IN-VITRO VASORELAXANT AND IN-VIVO CARDIOVASCULAR EFFECTS OF S-NITROSOTHIOLS - COMPARISON TO AND CROSS-TOLERANCE WITH STANDARD NITROVASODILATORS

The in vitro vasorelaxant and in vivo cardiovascular effects of synthe tic S-nitrosothiols (RSNOs) were compared to standard nitrovasodilator s. S-Nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteine (NACysNO), S-nitroso-galactopyranose (GPSNO), S-nitroso-thioglycerol (TGSNO) and S-nitroso-homocysteine (HCysNO) relaxed phenylephrine (PE) contracted rabbit aorta at 50% effective concentrations (EC(50)s) of 3-46 nM. Wh ile nitroglycerin (GTN) exhibited in vitro tolerance after preincubati on, the RSNOs were considerably less cross tolerant to GTN. In conscio us dogs, GSNO, NACysNO and GPSNO (1-20 mcg/kg/min i.v.) paralleled nit roprusside (SNP) in reducing mean arterial and central venous pressure (MAP; CVP) with mild tachycardia. GSNO, NACysNO and SNP were more hyp otensive and more resistant to isosorbide dinitrate (ISDN) cross toler ance than GTN. NACysNO showed mild self tolerance with low infusion (2 .5 mcg/kg/min x 4 h x 3 days) and blunted GTN's hypotension. These stu dies demonstrate that GSNO and NACysNO are SNP-like vasodilators in co nscious dogs, which exhibit less cross tolerance to ISDN than GTN. Fur ther RSNOs relax vascular smooth muscle seemingly independent of nitri c oxide (NO) liberation and nitrate tolerance may involve reduced RSNO formation or NO release rather than desensitized guanylate cyclase (G C).