EFFECTS OF THE NOVEL DUAL INHIBITOR OF NEUTRAL ENDOPEPTIDASE AND ANGIOTENSIN-CONVERTING ENZYME, CGS-30440, ON BLOOD-PRESSURE AND CARDIAC-HYPERTROPHY IN SPONTANEOUSLY HYPERTENSIVE RATS

This study examined the long-term effects of CGS 30440 on blood pressu re, heart rate, cardiac hypertrophy, and urinary parameters in conscio us spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Initial studies with CGS 30440 produced dose-related reductions in me an arterial pressure, with a dose of 30 mg/kg/day of CGS 30440 produci ng a maximal sustained response of 40 mm Hg. CGS 30440 significantly i nhibited plasma angiotensin-converting enzyme (ACE) activity by 82% in WKY rats. In SHRs, lung ACE and renal neutral endopeptidase (NEP) wer e inhibited by >60 and >90%, respectively. Urinary cyclic guanosine mo nophosphate (cGMP) excretion was significantly increased by CGS 30440 in SHRs but was unaltered in WKY rats. One hour after the final dose o f an 8-week regimen, blood pressure was 122 +/- 4 and 189 +/- 5 mm Hg in CGS 30440-treated (30 mg/kg/day) and vehicle-treated SHRs, respecti vely. Heart-rate responses were not different between treatment groups . Left ventricular hypertrophy (LV weight/body weight ratio) was reduc ed significantly in SHRs to 2.45 +/- 0.08 mg/g at 10 mg/kg/day and 2.2 6 +/- 0.07 mg/g at 30 mg/kg/day versus 2.91 +/- 0.09 mg/g in rats rece iving only vehicle. These results demonstrate that CGS 30440 is a pote nt, orally active antihypertensive agent with a long duration of actio n. The cardiac hypertrophy of established hypertension in the SHRs was attenuated by CGS 30440. Thus CGS 30440, an orally active prodrug, ha s been shown to be a novel antihypertensive agent with dual ACE/NEP in hibitory activity in SHRs.