Inhibition of phosphodiesterase type 5 and exercise in arterial hypertension
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Date
2010Author
Attinà, Teresa M.
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Abstract
Hypertensive patients exhibit impaired exercise capacity, a strong independent risk
factor for cardiovascular disease, and the mechanisms responsible for this are not
fully determined. Potential candidates may include endothelial vasomotor
dysfunction and arterial stiffness, both of which are associated with hypertension.
Impairment of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP)
pathway plays a major role in the development of these abnormalities, suggesting
that enhancement of NO-cGMP signalling through phosphodiesterase type 5 (PDE5)
inhibition may offer therapeutic potential in arterial hypertension. This thesis
investigated the effects of the PDE5 inhibitor sildenafil citrate on exercise-induced
vasodilatation, maximal exercise capacity and arterial stiffness in hypertensive
patients, using different studies involving local limb and whole body exercise.
Preliminary dose-ranging studies were initially performed to investigate the intraarterial
(brachial) effects of sildenafil on forearm blood flow (FBF), and to select an
appropriate, cGMP-independent, vasodilator to use as a control. On the basis on
these studies, it was established that sildenafil, infused at 50μg/min, and verapamil,
infused at 5μg/min, had similar vasodilator effect on FBF. Ten untreated
hypertensive patients and ten matched normotensive subjects were then studied in a
three-way, randomised, single-blind and placebo-controlled FBF study. The aim was
to investigate the effects of sildenafil on handgrip exercise-induced vasodilatation,
and to compare this response with verapamil and saline (placebo). Preinfusion
exercise-induced vasodilatation was significantly reduced in hypertensive compared
with normotensive subjects (P<0.001). However, after the infusions, while verapamil
did not affect the vasodilator response to exercise in either group, sildenafil
substantially enhanced this response in hypertensive patients, but not in
normotensive subjects (P<0.05). These results suggested that sildenafil, through an
increase in cGMP levels in the vasculature, substantially and selectively improves
the vasodilator response to handgrip exercise in hypertensive patients.