双重ACE-NEP抑制剂MDL-100,240与雷米普利对内源性血管紧张素II依赖性高血压患者高血压及心血管疾病的比较作用

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

作者信息

Rossi Gian Paolo, Bova Sergio, Sacchetto Alfredo, Rizzoni Damiano, Agabiti-Rosei Enrico, Neri Giuliano, Nussdorfer Gastone G, Pessina Achille C

机构信息

Department of Clinical and Experimental Medicine--Clinica Medica 4, University of Padova, University Hospital, Italy.

出版信息

Am J Hypertens. 2002 Feb;15(2 Pt 1):181-8. doi: 10.1016/s0895-7061(01)02278-6.

DOI:10.1016/s0895-7061(01)02278-6

PMID:11863255

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 microm 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 < or = .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.

摘要

我们在因血管紧张素II（Ang II）组织合成增强而导致严重心血管损伤（CVD）的高血压转基因大鼠模型（TGRen2）中研究了MDL - 100,240的作用。将雄性杂合子TGRen2大鼠（5周龄）分配接受MDL - 100,240、雷米普利（RAM）或安慰剂（PLAC）治疗4周，在此期间测量血压（BP）。然后我们评估：1）左心室（LV）和右心室（RV）、脑、肾和肾上腺重量；2）主动脉和肠系膜小动脉壁的结构变化；3）主动脉节段对去氧肾上腺素、氯化钾和内皮素 - 1的张力反应；4）肌酐、醛固酮、心房利钠肽（ANP）和环磷酸鸟苷（cGMP）的血浆水平。与PLAC相比，MDL - 100,240和RAM均显著（P <.001）降低了血压（4周后：PLAC为255±15 mmHg，MDL - 100,240为174±6，RAM为166±5）。它们抑制了左心室肥厚（PLAC为3.73±0.25 mg/g体重，MDL - 100,240为2.71±0.22，P <.001；RAM为2.36±0.2，P <.001）。MDL - 100,240还预防了主动脉扩张和肠系膜小动脉肥厚（中膜厚度，PLAC为25.3±0.5微米，MDL - 100,240为21.1±0.9，P <.007；RAM为20.2±1.5，P =.033），并降低了对去氧肾上腺素（P <.01）、氯化钾（P <.01）和内皮素 - 1（P <.001）的张力反应。血浆醛固酮（PLAC为710±153 pmol/L，MDL - 100,240为237±61，RAM为180±22）和肌酐水平（PLAC为0.69±0.33 mg/dL，MDL - 100,240为0.41±0.02，RAM为0.41±0.04）也降低了（P≤.001）。与PLAC相比，MDL - 100,240和RAM的血浆ANP水平分别高11%和2.4%（两者P均无统计学意义）；cGMP水平未受影响。因此，MDL - 100,240使严重高血压及相关CVD得到缓解，其在TGRen2中与全剂量雷米普利的效果相当。