Comparative effects of the dual ACE–NEP inhibitor MDL-100,240 and ramipril on hypertension and cardiovascular disease in endogenous angiotensin II-dependent hypertension

Abstract

We investigated the effects of MDL-100,240 in a transgenic rat model (TGRen2) of hypertension with severe cardiovascular damage (CVD) due to enhanced tissue synthesis of angiotensin II (Ang II). Male heterozygous TGRen2 rats (5 weeks old) were allocated to receive MDL-100,240, ramipril (RAM) or placebo (PLAC) for 4 weeks, during which blood pressure (BP) was measured. We then evaluated: 1) left ventricle (LV) and right ventricle (RV), brain, kidney and adrenals weight; 2) structural changes in the aorta and the mesenteric arterioles wall; 3) tension responses of segments of the aorta to phenylephrine, KCl, and endothelin-1; and 4) creatinine, aldosterone, atrial natriuretic peptide (ANP), and cyclic GMP (cGMP) plasma levels. Compared to PLAC, both MDL-100,240 and RAM significantly ( P < .001) lowered BP (after 4 weeks: 255 ± 15 mm Hg PLAC, v 174 ± 6 MDL-100,240, v 166 ± 5 RAM). They hindered LV hypertrophy (3.73 ± 0.25 mg/g body weight (PLAC) v 2.71 ± 0.22 (MDL-100,240) P < .001; v 2.36 ± 0.2 (RAM), P < .001). MDL-100,240 also prevented aortic dilatation and hypertrophy of the mesenteric arterioles (media thickness, 25.3 ± 0.5 μm PLAC, v 21.1 ± 0.9 MDL-100,240, P < .007; v 20.2 ± 1.5 RAM, P = .033) and lowered the tension responses to phenylephrine ( P < .01), KCl ( P < .01), and endothelin-1 ( P < .001). Plasma aldosterone (710 ± 153 pmol/L PLAC, v 237 ± 61 MDL-100,240, v 180 ± 22 RAM) and creatinine levels (0.69 ± 0.33 mg/dL PLAC, v 0.41 ± 0.02 MDL-100,240, v 0.41 ± 0.04 RAM) were also decreased ( P ≤ .001). Compared to PLAC, plasma ANP levels were 11% and 2.4% higher in MDL-100,240 and RAM, respectively (both P = not significant); cGMP levels were unaffected. Thus, severe hypertension and related CVD were regressed by MDL-100,240, which resulted to be as effective as a full dosage of ramipril in TGRen2.