Reversal of cardiac hypertrophy and fibrosis by S21402, a dual inhibitor of neutral endopeptidase and angiotensin converting enzyme in SHRs.

Abstract

The major advantage of dual inhibitors of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) is their ability to lower blood pressure irrespective of renin or volume status. The aim of this study was to determine whether dual NEP/ACE inhibition produces different effects on cardiovascular structure and fibrosis, hormonal parameters and inhibition of tissue enzymes compared with selective inhibition of ACE and NEP in the spontaneously hypertensive rat (SHR). Male SHRs received the dual NEP/ACE inhibitor (S21402, 100 mg/kg per day), the ACE inhibitor (captopril, 50 mg/kg per day), the NEP inhibitor (SCH42495, 60 mg/kg per day) or vehicle for 2 weeks. S21402 produced equivalent blood pressure lowering effects to captopril (vehicle, 220 +/- 1 mmHg; S21402, 189 +/- 2 mmHg; captopril, 187 +/- 3 mmHg), but was a more effective antihypertensive agent than SCH42495 (214 +/- 2 mmHg, P< 0.01). All treatments reduced left ventricular mass (P< 0.05) and cardiac fibrosis (P< 0.01). S21402 inhibited renal NEP and ACE (P< 0.01), SCH42495 inhibited renal NEP (P < 0.01), and captopril inhibited renal ACE (P< 0.01). Captopril and S21402 increased plasma renin activity (P< 0.05), but the rise with S21402 was attenuated compared with that caused by captopril (P< 0.01). All treatments reduced plasma aldosterone levels (P< 0.01), and NEP inhibition with SCH42495 and S21402 increased plasma atrial natriuretic peptide (ANP; P< 0.05). These results indicate that selective NEP inhibition has major benefits in the regression of cardiac hypertrophy and reduction of fibrosis but has limited antihypertensive effects. The dual NEP/ACE inhibitor S21402 offered no advantage over the selective ACE inhibitor in terms of blood pressure reduction, or attenuation of cardiac hypertrophy and fibrosis, but did increase plasma ANP and blunted the reactive rise in renin with ACE inhibition. Further studies are needed to determine whether more complete blockade of the renin-angiotensin system with dual NEP/ACE inhibition results in additional benefits in terms of morbidity and mortality in cardiovascular disease.