Effects of the soluble guanylyl cyclase activator, YC-1, on vascular tone,cyclic GMP levels and phosphodiesterase activity

1 The vasomotor and cyclic GMP-elevating activity of YC-1, a novel NO-indep endent activator of soluble guanylyl cyclase (sGC), was studied in isolated rabbit aortic rings and compared to that of the NO donor compounds sodium nitroprusside (SNP) and NOC 18. 2 Similarly to SNP and NOC 18, YC-1 (0.3-300 mu M) caused a concentration-d ependent, endothelium-independent relaxation that was greatly reduced by th e sGC inhibitor 1-H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ 10 mu M; 59% inhibition of dilation induced by 100 mu M YC-1) suggesting the activat ion of sGC as one mechanism of action. 3 Preincubation with YC-1 (3 and 30 mu M) significantly increased the maxim al dilator responses mediated by endogenous NO in aortic rings that was rel eased upon exposure to acetylcholine, and enhanced the dilator response to the exogenous NO-donors, SNP and NOC 18, by almost two orders of magnitude. 4 Vasoactivity induced by SNP and YC-1 displayed different kinetics as evid enced by a longlasting inhibition by YC-1 (300 mu M) on the phenylephrine ( PE)-induced contractile response, which was not fully reversible even after extensive washout (150 min) of YC-1, and was accompanied by a long-lasting elevation of intracellular cyclic GMP content. In contrast, SNP (30 mu M) had no effect on the vasoconstrictor potency of PE, and increases in intrav ascular cyclic GMP levels were readily reversed after washout of this NO do nor compound. 5 Surprisingly, YC-1 not only activated sGC, but also affected cyclic GMP m etabolism, as it inhibited both cyclic GMP break down in aortic extracts an d the activity of phosphodiesterase isoforms 1-5 in vitro. 6 In conclusion, YC-1 caused persistent elevation of intravascular cyclic G MP levels in vivo by activating sGC and inhibiting cyclic GMP break down. T hus, YC-1 is a highly effective vasodilator compound with a prolonged durat ion of action, and mechanisms that are unprecedented for any previously kno wn sGC activator.