RELAXANT EFFECT OF A WATER SOLUBLE CARBON MONOXIDE-RELEASING MOLECULE (CORM-3) ON SPONTANEOUSLY HYPERTENSIVE RAT AORTAS

Abstract Purpose - Both carbon monoxide (CO) and nitric oxide (NO) are two gaseous molecules performing relevant functions in mammals. In order to better understand their actions in the cardiovascular system, we have investigated the effects of CORM-3, (tricarbonylchloro(glycinato)ruthenium(II), a water soluble CO-releasing molecule and SNAP (S-nitroso-N-acetyl-DL-penicillamine, a well known NO-releasing molecule) on aortas of normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Methods - The isometric contraction of angiotensin II (AT-II) and endothelin-1 (ET-1) was evaluated in endothelium-denuded aortic strips. Results - In control conditions, AT-II induced a similar concentration-dependent contraction in both WKY and SHR, while ET-1 was more effective in SHR aortic strips. CORM-3 or SNAP (10-7-3x10-4 M) reduced the contraction induced by AT-II or ET-1 in a concentration-dependent way. Whereas the median inhibitory concentration of SNAP was significantly lower in WKY than in SHR, CORM-3 had a similar effect in both strains. The scaffold compound iCORM-3 was ineffective. Pretreatment with an inhibitor of soluble guanylyl cyclase (ODQ, 3x10-6 M) marginally reduced CORM-3 relaxation in both strains, whereas it reduced relaxation induced by SNAP in WKY and, to a lesser extent, in SHR. The benzylindazole derivative YC-1 (10-6M), a sensitizer of soluble guanylate cyclase to the action of NO, significantly increased the relaxant effect of SNAP in AT-II pre-contracted aortic strips. The blocker of calcium-activated potassium channels, charybdotoxin (10-8 M), reduced the relaxation induced by CORM-3 in both strains. Conclusions - Different mechanisms seem to be implicated in CO- and NO-mediated vascular relaxation. Since the relaxant properties of CO are conserved in SHR aortas, CORM-3 could be a new potential agent for the treatment of hypertension, when NO donors show sub-optimal or absent responses.