Effects of endothelin ETA receptor blocker LU 135252 on cardiac remodeling and survival in a hypertensive rat model of chronic heart failure
Abstract
Aim: To investigate whether the endothelin ETA receptor 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 mgkg-1d-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), increased LVD (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), reduced LVEDP (14±4 mmHg vs 274 mmHg; P<0.05) and improved LV dp/dtmax(4230±450 mmHg/s vs 1950±400 mmHg/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:
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 mgkg-1d-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), increased LVD (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), reduced LVEDP (14±4 mmHg vs 274 mmHg; P<0.05) and improved LV dp/dtmax(4230±450 mmHg/s vs 1950±400 mmHg/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.