Phosphodiesterase type 5 inhibition reverses impaired forearm exercise-induced vasodilatation in hypertensive patients

Objective Established hypertension is characterized byincreased peripheral vascular resistance and endothelialdysfunction, features that may underlie the reducedexercise-induced vasodilatation seen in hypertensivepatients. Sildenafil citrate is a phosphodiesterase type 5(PDE5) inhibitor used clinically for the treatment of maleerectile dysfunction. Its vasodilating properties are due tothe inhibition of cyclic guanosine monophosphate (cGMP)breakdown and prolongation of the signalling actions of thenitric oxide (NO)–cGMP pathway in vascular smoothmuscle cells. Sildenafil has beneficial effects on endothelialfunction and exercise tolerance in congestive heart failureand pulmonary hypertension, and we hypothesized that itwould improve exercise-induced vasodilatation inhypertensive patients.Methods and results Ten hypertensive patients and tenmatched normotensive subjects were studied in a three-way, randomized, single-blind and placebo-controlledstudy. On each study day, forearm blood flow (FBF)responses to handgrip exercise were assessed before andafter intra-arterial (brachial) infusion of sildenafil, verapamil(a control, cGMP-independent vasodilator), and saline(placebo). Preinfusion exercise-induced vasodilatation wassignificantly reduced in hypertensive patients compared tonormotensive controls. Sildenafil and verapamil infusionsboth caused a similar increase in baseline FBF. However,while verapamil did not affect the vasodilator response tohandgrip exercise in either group, sildenafil substantiallyenhanced this response in hypertensive patients, but not innormotensive subjects.Conclusions Our data suggest that sildenafil, through anincreaseincGMPlevels inthevasculature,substantiallyandselectively improves the vasodilator response to handgripexercise in hypertensive patients. These findings representan essential first step in support of further studies exploringthe potentially beneficial effects of PDE5 inhibition onexercise capacity in hypertension. J Hypertens 25:000–000Q 2007 Wolters Kluwer Health | Lippincott Williams &Wilkins.