Captopril-furosemide survival study in experimental heart failure.

The strategy of diuretic drug administration remains to be defined in heart failure as experimental and clinical evidence have clearly established the benefit of neurohormonal blockade. The impact of addition of diuretic treatment to angiotensin-converting enzyme inhibition on survival remains to be demonstrated. The objectives of the study were to evaluate cardiovascular and renal effects of addition of diuretic treatment to captopril (2 g/L, in drinking water), on survival, on the experimental model of heart failure. Rats were followed for 10 months after coronary ligation. Echocardiographic, hemodynamic, morphometry and renal function investigations were then performed on surviving rats. Survival (from 34 to 61%), diuresis and natriuresis were significantly improved compared to control group only in animals treated with a combination of captopril + furosemide. In treated group: cardiac dimensions were reduced with left ventricular fractional shortening significantly increased in combination group (from 22.4 to 28%); captopril + furosemide animals had highest heart rate and lowest systolic and diastolic blood pressures; body and heart weight were reduced, but kidney weight was significantly increased with furosemide (1.7 g in control vs. 2 g in capto + furo); plasma renin activity and angiotensin 1 were greatly increased, and moderately stimulated in control. In conclusion, this combination of drugs significantly improved cardiac remodeling and survival of animals, increased diuresis and natriuresis despite stimulation of plasma renin activity and kidney hypertrophy.

Inhibition of catecholamine-induced cardiac fibrosis by an aldosterone antagonist.

In heart failure, the renin-angiotensin-aldosterone and the sympathetic systems are overactivated and lead to formation of cardiac fibrosis, which contributes to the aggravation of cardiac function. The aim of the present study was to evaluate the role of aldosterone and angiotensin II on formation of left ventricular fibrosis induced by chronic beta-adrenergic stimulation with isoproterenol (iso) in the rat heart failure model induced by myocardial infarction (MI). Rats were submitted to chronic treatment with either the aldosterone receptor antagonist potassium canrenoate (pc, 20 mg/kg/d) or both aldosterone and angiotensin II receptor antagonists with addition of losartan (los, 10 mg/kg/d). Isoproterenol induced cardiac hypertrophy, which was completely inhibited by potassium canrenoate alone in atria and by potassium canrenoate plus losartan in infarcted ventricles. Isoproterenol also induced cardiac fibrosis, which was completely inhibited in infarcted rats by potassium canrenoate alone in right and left ventricles. In left ventricle, extent of fibrosis was, for control MI, 1.30 +/- 0.34%; MI + iso, 2.50 +/- 0.27%; MI + iso + pc, 0.82 +/- 0.11%; and MI + iso + pc + los, 1.47 +/- 0.31%. The deleterious effects of beta-adrenoceptor stimulation on cardiac fibrosis seem therefore to involve aldosterone action. These results suggest a transregulation between the adrenergic and mineralocorticoid pathways, most likely at the nucleus level, with activation of profibrotic genes.

Cytotoxic effects of kinetin riboside on mouse, human and plant tumour cells.

The cytotoxicity of two plant hormone compounds, kinetin and kinetin riboside, was studied on tumour cells, by colony forming assay with increased amount of cytotoxic molecules. The concentration of inhibitor required to reduce cell growth to 50% was determined for these molecules. Kinetin riboside was shown to only act on M4 Beu human and B16 murine melanoma cells at low concentration (1.5 and 0.2 microM). On mice with leukaemia P388, this product has no effect on the tumour growth, and it appears to be toxic at the dose of 25 mg/kg. Kinetin riboside was also shown to have a cytotoxic effect on plant tumour cells (crown-gall).

Potassium canrenoate, an aldosterone receptor antagonist, reduces isoprenaline-induced cardiac fibrosis in the rat.

The purpose of the present study was to determine whether the administration of an antagonist of aldosterone could prevent the fibrosis induced by an acute injection of isoprenaline. Male Wistar rats were submitted to one subcutaneous injection of isoprenaline (400 mg/kg) and were simultaneously treated with potassium canrenoate in drinking water (20 mg/kg/day) started 5 days before the injection of isoprenaline. Two months later, echocardiographic and hemodynamic measurements were performed. Then, the heart was prepared for morphometric histology and quantification of fibrosis in the left ventricle. Heart and left ventricular weights were increased significantly by isoprenaline. Potassium canrenoate attenuated this increase. The administration of isoprenaline increased significantly end diastolic diameter and end systolic volume compared with control. These changes were increased further with the addition of potassium canrenoate. In contrast, the fibrosis induced by isoprenaline was reduced significantly by potassium canrenoate at the three section levels. Potassium canrenoate attenuated the fibrosis but not the enhanced dilatation of the left ventricle induced by isoprenaline.