delapril and Cerebrovascular-Disorders

The effects of long-term oral administration of delapril (CAS 83435-67-0), indapamide (CAS 26807-65-8) and their combination on the occurrence of stroke and on mortality were investigated in young salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp) for 31 weeks of treatment (8th-39th week of age) and up to 8 weeks thereafter. Body weight and saline consumption were investigated at regular intervals and cerebrovascular lesions, renal and heart weight were assessed after sacrifice. Untreated SHRsp served as controls. About 50% of control animals died within 6 weeks of saline administration and in 56% of surviving animals cerebral lesions were present at sacrifice, while no death and no cerebral lesions were observed in animals drinking saline, to which delapril, indapamide and their combination had been added, up to the end of treatment. This protective effect was maintained even in the withdrawal period. All treatments induced a highly significant (p < 0.001) reduction of heart weight/body weight and kidney weight/body weight ratios.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Cerebrovascular Disorders; Diuretics; Drug Interactions; Hemodynamics; Hypertension; Indans; Indapamide; Longevity; Male; Organ Size; Rats; Rats, Inbred SHR; Sodium, Dietary

1. Stroke-prone spontaneously hypertensive rats (SHRsp) have been used widely to test agents putatively capable of vascular protection. These animals present an accelerated time course of hypertension and a reduced life-span. When fed a high-sodium diet from the eighth week of life, 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) inhibitors were repeatedly proved to prevent vascular lesions and death. Notably, this effect was independent of any hypotensive effect. On the contrary, diuretics were shown not to be equally effective. A combination of ACE inhibitors and diuretics, although known to have synergistic effects in the therapy of hypertension, has never previously been tested. 2. Our aim was to study the effects of long-term treatment with the ACE inhibitor delapril (12 mg day-1 kg-1), the thiazide-like diuretic 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 were assessed weekly. When control rats reached 50% mortality, they were killed, together with some drug-treated rats, to compare lesions in brain and kidney. The other drug-treated rats continued treatments until 50% mortality was reached in two treatment groups. 3. All drug treatments 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, diuresis and fluid intake that took place 3 weeks after the increase in blood pressure over the initial range. In delapril- or indapamide-treated 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 indapamide did not block the progressive increase in blood pressure as observed 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 we

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Brain; Cerebrovascular Disorders; Diuresis; Drug Therapy, Combination; Indans; Indapamide; Kidney; Male; Proteinuria; Rats; Rats, Inbred SHR; Sodium, Dietary; Time Factors

This study was performed to investigate the beneficial effects of prolonged treatment with an angiotensin converting enzyme (ACE) inhibitor, delapril, on the appearance of symptoms of hypertensive cardiovascular disease in stroke-prone spontaneously hypertensive rats (SHRSP). Cardiovascular disease symptoms: stroke, kidney dysfunction and cardiac hypertrophy, were evaluated by monitoring the incidence of stroke signs, urinary excretion of protein and the heart weight, respectively. The SHRSP that were kept under salt-loaded conditions (1% NaCl drinking solution) from six weeks of age developed severe hypertension, showed an increased incidence of stroke signs and increased urinary excretion of protein. Long-term treatment with delapril (10mg/kg/day, p.o. for four weeks) decreased the blood pressure and completely inhibited the incidence of stroke signs and the increase in urinary excretion of protein. In SHRSP that were kept under normal conditions (without 1% NaCl drinking solution), long term treatment with delapril at the same dose decreased the heart weight and, after five weeks of treatment, left ventricular weight was decreased significantly and the wall/lumen ratio of small coronary arterioles and the thickness of the left ventricular wall were decreased slightly. These results indicate that delapril can prevent the development of symptoms of hypertensive cardiovascular diseases: stroke, kidney dysfunction and cardiac hypertrophy, with antihypertensive activity in SHRSP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomegaly; Cerebrovascular Disorders; Drug Evaluation, Preclinical; Hypertension; Indans; Male; Proteinuria; Rats; Rats, Inbred SHR