Effects of endothelin ETA receptor blocker LU 135252 on cardiac remodeling and survival in a hypertensive rat model of chronic heart failure
Authors: XIA, Qin-gui; REINECKE, Alexander1; DORENKAMP, Marc2; DAEMEN, Mat Jap3; SIMON, Reichiger1; UNGER, Thomas2
Source: Acta Pharmacologica Sinica, Volume 27, Number 11, November 2006 , pp. 1417-1422(6)
Publisher: Blackwell Publishing
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Abstract:
Aim: To investigate whether the endothelin ETAreceptor blocker provides similar benefit on cardiac remodeling and survival in a hypertensive rat model of chronic heart failure (CHF). Methods: Male stroke-prone spontaneously hypertensive (SHR-SP) rats were subjected to permanent ligation of the left coronary artery and were treated for 6 weeks with the endothelin ETA receptor blocker LU 135252 (30 mg-kg−1-d−1) starting 24 h after ligation or untreatment. Sham-operated rats served as normal controls. The mean arterial blood pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular contractility (LV dp/dtmax), left ventricular inner diameter (LVD) and circumference (LVC), septal thickness, left ventricular interstitial collagen content (ICC) and heart weight (HW) were measured at the end of the treatment. Results: Compared with the untreated group, LU 135252 tended to increase HW (1.43 ± 0.03 vs 1.38 ±0.04 g; P<0.05), increasedLVD (7.65±0.24 mm vs 6.58±0.14 mm; P<0.05), markedly increased LVC (30.11±0.83 mm vs 24.82±0.85 mm; P<0.01) and reduced left ventricular ICC (3.79%±0.09%vs 6.71%±0.11%; P<0.01), slightly lowered MAP (132±6 mmHg vs 142±4 mmHg; P>0.05), reducedLVEDP (14 4 mmHgvs 27±4 mmHg; P<0.05) and improved LVdp/dtmax(4230±450mmHg/svs 1950±400mmHg/s;P<0.05); survival was not prolonged significantly (13%vs 11%; P=NS). Conclusion: In this hypertensive rat model of CHF, chronic endothelin ETA receptor blockade with LU 135252 improves cardiac hemodynamics, however, it does not affect long-term survival and worsens cardiac remodeling. Thus, endothelin ETA receptor antagonists are unlikely to have an important role in the management of patients with CHF.Keywords: myocardial infarction; heart failure; endothelin ETA receptor antagonism; LU 135252; cardiac remodeling; ventricular function; SHR-SP rats
Document Type: Research article
DOI: 10.1111/j.1745-7254.2006.00447.x
Affiliations: 1: Clinic of Cardiology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany 2: Institute of Pharmacology, Christian-Albrechts University of Kiel, 24105 Kiel, Germany 3: Department of Pathology, University of Maastricht, Maastricht, the Netherlands
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