Nitric oxide is released from the endothelium and causes relaxation of vascular
smooth muscle by stimulating guanylate cyclase to produce guanosine 3’,5’-cyclic
monophosphate (cGMP) which, in turn, is degraded by phosphodiesterase type 5
(PDE5). Inhibition of PDE5, with drugs like sildenafil citrate, promotes NOstimulated
relaxation of vascular smooth muscle. The overall aim of the work
contained within this thesis was to further characterise the systemic vascular effects
of PDE5 inhibition. Four clinical studies were performed.
The aims of the first study were to investigate in healthy men the effect of smoking
on endothelium-dependent vasomotor function measured as the change in peripheral
arterial wave reflection with inhaled salbutamol, and the effect of acute sildenafil
100 mg on this response. Smokers (n=12) exhibited a reduced response to inhaled
salbutamol compared to non-smokers (n=11) [mean(standard deviation) area under
the curve of the change in central augmentation index following salbutamol 400 μg:
-29(143) AU in smokers vs -159(124) AU in non-smokers, P=0.03]. In the smokers,
there was a trend to an improvement in the response to salbutamol following
sildenafil [-96(266) AU vs -29(143) AU with matched placebo; P=0.2].
The co-administration of glyceryl trinitrate (GTN) and sildenafil is absolutely
contraindicated because of the potential for profound hypotension. The aim of the
second study was to characterise the time course of this interaction. Twenty men
with stable angina, maintained on their usual medicines, were administered
sublingual GTN 400 μg 1, 4, 6 and 8 hours after sildenafil 100 mg or matched
placebo. Compared to the combination of GTN and placebo, the combination of
GTN and sildenafil resulted in greater mean maximum reductions from baseline in
sitting systolic blood pressure (BP) at 1, 4 and 8 hours, and in sitting diastolic BP at
all time points (all P<0.05). Compared to placebo, sildenafil alone reduced systolic
BP at 1, 4, 6 and 8 hours (P<0.01 at 1 hour and P<0.05 at 4, 6, and 8 hours) and
diastolic BP at 4, 6, and 8 hours (all P<0.01). Analysis of the change in BP from the
measures taken before each GTN challenge suggested that the interaction on BP might be synergistic at 1 hour after sildenafil, but no more than additive at 6 and 8
hours after sildenafil. Symptoms consistent with hypotension occurred following
GTN in 6 subjects at 1 hour and 3 subjects at 4 hours after sildenafil, but in no
subjects at 6 and 8 hours after sildenafil or at any time after placebo.
In the third study, 25 otherwise untreated hypertensives were given sildenafil 50 mg
or matched placebo three times daily for 16 days and the effects on ambulatory BP,
clinic BP, arterial wave reflection, carotid-femoral pulse wave velocity and brachial
artery flow-mediated dilatation were measured. Three subjects were withdrawn
because of side effects and the data from the remaining 22 subjects were analysed.
Sildenafil reduced ambulatory BP [change from baseline in average daytime BP:
systolic -8(9) mmHg vs 2(9) mmHg with placebo, P<0.01; diastolic -6(5) mmHg vs
0(6) mmHg, P<0.01] and clinic BP [change from baseline to 1 hour after drug
administration on day 16: systolic -5(11) mmHg vs 4(10) mmHg, P<0.01; diastolic
-5(5) mmHg vs 2(7) mmHg, P<0.01]. Sildenafil, but not placebo, reduced arterial
wave reflection [central augmentation index from 32(9)% at baseline to 30(10)% at 1
hour after administration on day 16, P<0.05; radial augmentation index from
88(13)% to 84(13)%, P<0.01], but the change in arterial wave reflection was not
statistically significant compared to the change with placebo. Sildenafil did not affect
pulse wave velocity or flow-mediated dilatation.
The fourth study investigated the potential of combined PDE5 inhibition and organic
nitrate for the management of treatment-resistant hypertension (TRH). In 6 patients
with TRH, maintained on their usual antihypertensives sildenafil 50 mg alone,
isosorbide mononitrate (ISMN) 10 mg alone and co-administered sildenafil and
ISMN all acutely reduced systolic BP and diastolic BP compared to placebo
(quantified as the area under the curve of the change from baseline to 4 hours after
drug administration; all P≤0.01). The combination produced a greater reduction in
systolic BP than did either sildenafil alone (P=0.03) or ISMN alone (P=0.01) and a
greater reduction in diastolic BP than did sildenafil alone (P=0.02). Compared to
placebo, from 1 to 3 hours after drug administration BP was on average 13/10 mmHg lower with sildenafil alone, 18/14 mmHg lower with ISMN alone and 26/18 mmHg
lower with the combination.
The following conclusions were made. (1) Smokers exhibit impaired vascular
responsiveness to inhaled salbutamol, indicating systemic endothelial dysfunction,
which may be improved by sildenafil. (2) In men with stable angina there is an
interaction on BP reduction between sildenafil 100 mg and sublingual GTN 400 μg
for at least 8 hours after sildenafil administration, but this interaction is no more than
additive from 6 hours after sildenafil administration. (3) Regular sildenafil
monotherapy reduces BP in hypertension. (4) In patients with TRH maintained on
their usual antihypertensives sildenafil alone and ISMN alone both acutely reduce
BP and there is additional BP reduction when these drugs are given in combination