The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil

Abstract

We investigated the potency and the selectivity profile of vardenafil on phosphodiesterase (PDEs) enzymes, its ability to modify cGMP metabolism and cause relaxation of penile smooth muscle and its effect on erections in vivo under conditions of exogenous nitric oxide (NO) stimulation. PDE isozymes were extracted and purified from human platelets (PDE5) or bovine sources (PDEs 1, 2, 3, 4 and 6). The inhibition of these PDEs and of human recombinant PDEs by vardenafil was determined. The ability to potentiate NO-mediated relaxation and influence cGMP levels in human corpus cavernosum strips was measured in vitro, and erection-inducing activity was demonstrated in conscious rabbits after oral administration together with intravenous doses of sodium nitroprusside (SNP). The effects of vardenafil were compared with those of the well-recognized PDE5 inhibitor, sildenafil (values for sildenafil in brackets). Vardenafil specifically inhibited the hydrolysis of cGMP by PDE5 with an IC 50 of 0.7 nM (6.6 nM). In contrast, the IC 50 of vardenafil for PDE1 was 180 nM; for PDE6, 11 nM; for PDE2, PDE3 and PDE4, more than 1000 nM. Relative to PDE5, the ratios of the IC 50 for PDE1 were 257 (60), for PDE6 16 (7.4). Vardenafil significantly enhanced the SNP-induced relaxation of human trabecular smooth muscle at 3 nM (10 nM). Vardenafil also significantly potentiated both ACh-induced and transmural electrical stimulationinduced relaxation of trabecular smooth muscle. The minimum concentration of vardenafil that significantly potentiated SNP-induced cGMP accumulation was 3 nM (30 nM). In vivo studies in rabbits showed that orally administered vardenafil dose-dependently potentiated erectile responses to intravenously administered SNP. The minimal effective dose that significantly potentiated erection was 0.1 mg=kg (1 mg=kg). The selectivity for PDE5, the potentiation of NOinduced relaxation and cGMP accumulation in human trabecular smooth muscle and the ability to enhance NO-induced erection in vivo indicate that vardenafil has the appropriate properties to be a potential compound for the treatment of erectile dysfunction. Vardenafil was more potent and selective than sildenafil on its inhibitory activity on PDE5.

Chuanxiongzine relaxes isolated corpus cavernosum strips and raises intracavernous pressure in rabbits

“…[7][8][9][10] Some drugs such as inhibitors of PDE 5 or other vasodilators, which can promote the relaxation of corpus cavernosum smooth muscle, can be potentially used to treat ED. [11][12][13][14][15][16][17][18][19] It has been shown that there are many Chinese traditional herbals that can enhance sexual activity. [20][21][22][23][24] Recently, there is an increasing interest in investigating their effective components.…”

Vardenafil preclinical trial data: potency, pharmacodynamics, pharmacokinetics, and adverse events

“…In a direct comparison with sildenafil, vardenafil was proven effective at lower concentrations. 1,2,3 Also, vardenafil significantly potentiated both acetylcholine (Ach)-induced and transmural electrical stimulation-induced relaxation of trabecular smooth muscle.…”

Implications of PDE4 structure on inhibitor selectivity across PDE families

“…Sildenafil has the IC 50 value of approximately 1 nM against PDE5, and about 1000-fold selectivity of PDE5 over PDE4. 16 The model demonstrated an overall well fit of sildenafil into the catalytic pocket of PDE4. Thus, the purine-like ring of sildenafil sits in the hydrophobic pocket and forms a hydrogen bond, respectively, with Gln369 and Tyr159.…”