Blood Pressure Lowering Effects of a New Long-Acting Inhibitor of Phosphodiesterase 5 in Patients With Mild to Moderate Hypertension

Abstract

Abstract-Inhibition of phosphodiesterase 5 is an attractive candidate mechanism for blood pressure (BP) lowering. In this study, a novel long-acting phosphodiesterase 5 inhibitor, PF-00489791, was evaluated in 133 patients with mild to moderate hypertension, randomized into 1 of 4 groups: placebo, 4 mg, 10 mg, and 20 mg titrated after 14 days of dosing to 40 mg. Study medication was administered once daily for 28 days. Ambulatory BP monitoring was used. There was a statistically significant decrease (compared with placebo) in mean daytime systolic BP on day 28 at the 10 and 20/40 mg doses (by Ϸ5 and Ϸ7 mm Hg, respectively). Changes in mean daytime diastolic BP corresponded with those in systolic BP. The magnitude of BP lowering was greater on day 1 than on days 14 and 28, but the response was sustained between days 14 and 28. PF-00489791 also exerted BP lowering effects on mean 24-hour ambulatory BP. There was a dose-related increase in plasma cGMP concentration (statistically significant at the 20/40 mg dose). There was an increased incidence of headaches at the 10 and 20/40 mg doses (22% and 21%, respectively, compared with 12% with placebo) and an increased incidence of dyspepsia/gastroesophageal reflux disease and musculoskeletal adverse events at the 20/40 mg dose. In conclusion, PF-00489791 causes a clinically meaningful and sustained BP lowering in patients with hypertension. It is generally safe and well tolerated at the clinically efficacious doses. Key Words: hypertension Ⅲ phosphodiesterase 5 Ⅲ PDE-5 inhibition Ⅲ PF-00489791 Ⅲ ABPM Ⅲ cGMP Ⅲ blood pressure I nhibition of phosphodiesterase 5 (PDE-5) is an attractive candidate mechanism for blood pressure (BP) lowering. PDE-5 is an enzyme that, among several other tissues, is also expressed in human arterial and venous vascular smooth muscle (VSM) cells, 1,2 where it mediates the breakdown of cGMP by metabolizing it to inactive 5Ј-GMP. Elevated cGMP reduces levels of intracellular calcium and thereby produces relaxation of arterial VSM cells and hence a decrease in arterial vascular resistance. Thus, inhibition of PDE-5 should lead to an increase in intracellular cGMP, arterial and venous vasorelaxation, and a consequent reduction in systemic arterial BP. In the present study, we evaluated BP lowering effects of a novel long-acting PDE-5 inhibitor, PF-00489791, in patients with mild to moderate hypertension. Methods Study Subjects and Study DesignPatients were recruited and the study was conducted at 17 participating study centers in the United States. Written informed consent was obtained from each study participant. The final protocol and informed consent documentation were reviewed and approved by the institutional review board at each of the investigational centers. The study was registered on ClinicalTrials.gov.Study subjects included males and females of nonchildbearing potential, between the ages of 18 and 70 years, who had a history of mild to moderate hypertension that was currently controlled with antihypertensive medication, or, if untreated, ...

Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy

“…19,27,28 PF-00489791 was safe and generally well-tolerated when administered at a dose of 20 mg daily for 12 weeks in T2DM subjects with overt DN. The most commonly observed AEs in the present study were consistent with those reported in subjects with mild-to-moderate hypertension treated with PF-00489791 for 28 days, 29 including headaches and upper gastrointestinal events. There was an imbalance in discontinuations because of (primarily) mild or moderate TEAEs which may reflect a mild intolerance to this medication, in line with other PDE5is.…”

Clinical Potential of Combined Organic Nitrate and Phosphodiesterase Type 5 Inhibitor in Treatment-Resistant Hypertension

“…2 Inhibitors of PDE5 are also vasodilators in the systemic circulation. Indeed, we 3 and others 4 have demonstrated previously that PDE5 inhibitors constitute effective regular antihypertensive therapy in untreated and treated subjects with mild-to-moderate hypertension.The organic nitrates, such as isosorbide mononitrate (ISMN), are antianginal drugs that dilate arteries and veins through their action as NO donors. 5 The simultaneous provision of exogenous NO from organic nitrates and inhibition of cGMP breakdown with PDE5 inhibition can result in substantial blood pressure (BP) reduction, as we have shown previously.…”

“…2 Inhibitors of PDE5 are also vasodilators in the systemic circulation. Indeed, we 3 and others 4 have demonstrated previously that PDE5 inhibitors constitute effective regular antihypertensive therapy in untreated and treated subjects with mild-to-moderate hypertension.…”

Potential Therapeutic Role of Phosphodiesterase Type 5 Inhibition in Hypertension and Chronic Kidney Disease

“…Current research is thus now turning to the assessment of the efficacy and safety of novel longer acting agents, such as tadalafil. 61 An alternative therapeutic option involves using PDE5 inhibitors in combination with existing hypertension therapies. The simultaneous provision of exogenous NO from organic nitrates and the inhibition of cGMP breakdown with PDE5 inhibitors is currently contraindicated because of the potential risk of clinically significant hypotension.…”