Schalcher Christoph, Schad Karin, Brunner-La Rocca Hans Peter, Schindler Ruth, Oechslin Erwin, Scharf Christoph, Suetsch Gabor, Bertel Osmund, Kiowski Wolfgang
Division of Cardiology, Department of Internal Medicine, University Hospital, Zürich, Switzerland.
Hypertension. 2002 Nov;40(5):763-7. doi: 10.1161/01.hyp.0000036027.71527.3e.
Sildenafil inhibits cGMP breakdown by phosphodiesterase 5. In vitro, increased cGMP levels inhibit cAMP breakdown by phosphodiesterase 3. It is uncertain, however, whether sildenafil increases biological effects of interventions increasing cAMP levels in vivo. The objective of the present study in 40 healthy male volunteers was to determine the existence and extent of interactions with sildenafil and vasodilators acting via cGMP or cAMP or independently from these mediators on the arterial tone of the human forearm. Forearm blood flow (FBF) responses (plethysmography) to brachial artery infusions of 3 doses each of nitroglycerin, which increases cGMP levels; of isoprenaline and milrinone, which increase cAMP levels; and of verapamil as a control were assessed at baseline and 80 minutes after 50 mg oral sildenafil in 10 volunteers each. Sildenafil increased FBF (2.5+/-0.1 to 3.5+/-0.2 mL/min per 100 mL, P<0.001; n=40). At equipotent vasodilator dosages, sildenafil increased FBF from 7.5+/-1.0 to 9.8+/-1.2 mL/min per 100 mL for nitroglycerin, from 8.3+/-1.0 to 10.4+/-1.4 mL/min per 100 mL for isoprenaline, and from 8.1+/-1.0 to 10.3+/-1.2 mL/min per 100 mL for milrinone and slightly decreased FBF from 7.7+/-1.3 to 7.1+/-1.2 mL/min per 100 mL for verapamil. ANOVA for repeated measures revealed a significant interaction between sildenafil and the type of vasodilator on FBF (P<0.01). The responses of FBF to nitroglycerin, milrinone, and isoprenaline after sildenafil were similarly increased compared with the response to verapamil (P<0.01). Sildenafil markedly enhanced the arterial vasodilator response to nitroglycerin, milrinone, and isoprenaline. The response to milrinone and isoprenaline is compatible with an interaction between cGMP and phosphodiesterase 3 or an enhancement of the NO component of cAMP-mediated vasodilation, and raises the possibility of enhanced biological effects of interventions leading to increases of cAMP in the presence of sildenafil.
西地那非可抑制磷酸二酯酶5对环磷酸鸟苷（cGMP）的分解。在体外，cGMP水平升高会抑制磷酸二酯酶3对环磷酸腺苷（cAMP）的分解。然而，西地那非是否会增强体内增加cAMP水平的干预措施的生物学效应尚不确定。本研究以40名健康男性志愿者为对象，目的是确定西地那非与通过cGMP或cAMP起作用或独立于这些介质作用于人体前臂动脉张力的血管舒张剂之间相互作用的存在情况及程度。通过体积描记法评估了10名志愿者在基线时以及口服50毫克西地那非80分钟后，肱动脉输注3种剂量的硝酸甘油（可增加cGMP水平）、异丙肾上腺素和米力农（可增加cAMP水平）以及作为对照的维拉帕米后前臂血流量（FBF）的反应。西地那非使FBF增加（从2.5±0.1增至3.5±0.2毫升/分钟/100毫升，P<0.001；n = 40）。在等效血管舒张剂剂量下，西地那非使硝酸甘油的FBF从7.5±1.0增至9.8±1.2毫升/分钟/100毫升，使异丙肾上腺素的FBF从8.3±1.0增至10.4±1.4毫升/分钟/100毫升，使米力农的FBF从8.1±1.0增至10.3±1.2毫升/分钟/100毫升，而使维拉帕米的FBF从7.7±1.3略微降至7.1±1.2毫升/分钟/100毫升。重复测量方差分析显示西地那非与血管舒张剂类型对FBF有显著交互作用（P<0.01）。与对维拉帕米的反应相比，西地那非给药后FBF对硝酸甘油、米力农和异丙肾上腺素的反应同样增加（P<0.01）。西地那非显著增强了对硝酸甘油、米力农和异丙肾上腺素的动脉血管舒张反应。对米力农和异丙肾上腺素的反应符合cGMP与磷酸二酯酶3之间的相互作用，或cAMP介导的血管舒张中一氧化氮（NO）成分的增强，并增加了在西地那非存在下导致cAMP增加的干预措施生物学效应增强的可能性。
