RESUMO
Human chorionic gonadotropin (hCG) promotes proliferation of endogenous neural stem cells, and erythropoietin (EPO) promotes differentiation of these cells into neural stem cells. The current study examined effects of sequential administration of these two compounds, initiated 24 h after stroke. At that time, rats were randomized into four treatment groups: hCG+EPO (3 IM doses hCG over 5 days, followed by 3 IV doses EPO over 3 days), hCG+Saline using the same schedule, Saline+EPO using the same schedule, or neither drug (Saline+Saline). The primary endpoint was the composite neurological score, measured 11 times, from 1 h until 12 weeks post-insult. The neurological score was different across treatment groups (p<0.03). Pairwise testing of groups found that the hCG+EPO group had significantly better behavior at 6/10 post-stroke time points as compared to Saline+Saline. The differences observed when comparing the two-drug group with placebo were less apparent when comparing either of the one-drug groups with placebo. The two one-drug treatment arms did not significantly differ at any time point. Treatment with hCG+EPO significantly reduced total lesion volume by 82-89% compared to the other three treatment groups. The current therapeutic strategy improved behavioral outcome and reduced lesion volume with a time window of 24 h after the onset of stroke. The results from these experiments provide new insight into the effects of these two growth factors on stroke in rats, and could suggest a potential for translation into human stroke studies.
Assuntos
Gonadotropina Coriônica/uso terapêutico , Eritropoetina/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Humanos , Infarto da Artéria Cerebral Média/patologia , Masculino , Distribuição Aleatória , Ratos , Ratos Long-Evans , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: The role of phosphorylation of the ryanodine receptor at serine-2808 (RyRS2808) in congestive heart failure (CHF) is controversial, and effects of RyRS2808 phosphorylation on contraction are unclear. It has been reported that diastolic sarcomere length (SL) fluctuations accompany propagating contractile waves due to propagating SR Ca2+ release in trabeculae from rats with CHF. Here, we studied the influence of RyR destabilization by FK506 and isoproterenol on twitch force (Ftw) and SL fluctuations in right ventricular (RV) trabeculae. We measured phosphorylation of RyRS2808 in rats with myocardial infarction (MI) with or without beta-blockade and in rats during isoproterenol stimulation in order to assess the role of RyRS2808 phosphorylation in SL fluctuations in failing hearts. METHODS: Five groups of male Lewis Brown-Norway rats were studied 3 months after MI: i) Sham; ii) MI with CHF (cMI); iii) MI without CHF; iv) metoprolol-treated MI, with and without CHF. The root mean square (RMSSL) of SL fluctuations in RV trabeculae was calculated. RESULTS: RMSSL increased strongly both following a short train of stimuli at 2.5 Hz and following catecholamine activation in trabeculae from MI with CHF, resulting in a decrease in Ftw in proportion to RMSSL. RyRS2808 phosphorylation was increased significantly in the left ventricle (LV; approximately 58%, P<0.05) but not in the RV (n.s.) in MI rats with CHF. FK506 tripled high frequency stimulation-induced RMSSL in nonfailing trabecula but did not further enhance RMSSL in failing trabecula. Isoproterenol increased RMSSL in nonfailing trabeculae only modestly despite a substantial increase in RyRS2808 phosphorylation in the RV (approximately 60%, P<0.05). Isoproterenol induced SL fluctuation without an increase in RV-RyRS2808 phosphorylation in failing trabeculae. Chronic beta-blockade decreased high frequency and catecholamine stimulation-induced RMSSL while RyRS2808 phosphorylation in the RV was indistinguishable from that in cMI. CONCLUSIONS: Acute RyRS2808 phosphorylation by itself does not cause spontaneous contractile waves owing to RyR2 destabilization. Spontaneous contractile waves in CHF are not caused by RyRS2808 phosphorylation alone, suggesting that factors other than RyRS2808 phosphorylation affect RyR function.
Assuntos
Insuficiência Cardíaca/metabolismo , Contração Miocárdica , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , Serina/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Diástole , Ecocardiografia , Insuficiência Cardíaca/fisiopatologia , Isoproterenol/farmacologia , Masculino , Metoprolol/farmacologia , Modelos Animais , Fosforilação , Ratos , Ratos Endogâmicos BN , Retículo Sarcoplasmático/efeitos dos fármacos , Tacrolimo/farmacologiaRESUMO
Hypertrophy and heart failure following a myocardial infarction in rodents are accompanied by a switch of myosin isoforms from V1 to V3. The angiotensin II receptor blocker, Losartan, has been demonstrated to improve cardiac function and long-term survival after myocardial infarction. In this study we have investigated whether chronic Losartan treatment affects myosin isoform composition in the hearts of rats following a myocardial infarction. Rats were subjected to coronary artery ligation and received either Losartan (1 g/L) in the drinking water or water only. Four months after myocardial infarction, rats were classified as having either congestive heart failure (cMI) or uncomplicated myocardial infarction (uMI) based on their lung weight to body weight ratio (LW/BW). Compared with sham operated rats, uMI rats showed a 68.5% increase in the relative contribution of V3 and a 33.7% decrease in the relative contribution of V1 (p < 0.05). Untreated cMI showed 39.7% more V3 and 38.2% less V1 when compared with untreated uMI (p < 0.05). Losartan treatment after myocardial infarction reduced the incidence of cMI from 30.4 to 4.5% and scar size from 1.52 +/- 0.07 to 0.94 +/- 0.11 cm2 respectively. The percentage of V1 in Losartan treated uMI (LuMI) was 25.2% higher than the percentage of V1 in untreated uMI (p < 0.05), whereas the percentage of V3 in LuMI was 24.2% lower than that in untreated uMI (p < 0.05). A positive correlation of V3 myosin and scar area was observed. Our study suggests that expression of V3 myosin in the left ventricle is associated with scar size and the progress of hemodynamic changes after myocardial infarction. Losartan treatment reduces scar size and wall stress of the heart after the infarct, and therefore inhibits the signals shifting myosin isoform expression from V1 to V3 after a myocardial infarction.