Vasodilator action in the nitroxylated cyanoamidine derivative, KRN2391, in rabbit basilar artery.
KRN2391 is a cyanoamidine derivative with a pyridine ring and a nitroxyl group. This gives the molecule a dual pharmacological action as both an ATP-sensitive K channel (K(ATP)) opener and an organic nitrate. In cerebrovascular disease with endothelial dysfunction, such a compound could be advantageous to prevent the negative consequences of a reduced synthesis of endogenous nitric oxide and endothelium-derived hyperpolarizing factor. The objective of this study was to characterise the vasodilator action of KRN2391 in a cerebral artery. As shown in the rabbit basilar artery contracted by endothelin-1 KRN2391 elicited a concentration-dependent relaxation. KRN2391 was unable to relax arteries contracted by a 60 mM K solution. The KRN2391-induced relaxation of endothelin-1-contracted arteries was unaffected by N(G)-nitro-L-arginine (0.1 mM), indomethacin (10 microM) or removal of the endothelium. The guanylate cyclase inhibitors ODQ (10 microM) and LY53583 (10 microM), and the cGMP phosphodiesterase inhibitor zaprinast (10 microM) each had no effect on the KRN2391-induced relaxation. Glibenclamide (1 microM), a blocker of K(ATP), caused a rightward shift of the concentration-response curve for KRN2391. The relaxation induced by the prototype K(ATP) opener levcromakalim was inhibited to a similar extent by glibenclamide. Addition of ODQ or LY53583, or the calcium-sensitive K channel blockers apamin (0.1 microM) and charybdotoxin (0.1 microM) in the presence of glibenclamide did not produce a significant further inhibition of the KRN-induced relaxation. KRN2391 (10 microM) did not influence the content of cGMP in the basilar artery, whereas the nitric oxide donor 3-morpholino-sydnonimine (0.1 mM) increased the cGMP level three-fold. Thus, KRN2391 is an effective vasodilator of the rabbit basilar artery, acting mainly through opening of KATP . The nitro-moiety of the molecule does not seem to contribute to the relaxant effect in this artery.
Ryman
T
T
Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University Hospital, Sweden.
Petersson
J
J
Högestätt
E D
ED
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D026902:Potassium Channel Blockers; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D011725:Pyridines; D014665:Vasodilator Agents; C070492:N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate; D019335:Nitroarginine; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D007213:Indomethacin