The
calcium channel-blocking activity and associated cardiovascular effects of
diproteverine, a novel compound derived from
papaverine, were investigated. Electrophysiological measurements in sheep Purkinje fibres showed
diproteverine to reduce the amplitude of the slow action potential (IC30 = 2 microM) and to shorten the duration of the fast action potential at 50% repolarisation (IC30 = 2.5 microM). Higher concentrations (4-5 times) were required to block block the
sodium channel, as assessed by a reduction in Vmax of the fast action potential.
Papaverine was found to possess marginal
membrane channel-blocking activity and to be much more potent than
diproteverine as a
cAMP-phosphodiesterase inhibitor. The most significant haemodynamic property of
diproteverine, seen in anaesthetised dogs and conscious dogs pretreated with
atropine, was to cause a reduction in heart rate. This appeared to be a particular feature of
diproteverine as the other
calcium antagonists studied produced either a smaller decrease in heart rate or
tachycardia as a reflex response to
hypotension. In a chronic
myocardial infarct model in dogs,
diproteverine caused a redistribution of the available coronary blood flow, to the benefit of an ischaemic area of the myocardium.
Diproteverine resembled
diltiazem in its effects on coronary blood flow, with both these agents being preferable to
nifedipine and
verapamil, which caused coronary steal in this model. The combination of the reduction in heart rate, to lower cardiac
oxygen demand, with the beneficial action on coronary blood flow should result in
diproteverine being particularly beneficial for the treatment of
angina pectoris.