Jean-Paul Clozel

Short-Term Endothelin Receptor Blockade With Tezosentan Has Both Immediate and Long-Term Beneficial Effects in Rats With Myocardial Infarction

OBJECTIVES We investigated the effects of short-term tezosentan treatment on cardiac function, pulmonary edema and long-term evolution of heart failure (HF) in a rat model of myocardial infarction (MI). BACKGROUND Endothelin (ET) may play a major role in the progression from MI to HF. Tezosentan is a new dual ET(A)/ET(B) receptor antagonist. METHODS Rats were subjected to coronary artery ligation and were treated with either vehicle or tezosentan (10 mg/kg IV bolus) at 1 h and 24 h after MI. Cardiac hemodynamics and lung weight were measured at 48 h after MI. Survival was assessed over a five-month period. RESULTS At 48 h after ligation, vehicle-treated rats developed HF, as evidenced by a marked increase in left ventricular end-diastolic pressure (LVEDP), reduction in dP/dt(max) and mean arterial pressure (MAP), and development of pulmonary edema. Tezosentan treatment attenuated the increase in LVEDP and in lung weight and slightly reduced MAP without affecting dP/dt(max). Infarct size was not modified by tezosentan. Despite the fact that treatment with tezosentan was stopped after 24 h, the initial tezosentan administration significantly reduced cardiac hypertrophy (22%) and decreased mortality by 51% at five months (50% survival vs. 19% survival in vehicle-treated rats, p < 0.001). CONCLUSIONS Tezosentan administered during the first day after MI in rats, in addition to improving acutely hemodynamic conditions, markedly increases long-term survival. This increase is associated with a decrease of pulmonary edema and prevention of cardiac hypertrophy. Tezosentan could be a safe and useful therapeutic agent in the prevention and treatment of ischemic HF.

Chronic endothelin receptor blockade prevents renal vasoconstriction and sodium retention in rats with chronic heart failure

OBJECTIVE Importance of endothelin in mediating the chronic renal alterations of chronic heart failure was studied in rats chronically treated with bosentan after myocardial infarction. METHODS Rats were subjected to coronary artery ligation and were treated for 8 weeks with placebo or bosentan, a dual ET(A) and ET(B) receptor antagonist, (approximately 100 mg/kg/day) as food admix. Sham-operated rats served as normal controls. Cardiac and renal functions were measured at the end of 8-week treatment. RESULTS Bosentan significantly reduced the elevated left ventricular end-diastolic pressure (from 26.6+/-3.3 to 11.4+/-2.2 mmHg, P<0.001) and the increased heart-to-body-weight ratio seen in untreated rats with myocardial infarction. Bosentan prevented the marked increase in renal vascular resistance (bosentan, 7.7+/-0.6; untreated, 15.6+/-2.5 mmHg/ml/min; P<0.001). This led to a significant increase in renal plasma flow resulting in a decrease in filtration fraction. Bosentan furthermore increased urinary sodium excretion. CONCLUSIONS Prolonged ET receptor blockade in rats with myocardial infarction has chronic renal vasodilatory effect and improves renal sodium excretory function. Thus, dual ET antagonists such as bosentan might be useful in the treatment of the progressive renal failure associated with human chronic heart failure.

Combination of non-hypotensive doses of valsartan and enalapril improves survival of spontaneously hypertensive rats with endothelial dysfunction

There is increasing evidence to suggest endothelial dysfunction as a critical factor in vascular diseases. Genetically predisposed spontaneously hypertensive rats (SHR) treated with inhibitors of nitric oxide (NO) synthase, develop a severe hypertensive nephrosclerosis without the necessity for surgical reduction in renal mass, nephrectomy, renal infarction or nephrotoxic drugs. In these animals, endothelial dysfunction is considered a valid model for assessment of the efficacy of cardiovascular therapy. SHR were treated with either the angiotensin-converting enzyme inhibitor enalapril or the angiotensin II (Ang II) AT1-receptor antagonist (AIIA) valsartan at sub-hypotensive doses and the effects on survival rates, cardiac and renal changes were monitored. Rats treated with valsartan, alone or in combination with enalapril, showed markedly higher survival rates (67—85%, respectively) than untreated animals (37%) or those treated with enalapril alone (55%). Valsartan at a dose which attenuated blood pressure increase led to even greater survival rates (95%). Despite these improved survival rates, at non-hypotensive doses the drugs had no effect on histological appearance, nor was kidney function improved. Plasma creatinine levels were reduced by valsartan, alone or in combination with enalapril, but proteinuria persisted with all treatments over the 12 weeks of the study. Aldosterone levels were significantly reduced by all treatments. The results suggest a beneficial role for endothelium in hypertension. Reduced renal perfusion pressure probably underlies the beneficial renal effects of high-dose valsartan.