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

Abstract

1 The vasomotor and cyclic GMP-elevating activity of YC-1, a novel NO-independent 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 mM) caused a concentration-dependent, endothelium-independent relaxation that was greatly reduced by the sGC inhibitor 1-H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ 10 mM; 59% inhibition of dilation induced by 100 mM YC-1) suggesting the activation of sGC as one mechanism of action.3 Preincubation with YC-1 (3 and 30 mM) signi®cantly increased the maximal dilator responses mediated by endogenous NO in aortic rings that was released 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 dierent kinetics as evidenced by a longlasting inhibition by YC-1 (300 mM) 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 mM) had no eect on the vasoconstrictor potency of PE, and increases in intravascular cyclic GMP levels were readily reversed after washout of this NO donor compound.5 Surprisingly, YC-1 not only activated sGC, but also aected cyclic GMP metabolism, as it inhibited both cyclic GMP break down in aortic extracts and the activity of phosphodiesterase isoforms 1 ± 5 in vitro. 6 In conclusion, YC-1 caused persistent elevation of intravascular cyclic GMP levels in vivo by activating sGC and inhibiting cyclic GMP break down. Thus, YC-1 is a highly eective vasodilator compound with a prolonged duration of action, and mechanisms that are unprecedented for any previously known sGC activator.

BAY 41-2272 [5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine]-Induced Dilation in Ovine Pulmonary Artery: Role of Sodium Pump

“…First, ODQ abolished BAY 41-2272-stimulated increase in tissue cGMP; and second, there was a substantial decay (24% at 30 min compared with 3-min level) in the cGMP level after prolonged exposure to BAY 41-2272. This is in contrast to significantly elevated tissue cGMP level for a prolonged period (52% of the maximal at 30 min) in rabbit aortic rings exposed to YC-1 (Galle et al, 1999). The fact that additional mechanisms to cGMP-mediated relaxation of ovine pulmonary artery in response to BAY 41-2272 are further evident from the observation that protein kinase G inhibitor KT-5823 had no effect on ODQ-insensitive relaxations.…”

“…YC-1, another NO-independent sGC activator, has been shown to stimulate an increase in tissue cGMP at least through two different mechanisms, one involving the activation of sGC and the other through the inhibition of phosphodiesterase type 5 (Galle et al, 1999). The structural similarity between BAY 41-2272 and YC-1 may suggest that both the compounds have similar mechanisms of action.…”

Dynamic Association of Nitric Oxide Downstream Signaling Molecules with Endothelial Caveolin-1 in Rat Aorta

“…YC-1 has been shown to not only activate sGC but also to potentiate the stimulatory action of NO (Friebe and Koesling, 1998;Schmidt et al, 2001). YC-1 also affects cGMP metabolism, inhibiting cGMP breakdown and the activity of phosphodiesterase (Galle et al, 1999), and it stimulates NO synthesis and release in endothelial cells independently of elevation in cGMP levels (Wohlfart et al, 1999).…”

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

“…YC-1 inhibits platelet aggregation and vascular contraction by activating soluble guanylyl cyclase [179,180]. Interestingly, YC-1 was reported to downregulate HIF-1α and to suppress IGF1R signaling, thus overcoming gefitinib resistance in NSCLC cells expressing activating EGFR mutations (2.3.)…”