Endothelium-derived nitric oxide is involved in the hypotensive and vasorelaxant effects induced by discretamine in rats

The aim of this study was to investigate the pharmacological effects of discretamine, an isoquinoline alkaloid isolated from Duguetia magnolioidea Maas, on the cardiovascular system, using a combined in vivo and in vitro approach. Blood pressure and heart rate measurements, as well as changes in isometric tension in rat superior mesenteric arterial rings, elicited by discretamine were recorded. In normotensive non-anaesthetized rats (n = 6), discretamine (0.01; 0.05; 0.1; 0.5; 1, 5 and 10 mg/kg i.v., randomly) injections produced hypotension (-5.2 ± 1.7; -5.1 ± 2.1; -7.7 ± 2; -8.9 ± 1.7; -9.6 ± 2.2; -16.8 ± 2.8 and -13.4 ± 1.3 mmHg, respectively) accompanied by tachycardia (24.2 ± 6.1; 36.8 ± 11.3; 44.2 ± 7.7; 45.9 ± 6.4; 48.2 ± 9.1; 72.1 ± 14.5 and 64 ± 17 bpm, respectively). Hypotensive and tachycardic responses were significantly attenuated after l-NAME (20 mg/kg, i.v.) administration. In isolated rat mesenteric artery rings, with endothelium intact, discretamine (10-12-10-5 M) induced concentration-dependent relaxation of the contractions induced by phenylephrine (10 μM) [pD2 = 6.8 ± 0.1]. The effect of the discretamine on phenylephrine induced contractions was significantly attenuated after removal of the vascular endothelium [pD2 = 5.8 ± 0.04]. Similar results were obtained after pre-treatment with l-NAME 100 μM [pD2 = 5.8 ± 0.04], l-NAME 300 μM [pD2 = 5.9 ± 0.06], Hydroxocobalamin 30 μM [pD2 = 5.8 ± 0.06] or ODQ 10 μM [pD2 = 5.8 ± 0.04]. In addition, in rabbit aorta endothelial cell line, discretamine significantly increased NO3- levels. These results suggest that the hypotensive effect induced by discretamine is probably due to a peripheral vasodilatation, at least, in part, due to the release of NO from vascular endothelium and consequent activation of soluble guanylyl cyclase (GC) in the vascular smooth muscle cells.