Relaxation of rabbit corpus cavernosum smooth muscle and aortic vascular endothelium induced by new nitric oxide donor substances of the nitrosyl-ruthenium complex

Abstract

Endothelial dysfunction characterized by endogenous nitric oxide (NO) deficiency made 56% of patients affected with erectile dysfunction decline treatment with PDE-5 inhibitors. New forms of treatment are currently being developed for this group of patients. The study compared the effect of sodium nitroprusside (SNP) and two substances of the nitrosyl-ruthenium complex, cis-[Ru(bpy)2(SO3)(NO)]PF-6-9 ("FONO1") and trans-[Ru(NH3)4(caffeine)(NO)]C13 ("LLNO1") on relaxation of rabbit corpus cavernosum smooth muscle and aortic vascular endothelium. The samples were immersed in isolated baths and precontracted with 0.1 microM phenylephrine (PE) and the corresponding relaxation concentration/response curves were plotted. In order to investigate the relaxation mechanisms involved, 100 microM ODQ (a soluble guanylate cyclase-specific inhibitor), 3 microM or 10 microM oxyhemoglobin (an extracellular NO scavenger) or 1 mM L-cysteine (a nitrosyl anion-specific scavenger) was added to the samples. All the NO donors tested produced a significant level of relaxation in the vascular endothelium. In corpus cavernosum samples, FONO1 produced no significant effect, but LLNO1 and SNP induced dose-dependent relaxation with comparable potency (pEC50 = 6.14 +/- 0.08 and 6.4 +/- 0.14, respectively) and maximum effect (Emax = 82% vs. 100%, respectively). All NO donors were found to activate soluble guanylate cyclase, since the addition of the corresponding inhibitor (100 microM ODQ) completely neutralized the relaxation effect observed. The addition of oxyhemoglobin reduced the relaxation effect, but did not inhibit it completely. In aortic vascular endothelium 3 microM oxyhemoglobin decreased the relaxation effect by 26% on the average, while 10 microM oxyhemoglobin reduced it by over 52%. The addition of 100 microM L-cysteine produced no significant inhibiting effect. These results suggest that LLNO1 and FONO1 are potent vasodilators. LLNO1 was shown to induce a significant level of relaxation in rabbit corpus cavernosum. The substances tested were shown to activate soluble guanylate cyclase and release intracellular NO.