title: Interaction of sildenafil with cAMP-mediated vasodilation in vivo.
abstract: 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.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University Hospital, Zürich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schalcher
authors.forename: Karin
authors.initials: K
authors.lastname: Schad
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Brunner-La Rocca
authors.forename: Ruth
authors.initials: R
authors.lastname: Schindler
authors.forename: Erwin
authors.initials: E
authors.lastname: Oechslin
authors.forename: Christoph
authors.initials: C
authors.lastname: Scharf
authors.forename: Gabor
authors.initials: G
authors.lastname: Suetsch
authors.forename: Osmund
authors.initials: O
authors.lastname: Bertel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kiowski
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D001916:Brachial Artery / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D005542:Forearm / Q000098:blood supply; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D005996:Nitroglycerin / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D012039:Regional Blood Flow / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000318:Adrenergic beta-Agonists; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D005996:Nitroglycerin; D006152:Cyclic GMP; D020105:Milrinone; D007545:Isoproterenol