| 1. |
- Strömer, Hinrik, et al.
(författare)
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Growth hormone- and pressure overload-induced cardiac hypertrophy evoke different responses to ischemia-reperfusion and mechanical stretch.
- 2006
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Ingår i: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - : Elsevier BV. - 1096-6374. ; 16:1, s. 29-40
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To compare the molecular, histological, and functional characteristics of growth hormone (GH)- and pressure overload-induced cardiac hypertrophy, and their responses to ischemia-reperfusion and mechanical stretch. DESIGN: Four groups of male Wistar rats were studied: aortic banding (n=24, AB) or sham (n=24, controls) for 10 weeks, and GH treatment (n=24; 3.5mg/kg/day, GH) or placebo (n=24, controls) for 4 weeks. At 13 weeks, the rats were randomly subjected to: (i) assessment of basal left ventricular mRNA expression of sarcoplasmic reticulum calcium-ATPase (SERCA-2), phospholamban (PLB), and Na(+)-Ca(2+) exchanger (NCX) and collagen volume fraction (CVF) (Protocol A, 8 rats in each group); (ii) left ventricular no-flow ischemia with simultaneous evaluation of intracellular Ca(2+) handling and ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) content (Protocol B, 12 rats in each group); or (iii) left ventricular mechanical stretch for 40 min with assessment of tumor necrosis-alpha (TNF-alpha) mRNA (Protocol C, 4 rats in each group). Protocol B and C were carried out in a Langendorff apparatus. RESULTS: In Protocol A, no difference was found as to myocardial mRNA content of Ca(2+) regulating proteins and CVF in GH animals vs controls. In contrast, in the AB group, myocardial mRNA expression of SERCA-2 and PLB was downregulated while that of NCX and CVF were increased vs. controls (p<0.05). In Protocol B, recovery of left ventricular function was significantly decreased in AB vs GH groups and controls and this was associated with 1.6-fold increase in intracellular Ca(2+) overload during reperfusion (p<0.05). Baseline ATP content was similar in the four study groups, whereas PCr and Pi was lower in AB vs GH rats and controls. However, the time courses of high-energy phosphate metabolic changes did not differ during ischemia and reperfusion in the four study groups. In Protocol C, no detectable TNF-alpha mRNA level was found in the left ventricular myocardium of GH treated rats and controls at baseline, while a modest expression was noted in AB animals. Mechanical stretch resulted in de novo myocardial TNF-alpha mRNA expression in GH group and controls, which was dramatically increased in AB animals ( approximately 5-fold above baseline, p<0.001). CONCLUSIONS: The data show that cardiac hypertrophy activated by short-term GH treatment confers cardioprotection compared with pressure overload with regard to molecular and histological characteristics, and responses to ischemia-reperfusion and mechanical stretch.
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| 2. |
- Cittadini, Antonio, et al.
(författare)
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Aldosterone receptor blockade improves left ventricular remodeling and increases ventricular fibrillation threshold in experimental heart failure.
- 2003
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Ingår i: Cardiovascular research. - 0008-6363. ; 58:3, s. 555-64
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To investigate the effects of aldosterone receptor blockade in postinfarction heart failure. METHODS: Eighty-seven rats with moderate myocardial infarction were randomized to receive either no drug or canrenone, the active metabolite of spironolactone, 20 mg/kg/day, or ramipril, 1 mg/kg/day, or a combination of the two drugs. Treatment was initiated 1 month after coronary ligation and lasted 4 weeks. Echocardiography was performed at baseline and after 4 weeks. LV catheterization, isolated heart studies, morphometric histology, myocardial norepinephrine and SERCA-2 mRNA were assessed at the end of the treatment period. RESULTS: Infarct sizes were 33+/-3, 32+/-3, 34+/-3, and 34+/-4% in the placebo, canrenone, ramipril, and combination groups, respectively. Canrenone attenuated LV remodeling, improved LV systolic and diastolic function, and markedly reduced interstitial and perivascular fibrosis. These effects were increased by concomitant ramipril therapy. Moreover, myocardial norepinephrine content was decreased while ventricular fibrillation threshold significantly augmented by canrenone. SERCA-2 levels remained unchanged. CONCLUSIONS: Canrenone attenuated LV dilation and interstitial remodeling, and improved LV filling dynamics and systolic function in the rat model of postinfarction heart failure. Addition of ramipril conferred further cardioprotection. Canrenone also reduced myocardial norepinephrine content and increased ventricular fibrillation threshold. The data provide a potential explanation for the decreased sudden death observed in the RALES study.The mechanisms of action of aldosterone inhibition are still poorly understood, despite its proven efficacy in heart failure. Rats with postinfarction heart failure were randomized to receive for 1 month either no drug or canrenone, or ramipril, or a combination of canrenone and ramipril. Canrenone treatment was associated with a significant attenuation of LV dilation, better LV diastolic and systolic dynamics, and a marked reduction of reactive fibrosis. These effects were enhanced by concomitant ramipril therapy. Moreover, canrenone increased ventricular fibrillation threshold and reduced myocardial norepinephrine content. The data may explain the reduced mortality demonstrated by the RALES.
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| 3. |
- Cittadini, Antonio, et al.
(författare)
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Growth hormone prolongs survival in experimental postinfarction heart failure.
- 2003
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Ingår i: Journal of the American College of Cardiology. - 0735-1097. ; 41:12, s. 2154-63
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We evaluated the effects of growth hormone (GH) on survival in experimental heart failure (HF). BACKGROUND: Growth hormone has been beneficial in various models of experimental HF. Whether GH also affects HF progression and survival is not known. METHODS: A total of 119 rats with moderate myocardial infarction were randomized to receive either GH (3.5 mg/kg every other day) or placebo for 28 days. Treatment was initiated one month after coronary ligation; the follow-up lasted 13 months. In the surviving animals, Doppler echocardiography and closed-chest Millar left ventricular (LV) catheterization were performed. Apoptosis, collagen volume fraction, and capillary density in the LV zone remote from infarction were measured. The early effects of GH on apoptosis were also assessed in a subgroup of eight infarcted rats, treated as specified earlier and euthanized at one month. RESULTS: Survival rate was 68% in GH-treated rats and 48% in the placebo group (p = 0.0377). Growth hormone had no effect on myocardial architecture, systolic function, and sarcoplasmatic reticulum calcium ATPase-2 messenger ribonucleic acid. Growth hormone improved LV relaxation; this was associated with a 50% reduction in collagen volume fraction and a 27% increase in capillary density. Growth hormone reduced the apoptotic index by 50% at one month and by 33% at 13 months. CONCLUSIONS: Growth hormone prolonged survival of rats with postinfarction HF. This effect was associated with marked attenuation of cardiomyocyte apoptosis and pathologic interstitial remodeling in the surviving myocardium and enhanced LV relaxation.
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