We previously reported that
CGS 35601, a potent triple inhibitor of
angiotensin-converting enzyme,
neutral endopeptidase, and
endothelin-converting enzyme 1, completely normalized mean arterial blood pressure (MABP) in 36-week-old spontaneously hypertensive rats, a normal
renin model. The aim of the present study was to determine the effects of this triple
vasopeptidase inhibitor (VPI) on the hemodynamic profile of instrumented, conscious, and unrestrained Dahl
salt-sensitive (DSS) rats, a gene-prone, high-
salt diet-induced low-
renin hypertension model. Male DSS rats (mean weight [+/-SEM], 385 +/- 10 g) were fed a normal diet (Group 1) or a high-
salt diet (Groups 2 and 3; 8% NaCl in food) for 6 weeks and then instrumented with a carotid
catheter and placed individually in metabolic cages for 30 days. The hemodynamic, hematological, and biochemical profiles were assessed daily. Dose-dependent treatment started after a 7-day stabilization period in Groups 1 and 2 (vehicle dosage, 250 microl/hr) and Group 3 (
CGS 35601 dosages of 0.1, 1, and 5 mg/kg/day for 6 days per dose by means of constant
intra-arterial infusion), followed by a 5-day washout period. Two additional groups included normotensive Wistar rats (Group 4) and DSS rats that received a double high-
salt solid (8% NaCl) and liquid (1% NaCl) diet (Group 5). The MABP in rats receiving
CGS 35601 decreased in a dose-dependent fashion toward the baseline level observed in DSS rats receiving a normal diet. The heart rate was unaffected. The hemodynamic profile returned to normal during the washout period. This novel triple VPI is a potent and effective
antihypertensive agent with a safe short-term profile that may be of interest for treating
hypertension and other
cardiovascular diseases. Other hypertensive rat models are being tested.