Many drugs have recently been introduced for the treatment of
hypertension and heart failure. These drugs may primarily affect the
heart or components of the peripheral circulation and may have adverse as
well as beneficial effects. Although animal studies can give some
indication of the mode of action, such drugs should be evaluated both by
measurement of their effects on the circulation and by appropriate
clinical trials to determine if there is any useful benefit. In this
dissertation this principle has been applied to inotropic and vasodilator
drugs used for treating heart failure and hypertension.
To study the circulatory effects of drugs, I have modified standard
radionuclide methods and developed a technique to examine peripheral
venous capacitance. The problems of assessing ventricular function
when afterload changes have been studied. To assess benefit I have
organised and conducted appropriate clinical trials.
The first section comprises two studies of drugs which modify inotropic
state. The haemodynamic effects of the beta-adrenergic antagonist
atenolol vere examined in patients with previously untreated essential
hypertension. Blood pressure was lowered but the underlying circulatory
abnormalities including the elevated peripheral vascular resistance were
not corrected. Patients with cor pulmonale were given the betaadrenergic agonist pirbuterol and the cardiovascular effects compared
with those of the pure vasodilator sodium nitroprusside. Pirbuterol was
shown to act as a vasodilator with some selectivity for the pulmonary
circulation but a minor positive inotropic effect was detected.
The second section reports studies where calcium channel antagonist
vasodilators were evaluated in hypertension. The cardiovascular effects
of nifedipine were studied at rest and during exercise in hypertensive
patients with and without beta-adrenergic blockade. In contrast to
atenolol, nifedipine reduced peripheral vascular resistance but a
negative inotropic effect was observed. Therefore the newer calcium
antagonist felodipine, which in animal experiments had been shewn to be
selective to the arterial circulation, was examined in patients and the
lack of cardiac depression was confirmed. Following these promising
results a clinical trial comparing felodipine with the most potent
vasodilator available, minoxidil, in severe hypertension was undertaken.
The results indicated that felodipine has an important role in the
treatment of severe hypertension.
This work demonstrates how cardiovascular effects of inotropic agents and
vasodilators can be assessed in intact man. Therapeutic benefit can
only be assessed by adequate clinical trials.