BENEFICIAL-EFFECTS OF DILTIAZEM ON THE NATURAL-HISTORY OF HYPERTENSIVE DIABETIC CARDIOMYOPATHY IN RATS

Hypertensive diabetic rats develop a cardiomyopathy characterized by systolic and diastolic ventricular dysfunction, myocardial hypertrophy and fibrosis, pulmonary congestion and a very high mortality rate. Alterations in contractile proteins and sarcoplasmic reticular calcium (Ca2+) transport in diabetic myocardium and their partial reversal with verapamil suggest that calcium channel blockade may prevent death from congestive heart failure in hypertensive diabetic rats. A large group of rats with renovascular hypertension and streptozotocin diabetes were divided into four groups: untreated animals (Group 1) and animals treated with 100 (Group 2), 300 (Group 3) or 600 (Group 4) mg/kg per day of sustained release diltiazem mixed in their food. Treatment was begun shortly after the onset of hypertension and diabetes. Mortality rates after 4 months were 59% (19 of 32), 53% (17 of 32), 27% (7 of 26) and 35% (12 of 34) in Groups 1, 2, 3 and 4, respectively; the mortality rate in age-matched control rats was 5% (1 of 19). The reductions in mortality rates in Groups 3 and 4 were statistically significant. Diltiazem did not change systolic blood pressure, serum glucose concentration, heart rate or left ventricular mass. There was a trend to decreased left ventricular interstitial fibrosis and perivascular fibrosis in diltiazem-treated animals. Ventricular collagen concentration was similar in untreated hypertensive diabetic and control rats; levels were higher in hypertensive diabetic rats that died than in those that survived. There was a trend to decreased collagen concentration as diltiazem dose increased. Myosin isoenzyme distribution was not changed in Groups 3 and 4 (in comparison with Group 1). In all hypertensive diabetic groups, rats that died had a higher blood pressure, heart rate, relative left ventricular mass, lung weight and lung water than did survivors. The mortality rate was two to three times higher among rats with an initial blood pressure greater-than-or-equal-to 180 mm Hg. The beneficial effects of diltiazem on survival were most significant among rats with severe hypertension.