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 IC50 of 0.7 nM (6.6 nM). In contrast, the IC50 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 IC50 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 stimulation-induced 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 NO-induced 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.

中文翻译：

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新型PDE5抑制剂伐地那非的磷酸二酯酶抑制选择性以及体外和体内效力。

我们研究了伐地那非对磷酸二酯酶（PDEs）酶的效力和选择性特征，其修饰cGMP代谢并引起阴茎平滑肌松弛的能力，以及在外源性一氧化氮（NO）刺激下对体内勃起的影响。从人血小板（PDE5）或牛源（PDE 1、2、3、4和6）中提取并纯化PDE同工酶。确定了伐地那非对这些PDE和人重组PDE的抑制作用。体外测定了增强人海绵体条中NO介导的舒张能力和影响cGMP水平的能力，口服静脉注射硝普钠（SNP）后，有意识的兔子表现出勃起诱导活性。将伐地那非的作用与公认的PDE5抑制剂西地那非（西地那非的值在方括号中的值）进行了比较。伐地那非特异性抑制PDE5水解cGMP，IC50为0.7 nM（6.6 nM）。相比之下，伐地那非对PDE1的IC50为180 nM；对于PDE6，为11 nM；对于PDE2，PDE3和PDE4，大于1000 nM。相对于PDE5，PDE1的IC50比为257（60），PDE6的IC50为16（7.4）。伐地那非在3 nM（10 nM）时可显着增强SNP诱导的人小梁平滑肌松弛。伐地那非还可显着增强ACh诱导的和经壁电刺激引起的小梁平滑肌松弛。显着增强SNP诱导的cGMP积累的伐地那非的最低浓度为3 nM（30 nM）。对兔子的体内研究表明，口服伐地那非对静脉内注射SNP剂量依赖性地增强了勃起反应。显着增强勃起的最小有效剂量为0.1 mg / kg（1 mg / kg）。PDE5的选择性，NO增强的小梁平滑肌中NO诱导的松弛和cGMP积累以及体内增强NO诱导的勃起的能力表明，伐地那非具有合适的性质，可作为治疗勃起功能障碍的潜在化合物。伐地那非对西地那非对PDE5的抑制活性比西地那非更为有效和选择性。PDE5的选择性，NO增强的小梁平滑肌中NO诱导的松弛和cGMP积累以及体内增强NO诱导的勃起的能力表明，伐地那非具有合适的性质，可作为治疗勃起功能障碍的潜在化合物。伐地那非对西地那非对PDE5的抑制活性比西地那非更为有效和选择性。PDE5的选择性，NO增强的小梁平滑肌中NO诱导的松弛和cGMP积累以及体内增强NO诱导的勃起的能力表明，伐地那非具有合适的性质，可作为治疗勃起功能障碍的潜在化合物。伐地那非对西地那非对PDE5的抑制活性比西地那非更为有效和选择性。