Sildenafil is a potent and selective inhibitor of the
cyclic GMP-specific
phosphodiesterase (PDE5) that is very effective in the treatment of
male impotence. It inhibits breakdown of cyclic
guanosine monophosphate (cGMP) formed in penile smooth muscle cells in response to stimulation by
nitric oxide resulting in muscle relaxation. PDE5 is widely distributed in the body, being present in the vasculature, platelets, and kidneys. In the kidney, PDE5 is involved in the regulation of
sodium excretion and
renin secretion. The aim of the present investigation was to investigate the effect of
sildenafil, in doses used clinically, on
renin secretion in human subjects. The studies were performed in two groups of healthy normotensive subjects: one in which
sodium intake was unrestricted, and one in which
sodium intake was restricted to 600 mg/day. Blood pressure and heart rate were monitored throughout the study, and blood samples for the measurement of plasma cGMP and cAMP concentrations and plasma
renin activity (PRA) were collected. After control measurements, the subjects ingested a
capsule containing
sildenafil or placebo. Cardiovascular measurements and blood sampling continued for the next 120 min.
Sildenafil had only minor cardiovascular effects. Diastolic pressure tended to be lower and heart rate was generally higher after
sildenafil than after placebo, but the differences were small.
Sildenafil caused a prompt and sustained increase in plasma cGMP concentration and a more gradual increase in plasma cAMP concentration. After the subjects received placebo, there was a progressive decrease in PRA during the 2-hr observation period, presumably reflecting the circadian rhythm in
renin secretion. In contrast, PRA failed to decrease after the subjects received
sildenafil, thus indicating that
sildenafil exerts a stimulatory action on
renin secretion. This action on
renin secretion may help explain why
sildenafil only has minor effect on blood pressure despite the widespread distribution of PDE5 in vascular tissues.