Vasodilator actions of acetylcholine, A23187 and bradykinin in the guinea-pig isolated perfused heart are independent of prostacyclin

Abstract

1. The involvement of prostacyclin (PGI2) in the vasodilator responses to acetylcholine (ACh), A23187 and bradykinin (Bk) has been investigated in guinea-pig, isolated, Krebs-perfused hearts. 2. ACh (0.01-10 nmol), A23187 (0.1-1.0 nmol) and Bk (0.3-10 pmol) each elicited dose-related and shortlasting (approximately 2 min) reductions in perfusion pressure. Larger maximal responses were obtained in preparations with coronary vascular tone elevated by platelet-activating factor (100 pmol) than in preparations at basal perfusion pressure. 3. Bk and A23187 elicited dose-related increases in the generation of PGI2 as measured by its chemically-stable breakdown product, 6-oxo-PGF1 alpha. Indomethacin (2.8 microM) prevented both basal and the stimulated generation of 6-oxo-PGF1 alpha, whereas the magnitudes of the vasodilator responses were unaffected. 4. Attempts to identify the release of vasodilator materials by on-line superfusion bioassay of cardiac effluent were unsuccessful, indicating a possible role for a labile vasodilator such as endothelium-dependent relaxing factor (EDRF). In addition, the inhibitors of EDRF action/production, mepacrine (3 microM) or diethylcarbamazine (300 microM), attenuated vasodilator responses to ACh without altering those to the endothelium-independent vasodilator, verapamil (1 nmol). 5. Haemoglobin (10 microM) reduced vasodilator responses to ACh, Bk and verapamil and abolished those induced by A23187. Inhibition of the endothelium-independent vasodilator, verapamil, was significantly less than that for the other compounds. 6. The present data indicate the existence of an indomethacin-resistant vasodilator mechanism in the coronary microcirculation in response to ACh, A23187 and Bk. EDRF is a candidate for mediating these responses; however, a direct vasodilator action of these substances cannot be excluded.