Effects of bradykinin in the rat isolated perfused heart: role of kinin receptors and endothelium‐derived relaxing factor

Abstract

1 The effects of bradykinin (BK) in the microcirculation of the isolated perfused heart of the rat were examined. The kinin receptors mediating the effects of BK were characterized and the role of endothelium-derived relaxation factor (EDRF) and prostacyclin investigated. 2 The dose-related vasodilator responses elicited by bolus doses of BK (0.001–10.0 nmol) were competitively blocked by the selective kinin B₂ receptor antagonist [d-Arg⁰,Hyp³,Thi^5,8,d-Phe⁷]-bradykinin (pA₂ = 6.8). Des-Arg⁹-bradykinin, a selective kinin B₁ receptor agonist had no vasodilator activity at doses of up to 10 nmol. 3 l-N^G-nitro arginine (100 μm; l-NOArg), an inhibitor of endothelium-dependent vasodilatation, reduced the duration but not the magnitude of the BK vasodilator response. This action of l-NOArg was not reversed by l-arginine (100 μm). 4 Superoxide dismutase (10 units ml⁻¹), haemoglobin (10 μm) and methylene blue (MB; 1 μm), all known to modify EDRF-mediated responses, failed to alter the vasodilator action of BK. 5 Gossypol (1–15 μm), a presumed inhibitor of EDRF biosynthesis, caused a marked drop in perfusion pressure followed by vasoconstriction. These changes in coronary tone were accompanied by an irreversible depression of cardiac contractility and heart rate. Over the same concentration range gossypol abolished the vasodilator action of BK (1.0 nmol), however it also blocked the endothelium-independent vasodilator response to sodium nitroprusside (30 nmol) and the vasoconstrictor effect of endothelin-1 (10 pmol) which suggests non-specific toxic actions of gossypol. 6 Bolus injections of BK (0.001–1.0 nmol) failed to elevate basal levels of prostacyclin (PGI₂) as shown by assaying for its stable metabolite 6-keto-PGF_α. In addition, BK-induced vasodilatation was not blocked by flurbiprofen (2 μm) or BW755C (7.5 μm) which are inhibitors of the arachidonic acid pathway. When added with l-NOArg (100 μm), flurbiprofen (10 μm) did not potentiate the inhibitory action of l-NOArg on the BK response. 7 These results show that the vasodilator action of BK in the rat heart is dependent on the activation of the kinin B₂ receptors but independent of PGI₂ release. Although a conclusive role for EDRF could not be established, this study has questioned the suitability of several agents commonly used as inhibitors of EDRF-mediated responses.