Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure

Abstract

ACE (angiotensin-converting enzyme) inhibitors and PDE5 (phosphodiesterase type 5) inhibitors have each been reported to improve endothelial function in cardiovascular disease patients, but the comparative and combined effects of these two classes have not been studied previously. We sought to characterize the acute effects of ramipril alone, sildenafil alone, or their combination on endothelial function in patients with CHF (chronic heart failure). CHF subjects (n=64) were randomized to receive placebo, 10 mg of ramipril alone, 50 mg of sildenafil alone or a combination of ramipril and sildenafil in a double-blind manner. FMD (flow-mediated dilation) of the brachial artery was determined by high-resolution ultrasound imaging before and at 1, 2 and 4 h after administration of the study drug. Ramipril alone increased FMD at 4 h compared with placebo (+2.3+/-1.3%, P=0.02). Sildenafil alone increased FMD at 1, 2 and 4 h compared with placebo (+3.9+/-1.4, +4.6+/-1.8 and +3.7+/-1.3% respectively, all P<0.02). Sildenafil in combination with ramipril increased FMD at 1, 2 and 4 h when compared with placebo (+3.5+/-1.5, +4.5+/-1.8 and +4.8+/-1.3% respectively, all P<0.03). Ramipril and sildenafil both acutely improved FMD in patients with CHF, with additive effects evident at 4 h during combination therapy. Therefore further work to characterize chronic effects of combined ACE and PDE5 inhibition on endothelial function are warranted.

PDE5 inhibitors beyond erectile dysfunction

“…25 A placebo-controlled study showed that acute PDE5 inhibition with sildenafil-increased endotheliumdependent, flow-mediated vasodilation in patients with chronic heart failure. 26 These findings were confirmed by Hryniewicz et al, 27 who compared sildenafil with the angiotensin-converting enzyme inhibitor ramipril, showing that both compounds improved flow-mediated dilation to a similar extent in patients with heart failure.…”

“…However, there are a number of other potential mechanisms by which PDE5 inhibitors may have a positive influence on heart failure, and the impact of these effects is, as yet, unclear. Therefore, despite a variety of encouraging 22 Heart failure Aortic banding in mice, 16 only minor effects in pacing induced heat failure in dogs 28 Improvement in flow-mediated vasodilatation in CHF patients 26,27 Raynaud's disease None Significant reduction in frequency and duration of Raynaud attacks 33 Cognitive dysfunction PDE5 expression profiling, [36][37][38][39] in vitro studies, 36,42 behavioral models with rodents [43][44][45][46][47] None Stroke Various stroke models in rats 42,[50][51][52][53] None Female sexual dysfunction PDE5 expression and activity in vitro [58][59][60] ; isolated organ bath 61,62 Moderate effects in pre-and post-menopausal women, [63][64][65][66] 126,127 Abbreviations: BPS, benign prostate syndrome; CHF, congestive heart failure; LUTS, lower urinary tract symptoms; PAH, pulmonary hypertension; PDE5, phosphodiesterase type-5.…”

Phosphodiesterase inhibitors for the treatment of pulmonary hypertension

“…Single 50-mg oral doses of sildenafil have been reported to prevent endothelial dysfunction induced by ischaemia and reperfusion in healthy volunteers [64] and in patients with chronic heart failure [65,66], when measured using a flowmediated dilation protocol. Administration of 20 mg tadalafil on alternate days for 4 weeks has been reported to improve endothelial function in males with increased cardiovascular risk (10-yr cardiovascular risk .20%) [67].…”

Clinical Use of Phosphodiesterase-5 Inhibitors in Chronic Heart Failure

“…61,62 In a report in which sildenafil was tested in patients with stable CHF, at the doses of 12.5, 25, and 50 mg, flow-mediated dilatation in the forearm circulation increased in a dose-dependent fashion and the lower effective dose was shown to be 25 mg. 61 When combined with the ACE inhibitor ramipril, sildenafil produced an additional benefit on endothelial function in patients with heart failure. 63 In MI indicates myocardical infraction; LV, left ventricular; COPD, chronic obstructive pulmonary disease; DLco, diffusion capacity for carbon monoxide; CHF, chronic heart failure; HR, heart rate; BP, blood pressure;…”