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Effects of endothelin ETA receptor blocker LU 135252 on cardiac remod-eling and survival in a hypertensive rat model of chronic heart failure

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Acta Pharmacologica Sinica 2006年第11期27卷 1417-1422页

作者： alexander reinecke Marc DORENKAMP Mat Jap DAEMEN Reichiger SIMON Thomas UNGER Clinic of Cardiology Christian-Albrechts-University of Kiel24105 KielGermany Institute of Pharmacology Christian-Albrechts University of Kiel24105 KielGermany Department of Pathology University of MaastrichtMaastrichtthe Netherlands

Aim:To investigate whether the endothelin ETAreceptor blocker provides similarbenefit on cardiac remodeling and survival in a hypertensive rat model of chronicheart failure（CHF）.Methods:Male stroke-prone spontaneously hypertensive（SHR-SP）rats were subjected to permanent ligation of the left coronary artery andwere treated for 6 weeks with the endothelin ETAreceptor blocker LU 135252(***-1.d-1)starting 24 h after ligation or ***-operated rats servedas normal *** mean arterial blood pressure（MAP）,heart rate（HR）,leftventricular end-diastolic pressure（LVEDP）,left ventricular contractility(LVdp/dtmax),left ventricular inner diameter（LVD）and circumference（LVC）,septalthickness,left ventricular interstitial collagen content（ICC）and heart weight（HW）were measured at the end of the ***:Compared with the untreatedgroup,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;P0.05）,reduced LVEDP（144mmHg vs 27±4 mmHg;P<0.05）andimproved LV dp/dtmax（4230±450 mmHg/s vs 1950±400 mmHg/s;P<0.05）;survivalwas not prolonged significantly（13% vs 11%;P=NS）.Conclusion:In this hyper-tensive rat model of CHF,chronic endothelin ETA receptor blockade with LU 135252improves cardiac hemodynamics,however,it does not affect long-term survivaland worsens cardiac ***,endothelin ETAreceptor antagonists areunlikely to have an important role in the management of patients with CHF.

关键词： myocardial infarction heart failure endothelin ET_A receptor antagonism LU 135252 cardiac remodeling ventricular function SHR-SP rats

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Comparison of cardioprotective effects of mibefradil and ramipril in stroke-prone spontaneously hypertensive rats

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Acta Pharmacologica Sinica 2004年第6期 61-66页

作者： alexander reinecke,Marc DORENKAMP,Christain STORZ,Havvo BITTERLING,Susanne PENZ,Jack CLEUTJENS,Mat JAP DAEMEN,Reichiger SIMON,Thomas UNGER Institute of Pharmacology University of Kiel 24105 Kiel Germany Institute of Pharmacology University of Kiel 24105 Kiel Germany Clinic of Cardiology Institute of Pharmacology University of Kiel 24105 Kiel Germany Institute of Pharmacology University of Kiel 24105 Kiel Germany University of Kiel Department of Pathology University ofMaastricht Maastricht The Netherlands Clinic of Cardiology University of Kiel 24105 Kiel Germany 24105 Kiel Institute of Pharmacology University of Kiel 24105 Kiel Germany Germany Institute of Pharmacology University of Kiel 24105 Kiel Germany

AIM: To elucidate the cardioprotective effects of T-type calcium channel blocker mibefradil and compare with that of the angiotensin-converting enzyme inhibitor ramipril in a stroke-prone spontaneously hypertensive rats (SHR- SP) model of congestive heart failure (CHF) after myocardial infarction (MI). METHODS: SHR-SP rats were subjected to permanent ligation of the left anterior decending coronary artery. Treatment with mibefradil (10 mg·kg-1·d-1), ramipril (10 mg·kg-1·d-1), or placebo was initiated 4 weeks before surgery and continued up to 6 weeks after induction of MI. Sham-operated rats served as controls. RESULTS: In placebo-treated MI rats, six weeks after MI, left ventricular circumference, inner diameter, and left ventricular end-diastolic pressure (LVEDP) were increased, whereas mean arterial blood pressure (MAP) and maximum rate of rise of left ventricular pressure (dp/ dtmax) were decreased compared with sham-operated controls (P05), and dp/dtmax was improved (P<0.01) compared with placebo-treated MI rats. In contrast, in mibefradil-treated MI rats, heart weight, heart weight to body weight ratio were slightly but not signifi- cantly reduced, LVEDP was slightly elevated compared with placebo-treated MI rats, and was elevated (P<0.05) compared with ramipril-treated MI rats, although interstitial collagen content were reduced (P<0.01) compared with placebo-treated MI ***: Chronic treatment with ramipril diminishes cardiac remodeling of heart failure after MI to a greater extent than mibefradil. Moreover, 6 weeks after MI, mibefradil treatment results in a slight rise in LVEDP compared with placebo-treated rats. Therefore, treatment with mibefradil might be deleterious rather than beneficial compared with ramipril or even placebo treatment in experim

关键词： mibefradil ramipril angiotensin-converting enzyme inhibitors calcium channel blockers myocar- dial infarction heart failure cardiac remodeling ventricular function SHR-SP rats

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