Prolonged oxytocin treatment in rats affects intracellular signaling and induces myocardial protection against infarction

Abstract

Oxytocin is a hormone, which is released into the circulation in response to acute or chronic stress stimuli. One of the important targets of oxytocin is cardiovascular system. Present studies were aimed at testing the hypothesis that prolonged treatment with oxytocin (simulation of stress-induced rise in circulating oxytocin) activates intracellular signaling pathways playing a role in ischemia/reperfusion injury. Furthermore, we tested protective effects of oxytocin treatment in vivo against cardiac injury induced by ischemia/reperfusion of isolated hearts. Male Wistar rats were treated with oxytocin or vehicle continuously via osmotic minipumps for 2 weeks. The hearts were used for biochemical measurements or isolated for Langendorff perfusion. Treatment with oxytocin resulted in a significant increase in specific phosphorylation (activation) of p38-MAPK and Akt kinase, an increase in phosphorylated Hsp27 and an elevation in atrial natriuretic peptide (ANP) levels in left ventricular heart tissue. There were no significant changes in the activation of MMP-2 and ERK in the left heart ventricle of oxytocin-treated rats. Postischemic recovery of functional parameters LVDP, RPP, +dP/dtmax and -dP/dtmax was better in the hearts of oxytocin-treated rats compared to that in the controls. Oxytocin treatment significantly reduced infarct size to 15.1 + 3.2% as compared to 32.4 + 3.5% in vehicle-treated rats (p < 0.01). This is the first evidence for cardioprotective effects of oxytocin administered in vivo simulating chronic stress-induced elevation in plasma oxytocin. The present results show that positive effects of oxytocin that may ameliorate negative consequences of stress on the heart are, at least in part, mediated through p38-MAPK and Akt kinase pathways.

Increased Activity of the Intracardiac Oxytocinergic System in the Development of Postinfarction Heart Failure

“…Most of the up-to-date studies on the role of oxytocin in myocardial infarction were based on experimental methods involving an ischaemia-reperfusion model in vitro [19, 26, 27] or in vivo [16, 17]. In the study by Jankowski et al, myocardial infarction was evoked by chronic ligation of the left anterior descending coronary artery [17].…”

“…The authors of that study did not measure oxytocin mRNA expression and protein level at the same time; thus, it cannot be excluded that endogenous intracardiac OT could be partially responsible for the observed cardioprotective effects. In the other study, pretreatment with OT before ischaemia-reperfusion exposure resulted in the reduction of infarct size and activation of the prosurvival p38-MAPK and Akt-kinase pathways [26, 27]. In the in vitro model of ischaemia-reperfusion-induced myocardial damage, Ondrejcakova et al showed that exposure to OT prior to ischaemia resulted in the reduction of the infarct size due to the negative chronotropic effect [19].…”

Role of oxytocin signaling in the regulation of body weight

“…This is particularly exciting given that other substances, such as exendin-4, typically fail to maintain body weight loss after 17 days [218]. Of obvious clinical significance are findings that indicate oxytocin reduces anxiety [219], blood pressure [220], the size of cardiac infarcts [221], and is not causally related to the development of a CTA [222] in rats. Moreover, CNS [13] administration of oxytocin fails to elicit a CTA at doses that suppress food intake and body weight in rodents [12, 14, 36].…”

Unique Transcriptional Profile of Sustained Ligand-Activated Preconditioning in Pre- and Post-Ischemic Myocardium

“…Potential protection via SLP-dependent ANP/BNP expression is consistent with impaired I-R tolerance in mice lacking the natriuretic peptide receptor guanylyl cyclase-A [33]. Furthermore, cardioprotection with prolonged oxytocin is associated with ANP expression [34], and post-ischemic Nbbp correlates with I-R tolerance in a model of epoxyeicosatrienoic acid mediated protection [35]. Nonetheless, mechanistic involvement of the peptides in these and other protective responses remains to be established.…”