Neuromodulation and Oxytocin
Open Access DepositedMechanisms and Sex-Based Differences in Cardioprotection After Myocardial Injury
Heart disease remains a leading cause of morbidity and mortality worldwide, and better strategies are needed to improve outcomes for acute myocardial infarction (MI) and chronic heart failure (HF). A common feature of these conditions is autonomic imbalance, characterized by increased sympathetic activity and reduced parasympathetic tone, which causes electrical instability, tissue injury, and worsens disease progression. This dissertation examined whether targeted autonomic modulation could provide cardioprotection in models of acute ischemia and pressure-overload HF. Our results suggest that parasympathetic and oxytocinergic pathways are promising therapeutic targets for reducing ischemic injury, suppressing arrhythmia susceptibility and slowing the progression of heart disease. We tested an ex vivo MI model using excised perfused hearts from transgenic rats that expressed Designer Receptors Exclusively Activated by Designer Drugs in cholinergic neurons within the intrinsic cardiac ganglia (ICG). We permanently ligated the left anterior descending coronary artery to create an ischemic zone, and cholinergic ICG neurons were activated using the synthetic ligand clozapine-N-oxide (CNO). We found that chemogenetic activation of ICG cholinergic neurons improved tissue oxygenation in the ischemic border zone and decreased overall arrhythmia incidence. These effects were blocked when the muscarinic antagonist atropine was administered before CNO. These results indicate that selective stimulation of cholinergic ICG neurons could improve local delivery of oxygen to the ischemic border zone shortly after a coronary occlusion and reduce arrhythmia burden. We then studied whether administration of oxytocin would improve cardiac function in male and female rats that had pressure overload HF induced by transverse aortic constriction (TAC). Intraperitoneal oxytocin was administered daily to adult HF rats and healthy controls. Although echocardiographic measures of cardiac structure and systolic function were not different between groups, optical mapping revealed significant electrophysiological differences, including shorter action potential duration, faster repolarization, and faster conduction of ventricular action potentials. The effect of oxytocin treatment was also different between male and female HF rats, where males exhibited an improved treatment response compared to females. Co-administration of the selective oxytocin receptor antagonist L-371,257 reduced the electrophysiological benefits of oxytocin, suggesting that these responses were partially mediated through peripheral oxytocin receptor signaling. These findings suggest that oxytocin may promote a healthier electrophysiological substrate in male rats during pressure-overload HF.
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