Vasodilator action of the nitroxylated cyanoamidine derivative, KRN2391, in rabbit basilar artery

KRN2391 is a cyanoamidine derivative with a pyridine ring and a nitroxyl gr oup. This gives the molecule a dual pharmacological action as both an ATP-s ensitive K channel (K-ATP) Opener and an organic nitrate. In cerebrovascula r disease with endothelial dysfunction, such a compound could be advantageo us to prevent the negative consequences of a reduced synthesis of endogenou s nitric oxide and endothelium-derived hyperpolarizing factor. The objectiv e of this study was to characterise the vasodilator action of KRN2391 in a cerebral artery. As shown in the rabbit basilar artery contracted by endoth elin-1 KRN2391 elicited a concentration-dependent relaxation. KRN2391 was u nable to relax arteries contracted by a 60 mM K solution. The KRN2391-induc ed relaxation of endothelin-l-contracted arteries was unaffected by N-G-nit ro-L-arginine (0.1 mM), indomethacin (10 mu M) or removal of the endotheliu m. The guanylate cyclase inhibitors ODQ (10 mu M) and LY53583 (10 mu M), an d the cGMP phosphodiesterase inhibitor zaprinast (10 mu M) each had no effe ct on the KRN2391-induced relaxation. Glibenclamide (1 mu M), a blocker of K-ATP, caused a rightward shift of the concentration-response curve for KRN 2391. The relaxation induced by the prototype K-ATP Opener leveromakalim wa s inhibited to a similar extent by glibenclamide. Addition of ODQ or LY5358 3, or the calcium-sensitive K channel blockers apamin (0.1 mu M) and charyb dotoxin (0.1 mu M) in the presence of glibenclamide did not produce a signi ficant further inhibition of the KRN-induced relaxation. KRN2391 (10 mu M) did not influence the content of cGMP in the basilar artery, whereas the ni tric oxide donor 3-morpholino-sydnonimine (0.1 mM) increased the cGMP level three-fold. Thus, KRN3391 is an effective vasodilator of the rabbit basila r artery, acting mainly through opening of K-ATP The nitro-moiety of the mo lecule does not seem to contribute to the relaxant effect in this artery.