PROTECTIVE EFFECTS OF DELAPRIL, INDAPAMIDE AND THEIR COMBINATION CHRONICALLY ADMINISTERED TO STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS FED A HIGH-SODIUM DIET

1. Stroke-prone spontaneously hypertensive rats (SHRsp) have been used widely to test agents putatively capable of vascular protection. Thes e animals present an accelerated time course of hypertension and a red uced life-span. When fed a high-sodium diet from the eighth week of li fe, a further acceleration in blood pressure increase is obtained, and rats start to die after 5 weeks of diet as a consequence of cerebral haemorrhage. In this model, angiotensin-converting enzyme (ACE) inhibi tors were repeatedly proved to prevent vascular lesions and death. Not ably, this effect was independent of any hypotensive effect. On the co ntrary, diuretics were shown not to be equally effective. A combinatio n of ACE inhibitors and diuretics, although known to have synergistic effects in the therapy of hypertension, has never previously been test ed. 2. Our aim was to study the effects of long-term treatment with th e ACE inhibitor delapril (12 mg day(-1) kg(-1)), the thiazide-like diu retic indapamide (1 mg day(-1) kg(-1)), and their combination (12 and 1 mg day(-1) kg(-1) respectively), on the survival of SHRsp rats fed a high-sodium diet from the eighth week of life onwards. The effects of the treatments on blood pressure, body weight, food and fluid intake, diuresis, proteinuria and the appearance of lesion signs and death we re assessed weekly When control rats reached 50% mortality, they were killed, together with some drug-treated rats, to compare lesions in br ain and kidney. The other drug-treated rats continued treatments until 50% mortality was reached in two treatment groups. 3. All drug treatm ents were able to delay death significantly when compared with control rats, which reached 50% mortality after 6 weeks of salt loading. This event was preceded by a highly significant increase in proteinuria, d iuresis and fluid intake that took place 3 weeks after the increase in blood pressure over the initial range. In delapril-or indapamide-trea ted SHRsp these changes were never seen, even when animals started to die. In the combination-treated group, a significant increase (P<0.01) in fluid intake and diuresis, but not proteinuria, was observed from the third week of treatment onwards. 4. Treatment with delapril or ind apamide did not block the progressive increase in blood pressure as ob served in control animals. However, the increase in blood pressure was markedly retarded with respect to control rats. At variance with this , in combination-treated animals blood pressure levels were maintained until the end of the experiment within the 99% confidence interval in itially observed in control animals. 5. Infarctual and haemorrhagic ce rebral lesions were observed in 38% of control rats; no lesions were n oted in brains of age-matched rats receiving a drug treatment. Kidneys from control animals presented major degenerative lesions of glomerul i and arteries, characterized by fibrinoid necrosis. This condition wa s absent in drug-treated animals, which presented minor signs of ischa emic lesion. Heart hypertrophy when heart weight was expressed as a pe rcentage of body weight, was similar in saline-, delapril-or indapamid e-treated rats. At variance with this, in combination-treated animals the heart weight to body weight ratio was significantly (P<0.01) lower than in the other groups. 6. In conclusion, the diuretic indapamide s howed similar protective effects as the ACE inhibitor delapril on acut e vascular lesions and survival of SHRsp. Moreover, their combination synergized in preventing heart hypertrophy consequent to long-term hyp ertension. This result is probably related to the enhanced diuresis an d the better control of blood pressure levels selectively found in com bination-treated animals.