Melatonin ameliorates calcium homeostasis in myocardial and ischemia–reperfusion injury in chronically hypoxic rats

Abstract

Chronic hypoxia (CH) leads to the deterioration of myocardial functions with impaired calcium handling in the sarcoplasmic reticulum (SR), which may be mediated by oxidative stress. We hypothesized that administration of antioxidant melatonin would protect against cardiac and ischemia-reperfusion (I/R) injury by ameliorating SR calcium handling. Adult Sprague-Dawley rats that had received a daily injection of melatonin or vehicle were exposed to 10% oxygen for 4 wk. The heart of each rat was then dissected and perfused using a Langendorff apparatus. The ratio of heart-to-body weight, ventricular hypertrophy and hematocrit were increased in the hypoxic rats compared with the normoxic controls. Malondialdehyde levels were also increased in the heart of hypoxic rats and were lowered by the treatment of melatonin. The hearts were subjected to left coronary artery ischemia (30 min) followed by 120-min reperfusion. Lactate dehydrogenase leakage before ischemia, during I/R and infarct size of the isolated perfused hearts were significantly elevated in the vehicle-treated hypoxic rats but not in the melatonin-treated rats. Spectroflurometric studies showed that resting calcium levels and I/R-induced calcium overload in the cardiomyocytes were more significantly altered in the hypoxic rats than the normoxic controls. Also, the hypoxic group had decreased levels of the SR calcium content and reduced amplitude and decay time of electrically induced calcium transients, indicating impaired contractility and SR calcium re-uptake. Moreover, there were reductions in protein expression of calcium handling proteins, markedly shown at the level of SR-Ca(2+) ATPase (SERCA) in the heart of hypoxic rats. Melatonin treatment significantly mitigated the calcium handling in the hypoxic rats by preserving SERCA expression. The results suggest that melatonin is cardioprotective against CH-induced myocardial injury by improving calcium handling in the SR of cardiomyocytes via an antioxidant mechanism.

Melatonin Attenuates Intermittent Hypoxia-Induced Lipid Peroxidation and Local Inflammation in Rat Adrenal Medulla

“…Although it is not a direct measurement of oxidative stress, we found an increased MDA level in the adrenal medulla of hypoxic rats, suggesting elevated levels of lipid peroxidation, which could be mediated by CIH-induced oxidative stress. This is consistent with our previous studies reporting antioxidant melatonin attenuated the elevated MDA levels and cellular injuries induced by CIH-induced lipid peroxidation [7,8]. Also, our results showed the increased level of NTR-immunoreactivity in the adrenal medulla of CIH rats.…”

“…Studies have also shown that recurrent episodes of apnea/hypopnea cause chronic intermittent hypoxia (CIH), which induces lipid peroxidation and subsequently causes the pathophysiological change in the OSA patient [4,5,6]. Indeed, we have shown that CIH-induced lipid peroxidation plays a significant pathogenic role in the hippocampal injury in a rat model with chronic exposure to intermittent hypoxia mimicking a severe OSA condition, which underpins the involvement of overproduction of reactive oxygen species (ROS) and free radicals in apoptotic cell death and neuronal dysfunction [7,8]. In addition, it has been shown that that cellular injuries caused by lipid peroxidation lead to inflammation, which induces the inflammatory response that could be an important contributing factor in promoting cardiovascular morbidity in OSA patients [9,10].…”

The effect of tumor necrosis factor-α inhibitor soon after hypoxia-ischemia on heart in neonatal rats

“…In another research study by Yeung et al (2008), the effects of chronic hypoxia (10% oxygen for 28 days) on myocardial functions were investigated in isolated perfused rat hearts. They reported that the ratio of heart-to-body weight was increased in the chronically hypoxic rats.…”

A review of melatonin as a suitable antioxidant against myocardial ischemia–reperfusion injury and clinical heart diseases

“…Electrophysiologically, the heart also benefits from melatonin [49]. Yeung et al [50] suggested that melatonin is cardioprotective against chronic hypoxia-induced myocardial injury because it improves calcium handling in the sarcoplasmic reticulum (SR) of cardiomyocytes via an antioxidant mechanism. Furthermore, Genade et al [51] showed that melatonin-induced cardioprotection may be receptor dependent and that its anti-adrenergic actions, mediated by NOS and guanylyl cyclase activation, are important contributors to its ability to forestall molecular damage in the cardiomyocyte due to IR.…”