Dual inhibition of ACE and NEP provides greater cardioprotection in mice with heart failure.

Abstract

BACKGROUND:

Vasopeptidase inhibitors (VPi) may provide a new means of treating hypertension and congestive heart failure, because they simultaneously block angiotensin-converting enzyme (ACE) and neutral endopeptidase-24.11 (NEP-24.11), thereby inhibiting the renin-angiotensin system and enhancing vasodilator and natriuretic substances such as kinins and natriuretic peptides.

METHODS:

Using B(2) kinin receptor gene knockout mice (B(2)-/-), we tested the hypotheses that (1) VPi may provide better cardioprotection than ACE or NEP inhibitors alone (ACEi and NEPi) and (2) the effects of these inhibitors are partially mediated by kinins. Four weeks after myocardial infarction, B(2)-/- mice and B(2)+/+ mice were started on vehicle, ACEi (ramipril, 2.5 mg/kg/d), NEPi (candoxatril, 20 mg/kg/d) or VPi (omapatrilat, 50 mg/kg/d), which was continued for 20 weeks. Systolic blood pressure was measured weekly and cardiac function evaluated monthly by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were measured histopathologically.

RESULTS:

We found that ACEi or NEPi improved cardiac function and remodeling and that these effects were more obvious in mice receiving VPi. Furthermore, the beneficial cardiac effects of ACEi, NEPi, and VPi were significantly attenuated in B(2)-/- mice. We concluded that dual inhibition of ACE and NEP with VPi provides better cardioprotection than ACEi or NEPi alone in mice with congestive heart failure induced by myocardial infarction, and these effects are mediated at least in part via kinins.

• Authors: Jiang Xu, Oscar A Carretero, Yun-He Liu, Fang Yang, Edward G Shesely, Nancy Oja-Tebbe, Xiao-Ping Yang
• Journal: Journal of cardiac failure (J Card Fail) Vol. 10 Issue 1 Pg. 83-9 (Feb 2004) ISSN: 1071-9164 [Print] United States
• PMID: 14966779 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Antihypertensive Agents
• Indans
• Propionates
• Pyridines
• Thiazepines
• omapatrilat
• Collagen
• candoxatril
• Neprilysin
• Ramipril

Topics

• Angiotensin-Converting Enzyme Inhibitors (pharmacology, therapeutic use)
• Animals
• Antihypertensive Agents (pharmacology, therapeutic use)
• Collagen (metabolism)
• Disease Models, Animal
• Echocardiography
• Heart (anatomy & histology, drug effects)
• Heart Failure (drug therapy)
• Indans (pharmacology, therapeutic use)
• Liver (drug effects, pathology)
• Lung (drug effects, pathology)
• Mice
• Mice, Knockout
• Muscle Cells (drug effects, pathology)
• Neprilysin (antagonists & inhibitors)
• Organ Size (drug effects)
• Propionates (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Ramipril (pharmacology, therapeutic use)
• Thiazepines (pharmacology, therapeutic use)
• Treatment Outcome
• Ventricular Function, Left (drug effects)
• Ventricular Remodeling (drug effects)