-23 +/- 9% change in diamete r vs. baseline). Pretreatment with the ET-converting enzyme inhibitor phosp horamidon or the ETA-receptor antagonist FR-139317 prevented the PE-induced constriction at 120 min (-1 +/- 3 and -6 +/- 3%, respectively, P < 0.01 vs . PE). Pretreatment with the selective al-adrenergic antagonist prazosin (P rz) also prevented the sustained constriction (0 +/- 2%, P < 0.01 vs. PE) b ut Prz given 60 min after PE infusion did not (-13 +/- 3%). In the aggregat e, these results show that vasoconstriction of epicardial coronary arteriol es via al-adrenergic activation is blocked by an ET antagonist and an inhib itor of its production. From these data, we conclude that al-adrenergic act ivation promotes the production and/or release of ET, which produces or fac ilitates microvascular constriction of epicardial canine coronary arteriole s.