Effects of the ECE/NEP inhibitor CGS 34225 on the big ET-1-induced pressor response and plasma atrial natriuretic peptide concentration in conscious rats

Abstract

CGS 34226 is a thiol-containing, potent dual inhibitor of endothelin converting enzyme-1 (ECE-1) and neutral endopeptidase 24.11 (NEP) with IC50 values of 11 and 5nM respectively. The purpose of the present study was to characterize the inhibitory effects of CGS 34225, an orally active prodrug of CGS 34226, on ECE-1 and NEP in vivo. The effects on ECE-1 and NEP were assessed by determining the inhibition of big endothelin-1 (big ET-1)-induced increases in mean arterial pressure (MAP) and increases in plasma atrial natriuretic peptide (ANP) concentrations respectively, in conscious rats. Thirty and 120min after the administration of vehicle, big ET-1 (0.3nmol/kg, intravenously; i.v.) produced pressor responses of approximately 800mmHg·min (area under the curve for change in MAP×time). Treatment with CGS 34225 at 1mgEq/kg, per os (p.o.), decreased the pressor effect of big ET-1 by 39 and 53% at 30 and 120min respectively (P<0.05, both times). Increasing the dose of CGS 34255 to 30mgEq/kg, p.o., resulted in greater inhibition, 84 and 92% (P<0.05) at 30 and 120min respectively. Furthermore, at this higher dose, the inhibitory effect on ECE-1 was long-lasting, averaging 86, 75 and 30% (P<0.05, all times) at 4, 8 and 24h respectively. In rats treated with vehicle, the infusion of ANP at 450ng/kg per min i.v. resulted in plasma ANP concentrations of 3.9–4.8ng/ml that remained relatively constant for 4h. Treatment with CGS 34225 at 10mgEq/kg, p.o., increased the ANP level to 7.7±1.0 and 10.6±1.8ng/ml at 1 and 4h after dosing (P<0.05, both times). These data demonstrate that CGS 34225 is a potent, orally active and long-acting inhibitor of ECE-1 and NEP in vivo. It is anticipated that compounds with this dual function may be useful in the treatment of cardiovascular diseases where the ET system plays a pathogenic role and the potentiation of ANP elicits therapeutic benefits.