We have previously observed that intracoronary administration of the ₁-adrenergic agonist phenylephrine (PE) over a period of minutes induced both an immediate and long-lasting (2 h) vasoconstriction of epicardial coronary arterioles. Because it is unlikely that ₁-adrenergic constriction would persist for hours after removal of the agonist, this observation supports the view that another constrictor(s) is released during ₁-adrenergic activation and induces the prolonged vasoconstriction. Therefore, we hypothesized that the prolonged microvascular constriction after PE is due to the production of endothelin (ET). We focused on ET not only because this peptide produces potent vasoconstriction but also because its vasoconstrictor action is characterized by a long duration. To test this hypothesis, the diameters of coronary arterioles (<222 µm) in the beating heart of pentobarbital-anesthetized dogs with stroboscopic intravital microscopy were measured during a 15-min intracoronary infusion of PE (1 µg · kg¹ · min¹) and at 15-min intervals for a total of 120 min. All experiments were performed in the presence of -adrenergic blockade with propranolol. At 120 min, arterioles in the PE group were constricted (23 ± 9% change in diameter vs. baseline). Pretreatment with the ET-converting enzyme inhibitor phosphoramidon or the ET_A-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 ₁-adrenergic antagonist prazosin (Prz) also prevented the sustained constriction (0 ± 2%, P < 0.01 vs. PE) but Prz given 60 min after PE infusion did not (13 ± 3%). In the aggregate, these results show that vasoconstriction of epicardial coronary arterioles via ₁-adrenergic activation is blocked by an ET antagonist and an inhibitor of its production. From these data, we conclude that ₁-adrenergic activation promotes the production and/or release of ET, which produces or facilitates microvascular constriction of epicardial canine coronary arterioles.

coronary microcirculation; coronary circulation; phenylephrine

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