Sex-specific cardioprotective effects of oxytocin in a rat model of pressure-overload heart failure

Introduction: Oxytocin (OT) is a peptide made in the hypothalamus and released into circulation by the pituitary gland. Known for its role in childbirth and lactation, recent research suggests that OT has significant cardiovascular benefits, reducing the risk of cardiovascular diseases such as hypertension and atherosclerosis. OT receptors and hormone levels show notable variations between males and females, which could influence the cardiovascular effects of OT. We tested if OT has beneficial effects on cardiovascular function in a rat model of pressure-overload heart failure (HF) and whether this effect differs between male and female rats. Given the increasing prevalence of cardiovascular disease, understanding the sex-specific cardiovascular effects of OT can help in developing tailored therapeutic approaches, enhancing treatment efficacy and clinical outcomes for males and females with cardiovascular disease.

Materials and

Methods: Neonatal Sprague Dawley male and female rats underwent transaortic constriction (TAC) to induce pressure overload and cardiac dysfunction which progressed as animals matured. Echocardiography at 5 weeks of age confirmed reduced ejection fraction. Animals were then randomly assigned to receive daily IP injections of either OT (treatment) or saline (control) for two weeks. Echocardiography was performed again before hearts were excised for optical mapping studies to test for electrophysiological differences between groups. Hearts were electromechanically uncoupled using blebbistatin and transmembrane potential (RH237) and intracellular Ca2+ (Rhod2am) were simultaneously mapped during a dynamic restitution protocol.

Results, Conclusions, and Discussions: Preliminary results indicate that male rats treated with OT (n=5) had improved cardiac function compared to controls (n=4), with improvements to ejection fraction (64.00 ± 11.76 vs. 30.59 ± 17.47, p=0.0109), higher cardiac output (61.61 ± 8.475 vs. 23.77 ± 8.461, p=0.0003), and greater stroke volume (177.0 ± 16.34 vs. 83.58 ± 36.01, p=0.0012). Conversely, preliminary results indicate the female rats treated with OT (n=5) showed no significant improvement in cardiac function compared to controls (saline, n=7) with similar ejection fraction (66.78 ± 9.408 vs. 63.65 ± 15.26, p=0.6948), similar cardiac output (63.21 ± 8.424 vs. 66.87 ± 22.36, p=0.7372), and similar stroke volume (202.7 ± 30.49 vs. 197.3 ± 58.07, p=0.8528). Optical mapping results indicate that the hearts of OT-treated male rats (n=6) have lower steady state action potential duration (APD) compared to controls (n=2). APD60 decreased from 109.5 ± 10.09 to 78.48 ± 16.5 (p=0.0615) indicating preservation of repolarizing currents corresponding to healthier electrophysiological function. In females, OT treatment did not decrease APD60 (90.92 ± 23.74 vs. 75.44 ± 13.67, p=0.4405). In summary, our preliminary results suggest exogenous IP OT administration could have a potent cardioprotective effect in male rats with chronic and severe pressure overload but may only have minimal benefit for the hearts of female rats. Future work will investigate potential mechanisms of OT’s sex-specific cardio-protective effects, including sites of action and the role of estrogen in modulating the cardiovascular effects of OT.

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