Phosphodiesterase type 5 inhibition in cardiovascular disease: experimental models and potential clinical applications

Abstract

Inhibition of phosphodiesterase type 5, with amplification of the nitric oxide-cyclic nucleotide signalling pathway, and smooth muscle relaxation within erectile tissues and the penile vasculature, is the mechanism underlying the pro-erectile effects of sildenafil citrate. However, this enzyme is also expressed in other vascular beds, and preliminary findings have suggested that phosphodiesterase type 5 inhibition represents a promising treatment strategy for a range of cardiovascular conditions, including hypertension and chronic heart failure. Administered either alone or in concert with an inhaled prostacyclin analogue, sildenafil exhibited beneficial vasodilator effects in patients with pulmonary hypertension, reducing pulmonary arterial pressure and pulmonary vascular resistance, as well as prolonging exercise time and enhancing quality of life. Among patients with heart failure, sildenafil also significantly increased brachial artery diameter (versus placebo) in a flow-mediated vasodilatation paradigm and augmented the blood pressure lowering effects of a calcium channel blocker in men with essential hypertension. Sildenafil was also well tolerated and/or increased the ischaemic threshold during exercise testing in men with stable coronary heart disease. Concomitant therapy with sildenafil and nitrates or nitric oxide donors can cause profound hypotension (and other adverse effects), and is thus absolutely contraindicated.