Diproteverine (BRL 40015): a new type of calcium antagonist with potential antianginal properties.
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.
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Les Laboratoires Beecham, Unité de Recherches, B.P. 58, St.-Grégoire, France.
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D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers; D003714:Denervation; D004285:Dogs; D005260:Female; D006321:Heart / Q000294:innervation; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010208:Papaverine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors; D051381:Rats; D012756:Sheep
D002121:Calcium Channel Blockers; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; C049847:diproteverine; D010208:Papaverine