Preclinical considerations and results with the combination of verapamil and trandolapril: blood pressure reduction and beyond.

Preclinical studies were designed to investigate whether the combination of verapamil and trandolapril was more potent than either drug alone for the treatment of hypertension and concomitant cardiovascular or metabolic diseases. In spontaneously hypertensive rats (SHR) oral treatment with the combination of verapamil plus trandolapril not only significantly reduced elevated blood pressure for 24 h but, after terminating treatment, the antihypertensive effect lasted longer than 48 h, indicating potentiation of each compound's effect. In stroke-prone SHR, life-long oral treatment with low doses of verapamil, trandolapril or their combination significantly prolonged life in each case, but results obtained with the combination were additive compared with monotherapy. In an animal model of non-insulin-dependent diabetes, the obese Zucker rat, 2 weeks oral treatment with verapamil, trandolapril or both combined significantly improved leukocyte rheology, but only the combination treatment normalized the microcirculation. In insulin-dependent diabetes (streptozotocin-induced) in SHR, oral treatment with the combination for 12 weeks additively reduced blood pressure and totally normalized proteinuria and albuminuria. Verapamil was least effective. Trandolapril showed intermediate protection against insulin-dependent diabetes-related renal failure. In SHR, almost in parallel with the progression of hypertension, progressive renal failure develops, as indicated by increasing proteinuria and albuminuria. With lifelong treatment in these rats, verapamil + trandolapril combined inhibited the progression towards end-stage renal failure more effectively than either compound used as monotherapy and also significantly prolonged survival. In a second study, in older rats with hypertension and proteinuria, chronic treatment with the combination reduced renal insufficiency in parallel with a reduction in glomerulosclerosis independently of a blood pressure reduction and significantly more potently than each drug alone. In pigs subjected to consecutive left anterior descending artery occlusions, intravenous verapamil dose-dependently reduced ischaemic myocardial K+ loss. Trandolapril alone was ineffective. Combining two ineffective doses (0.02 mg/kg verapamil plus 0.1 mg/kg trandolapril) led to a significant, additive reduction in extracellular K+ concentrations during ischaemia. Combined intracoronary application of 0.5 mg/kg trandolapril and 0.1 mg/kg verapamil before occlusion in dogs improved myocardial contractility 3 h after reperfusion to a greater extent than monotherapy and reduced the incidence of reperfusion arrhythmias. In dogs exposed to hypoxaemia after ischaemic reperfusion injury, paradoxical coronary constriction was observed. Treatment with trandolapril (0.05 mg/kg) plus verapamil (0.1 mg/kg) inhibited this vasoconstriction in response to repeated hypoxia. In anaesthetized dogs, cyclic coronary flow reductions were induced. Trandolapril reduced these by 70-80% from a dose of 0.1 mg/kg onwards. Verapamil (0.2 mg/kg) had no effect. Combining ineffective doses of trandolapril (0.05 mg/kg) and verapamil (0.1 mg/kg) led to a 70% fall in the flow reductions. Further experiments using either the bradykinin B2 antagonist HOE 140 or the angiotensin II AT1-receptor antagonist Exp 3174 showed that this effect was not mediated by increases in bradykinin levels but by a decrease in angiotensin II. Two weeks after occlusion of the left anterior descending artery, surviving rats were randomly allocated to no treatment or to verapamil at 20 or 40 mg/kg per day or to trandolapril at 0.3 or 0.7 mg/kg per day or to combinations of both drugs, orally for 24 weeks. (ABSTRACT TRUNCATED)