Involvement of the NO/sGC/cGMP/K channels pathway in vascular relaxation evoked by two non-quinazoline α-adrenoceptor antagonists.

The aim of this study was to explore the α-adrenoceptor-independent mechanisms involved in the vasorelaxant properties of two non-quinazoline α-adrenoceptors antagonists (MH-76 and MH-79). Endothelium intact and endothelium denuded rat aorta was contracted with 1 μM phenylephrine to plateau, and the vasodilatory effect of MH-76 and MH-79 was examined in the absence or presence of inhibitors of the different signal transduction pathways. cGMP concetration was measured in rat aorta (enzyme immunoassay kit). In human aortic endothelial cells (HAEC) NO production was examined using a DAF-FM DA fluorescent indicator, whereas in human aortic smooth muscle cells the influence of the title compounds on K efflux was evaluated. The vasorelaxant effect of MH-76 and MH-79 was attenuated by endothelium removal, N-Nitro-l-arginine methyl ester (L-NAME) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) pretreatment to the level characteristic for α-adrenoreceptor blocking activity. In addition, the MH-76 and MH-79 induced relaxation was reduced by K channels blockers. In endothelium intact rat aorta, MH-76 and MH-79 caused an increase in cGMP level, whereas in HAEC they increased NO generation. In contrast, the reference, quinazoline based α-antagonist prazosin, did not influence NO production. Our findings suggest that the mechanisms underlying the vasodilatory properties of non-quinazoline based α-adrenoceptors antagonists MH-76 and MH-79 involve not only α-adrenoceptor blocking activity but also the activation of the endothelial NO-cGMP signalling pathway and the subsequent opening of K channels. Our studies show that such double mechanism of action is superior to pure α-adrenoceptor blockade, and may be considered as a promising alternative for the prevention and treatment of cardiovascular diseases.