Study On Mechanisms Of Chronic Intermittent Hypoxia Inducing Heart And Brain Damages Of Rats And The Effect Of Drug Intervention

[objective] NO and NO synthase (NOS) are known to play key roles in the development of myocardial apoptosis induced by ischemia/hypoxia. Current evidence suggests that angiotensin II type1receptor blockers, such as telmisartan, lower blood pressure, and produce beneficial regulatory effects on NO and NOS. Here, we examined the protective role of telmisartan in myocardial apoptosis induced by chronic intermittent hypoxia (CIH).[Method] Adult male Sprague-Dawley rats were subjected to8hours of intermittent hypoxia/day during the daytime,7days/week, with/without telmisartan for8weeks. Myocardial apoptosis, NO and NOS activity, and levels of inflammatory mediators and radical oxygen species in myocardial tissue were determined.[Results] Treatment with telmisartan preserved endothelial NOS expression, inhibited inducible NOS and excessive NO generation, while reducing oxidation/nitration stress and inflammatory responses. Administration of telmisartan before CIH significantly ameliorated the CIH-induced myocardial apoptosis.[Conclusion] This study show that pre-CIH telmisartan administration ameliorated myocardial injury following CIH by attenuating CIH-induced myocardial apoptosis via regulation of NOS activity and inhibition of excessive NO generation, oxidation/nitration stress, and inflammatory responses. [Objective] Inflammatory processes and oxidative stress mediated by TLR4/MYD88pathway are known to play a key role in the development of organ damage induced by ischemia/hypoxia. Besides improving lipid metabolism, atorvastatin is also considered effective in improving ischemia/hypoxia-induced organ damage. The purpose of this study was to investigate whether atorvastatin can reduce chronic intermittent hypoxia-induced myocardial injury and its possible mechanism.[Method] OxyCycler A84anoxic tank is used to make chronic intermittent hypoxia. The28male Wistar rats were randomly divided into the normoxic control+placebo group, normoxia+atorvastatin group, intermittent hypoxia+placebo group and intermittent hypoxia+atorvastatin group, with10rats in each group. CIH rats were exposed to intermittent hypoxia during daytime sleep periods,8hours/day,7days/week for6weeks. The mRNA and protein of TLR4and MYD88in the left ventricular free wall were detected by Western blot and real-time PCR. The mRNA of pro-inflammatory cytokines TNF-a, IL-6, IL-1β and ICAM-lin the left ventricular free wall were detected by real-time PCR. The kit was used to detect the lipid peroxidation product malondialdehyde expression in the left ventricular free wall. Heart weight was measured in rat and the proportion of heart and body weight was calculated.。[Results] Compared with the normoxic control group, expressions of TLR4and MYD88mRNAs and proteins were significantly increased in left ventricular free wall of rats in the intermittent hypoxia+placebo group, and levels of pro-inflammatory cytokines TNF-a, IL-6, IL-1β and ICAM-1mRNA as well as lipid peroxide—MDA were also significantly increased. However, exogenous atorvastatin intervention can effectively inhibit high expressions of TLR4and MYD88mRNAs and proteins in left ventricular free wall of rats exposed to chronic intermittent hypoxia, meanwhile, it effectively inhibits expressions of pro-inflammatory cytokines TNF-α IL-6, IL-1β, ICAM-lmRNA and lipid peroxide-MDA in left ventricular free wall of rats. Compared with the normoxic control group, chronic intermittent hypoxia leaded to ventricular hypertrophy of rats and significantly increased the proportion of heart net weight in their body weights, but this kind of damage could be effectively improved by exogenous atorvastatin intervention.[Conclusion] This study show that pre-CIH atorvastatin administration may attenuate TLR-4/MYD88mediated inflammatory processes and oxidative stress in the injured rat myocardium, and this may be one mechanism by which atorvastatin ameliorated myocardial injury following CIH [Objective] Excessive apoptosis of hippocampal neurons is the most characteristic pathophysiological change of Alzheimer’s disease (AD). Nitric oxide synthase (NOS) and nitric oxide (NO) are known to play key roles in the development of neuronal apoptosis in the hippocampus. Several studies have confirmed that an angiotensin Ⅱ type1receptor blocker—telmisartan, beneficially regulates NOS and NO. This study was to investigate the role of telmisartan in chronic intermittent hypoxia (CIH) induced hippocampal neuronal injury.[Method] OxyCycler A84anoxic tank is used to make chronic intermittent hypoxia. Forty Sprague Dawley(SD) rats were randomly assigned to the normoxic control group, the CIH group and the CIH+telmisartan group. CIH rats were exposed to intermittent hypoxia in the sleep period for8h per day,7days a week during the daytime for8weeks. Neuronal apoptosis in the hippocampal CA1region, NOS activity, NO content, and the presence of inflammatory agents and radical oxygen species in the hippocampus were determined after the end of eight weeks of hypoxia.[Results] The results showed that CIH activated inducible nitric oxide synthase (iNOS), increased NO content, and enhanced lipid peroxidation and inflammatory responses in the hippocampus. Treatment with telmisartan inhibited excessive iNOS and NO generation and reduced lipid peroxidation and inflammatory responses. In addition, telmisartan significantly ameliorated the hippocampal apoptosis induced by CIH[Conclusion] Pre-CIH telmisartan administration attenuated CIH-induced hippocampal apoptosis partly by regulating iNOS activity, inhibiting excessive NO generation, and reducing lipid peroxidation and inflammatory responses.