Biology Reference
In-Depth Information
5.2 Potentiating NO Action with PDE5 Inhibitors
For the fascinating success of the prototypic PDE5 inhibitor sildenafil, three
paths to discovery had to meet: (1) basic and clinical concepts for vasodilation,
(2) development of potent and efficacious compounds and (3) the discovery of NO
and its role in male sexual function.
The vasodilating properties of papaverine in coronary arteries and the potentia-
tion of nitroglycerine, which had been used for more than 100 years for treatment of
coronary heart disease, had been described originally in 1979 by Kukovetz in the
isolated organ model (Kukovetz et al.
1979
). It was further clarified that the action
of nitrates and also the vasodilating hormone atrial natriuretic peptide (ANF) was
mediated by an intracellular increase in cGMP. The cGMP-hydrolysing enzyme
had been isolated and described by Francis and Corbin (Francis et al.
1980
), and
these pieces of knowledge led to the hypothesis that PDE inhibitors of this enzyme
being more selective and potent than papaverine should have potential as drugs
for treatment of coronary artery disease and vascular maladies. With zaprinast,
which had a broad spectrum of activities in vasodilation and also in asthma, a
compound for chemical optimisation was identified. The new compounds could be
characterised with the already established models for vasodilation in vitro and
in vivo (Table
5
), and in 1989 the compound sildenafil acquired candidate status
for clinical development as an anti-hypertensive (Campbell
2000
).
Erectile dysfunction had been considered by most clinicians and by the consultants
for industry as a trivial, “non-ethic” issue and a condition predominantly attributable
to psychologic causes. On the contrary, the interest of treating impotence was high, the
number of men suffering from this condition was enormous, and a variety of proce-
dures were applied in an attempt to treat impotence in men including (1) injecting
sheep testis extracts, (2) using under-pressure devices and (3) surgical procedures.
During such a surgical operation, papaverine was used as intraoperative vasodilator
Table 5 Animal models available for studies of cardiovascular regulation and myocardial
contractility in 1985
Animal model
Heart
rate
Blood
pressure
Coronary
flow
Cardiac
functions
Pulmonary
artery pressure
Anaesthetised dog
x
x
x
x
x
Conscious dog
x
x
x
Anaesthetised rat
x
x
x
(x)
Pithed rat
x
x
x
Hypertensive,
conscious rat
x
x
Animal models and the techniques for measurement of hemodynamic parameters were established
for the development of antihypertensive and cardiotonic drugs. The efficacy of PDE3 and PDE5
inhibitors on cardiac contractility, coronary and pulmonary pressures and flows has been quanti-
fied in these models. Primary read-outs were measured after placing catheters into carotid, femoral
or pulmonary artery and left cardiac ventricle and flow probes on peripheral and coronary arteries.
Anaesthetised, instrumentalised animals were mechanically ventilated via endotracheal tubes and
usually venous catheters were used for drug administration. Detailed descriptions of these methods
are found in Vogel (
2002
).
