| Background:Chronic heart failure (CHF) is the final clinical manifestation of a variety of human heart diseases, including dilated cardiomyopathy (DCM), coronary artery disease (CAD), hypertensive heart disease (HHD) and rheumatic heart disease (RHD). CHF is characterized by complex clinical syndromes with decrease function of the left ventricle, insufficient cardiac output, fluid retention and elevated venous pressures. CHF has been considered to be heterogenous in etiology and pathogenesis. A 10 -year -study indicated although many therapeutic measurements had been used to eliminate the characteristic syndromes, the prognosis of CHF still had not been improved. The survival rate is the same as 10 years ago. This result implicated that some unknown actions in CHF process. Approaching on these actions has important theoretical and practical meanings for CHF prevention and treatment. When myocardium injured, the heart can not pump enough blood throughout the body. This information input to central neural system and provides for a sympathoexcitatory process. Noradrenaline released from sympathetic nerve ending increase heart rate and myocardium contractility. On the other hand, perseverative excess raise of sympathetic nerve activity increase myocardium consummation of oxygen, this vacious cycle lead to heart failure. Therefore, inhibiting sympathoexcitation has important theoretical and practical meanings for CHF prevention and treatment.Along with neuroanatomy development, the investigators found that rostral ventrolateral medulla (RVLM) neurons project to all levels of the intermediolateral cell column (IML) of the spinal cord to excite preganglionic sympathetic neurons. These provide a new thread for heart failure research.The paraventricular nucleus (PVN) of the hypothalamus is an important center regulating cardiovascular and fluid homeostasis. Recent literatures have implicated that many active substance increased in the PVN in CHF rats. Francis et al demonstrated that cytokines are not only increased in the circulation and left ventricular (LV) tissues but also in the hypothalamus of CHF rats. There are two possible mechanisms for TNF-αincreased expression in the PVN: (1) circulating TNF-αinto the brain through the circumventricular organs (CVOs) which are specialized brain regions that lack a blood-brain barrier; (2) activated microglia in the brain can synthesis TNF-α. Francis et al also demonstrated that a nervous system was linked in the activation of cytokines in CHF. Injection of TNF-αin the PVN or rostral ventrolateral medulla (RVLM) increased sympathetic activity, suggesting a direct role of TNF-αin sympathetic activity. Nevertheless, the mechanisms by which TNF-αcontribute to the sympathoexcitation in heart failure are not known.Double-labeling for CRH and Fra-LI activity demonstrated an increase of CRH expression in the PVN of HF rats which contribute to sympathoexcitation and heart deterioration. This indicated that CRH neuronal activation is involved in the pathogenesis of heart failure. In addition, investigators discovered that CRH neurons have fiber project to the intermediolateral cell column (IML) of the spinal cord to excite preganglionic sympathetic neurons. Therefore, we hypothesized that high level of CRH expression in PVN and HPA axis activation are important factors in heart failure process. In our previous study, we used Lewis rats (has defective HPA axis) and Fischer rats (has susceptive HPA axis) for research and demonstrated that heart function of Lewis rats in HF were significantly better than that of Fisher rats in HF, the Lewis rats have lower sympathoexcitation, better general survival conditions and significantly increased four-week survival rate.Investigators have discovered the close relationship between the neuroendocrine system and the immune system long times ago. Neuroendocrine system has general effect on the growth of immune organs, maturation of immune cells and regulation of immune response. Immune system also has an important effect on neuroendocrine system. Therefore, we hypothesized that elevated TNF-αmodulate the expression of CRH in the PVN and contributes to the exaggerated sympathetic activity.Objective:1. To observe whether TNF-αlevel was increased in PVN of HF rats, and the relationship between TNF-αand sympathetic nerve activity.2. To observe the effect of PVN TNF-αon CRH, and the relationships among TNF-α, CRH and sympathetic nerve activity. To investigate whether TNF-αincrease sympathetic nerve activity mediated by HPA axis. Methods:72 adult male Sprague-Dawley rats weighing (250±50) g (provided by Animal Unit of Shanxi Medical University) were randomly divided six groups:(1) Sham group (n=12): rats'left anterior descending artery (LAD) was only exposed without ligation;(2) Sham+PTX group (n=12): rats'left anterior descending artery (LAD) was only exposed without ligation,then ICV treated with PTX (10μg/h) for 4 weeks;(3) Sham+αh-CRH group (n=12): rats'left anterior descending artery (LAD) was only exposed without ligation,then ICV treated withαh-CRH (15μg/h) for 4 weeks;(4) HF group (n=12): rats'left anterior descending coronary artery (LAD) was ligated to establish the heart failure model;(5) HF+PTX group (n=12): rats'left anterior descending artery (LAD) was ligated, and then ICV treated with PTX (10μg/h) for 4 weeks;(6) HF+αh-CRH group (n=12): rats'left anterior descending artery (LAD) was ligated, and then ICV treated withαh-CRH (15μg/h) for 4 weeks.4 weeks later, the myocardial infarct size was determined by Mallory trichromatic stains. Cardiac function was reflected by hemodynamic measurement, lung / body weight ratio, right ventricle / body weight. And the levels of TNF-αand CRH in the PVN were examined by immunofluorescence, immunohistochemistry, and Western blot. The renal sympathetic nerve activity was also recorded. Plasmas were collected to measure norepinephrine and IL-1βby ELISA.Results:1. Effect of PTX on TNF-αexpression in PVN of each group ratsCompared with Sham groups, HF rats had more TNF-αpositive cell in PVN (Fig. 5), Western blot revealed that TNF-αprotein in hypothalamus increased significantly in HF rats than in Sham rats (Fig.5). PTX is a phosphodiesterase inhibitor; it has been reported to inhibit the production of TNF-α. ICV treatment of PTX after left anterior descending coronary artery ligated significantly decreased TNF-αexpression in the PVN. There was no significant difference in TNF-αexpression among Sham groups.2. Effect of PTX on CRH expression in PVN of each group ratsCorticotropin-releasing hormone (CRH) is an important component of the hypothalamic-pituitary-adrenal axis. CRH positive neurons were elevated (Fig.6), and CRH protein was increased in the PVN of HF rats when compared with Sham rats (Fig.6). PTX treatment can significantly decrease CRH positive neurons and CRH protein expression in HF rats.3. Effects of drugs on plasma norepinephrine and proinflammatory cytokines levels of each group ratsPlasma norepinephrine is an indicator of sympathetic nerve activation. HF rats have excessively activated sympathetic nerves, and high level of plasma norepinephrine, when compared with Sham rats (Table.3). PTX treatment attenuates the active effect of central nerves on sympathetic nerves, the plasma norepinephrine also decreased.αh-CRH inhibits the active effect of CRH on HPA axis, plasma norepinephrine decreased, this indicated that inhibited HPA axis can attenuates sympathetic nerve activity in HF rats. Drugs in lateral ventricles have no effect on plasma cytokines.4. Effects of drugs on sympathetic nerve activity of each group ratsEnhanced sympathetic nerve activity is one of the characteristics of heart failure. Renal sympathetic neuronal activity recording shows that HF rats produced a sympathoexcitatory response characterized by significant increases from baseline in RSNA (Fig.7). Both PTX andαh-CRH can attenuate sympathetic nerve activity in HF rats, but have no effect on sympathetic nerve activity in Sham rats.5. Effects of drugs on hemodynamic measurements, RV/BW ratio and Lung/BW ratio of each group ratsOur results revealed increased RV/BW ratio and Lung/BW ratio in HF rats. This indicated hypertrophy in right ventricle and pulmonary venous pleonaemia. Left ventricle function of HF rats was damaged, characterized as lower LVEDP, higher LV+dp/dtmax and LV-dp/dtmax compared with Sham rats. HF rats treated with PTX, like those treated withαh-CRH, had lower right ventricle/BW and lung/BW ratios (Table. 2), lower LVEDP levels, higher LV+dp/dtmax and LV-dp/dtmax levels (Fig.2, Table.1) compared with vehicle treated HF rats. Conclusion:1. HF rats had increased TNF-αexpression in the PVN, and produced a sympathoexcitatory response characterized by significant increases from baseline. ICV treatment with PTX attenuates sympathetic nerve activity in HF rats. This result indicated that TNF-αin PVN is involved in heart failure process and contribute to sympathoexcitation.2. ICV treatment withαh-CRH treatment significantly decreased sympathetic nerve activity in HF rats, and improved cardiac function. This result indicated that HPA axis was activated by heart failure, and is involved in heart failure process and contributes to sympathoexcitation.3. ICV treatment with PTX decreased PVN TNF-αexpression and CRH expression in HF rats, and decreased sympathoexcitation, improved cardiac function. This result indicated that PVN TNF-αregulates sympathetic nerve activity in HF rats contribute to HPA axis. |
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