Sex differences in sensitivity to β-adrenergic agonist isoproterenol in the isolated adult rat heart following prenatal protein restriction

Abstract

Hypertension is a major risk factor for the development of CVD. Epidemiological studies have shown that low birth weight increases the risk of developing hypertension in adulthood. Hypertension increases the risk of suffering IHD and early findings provide evidence that hearts from prenatally protein-restricted, hypertensive, male offspring are more susceptible to cardiac dysfunction following ischaemic events. Hypertension and abnormalities in cardiac function following ischaemia-reperfusion in the human population are treated therapeutically with beta-adrenergic antagonists. We hypothesised that increased susceptibility to myocardial ischaemia-reperfusion injury in prenatally programmed offspring may be due to sympathetic hyperactivity. Pregnant Wistar rats were fed control or low-protein (maternal low protein; MLP) diets throughout gestation. At age 6 months, hearts were rapidly excised and retro-perfused using the Langendorff apparatus, to assess isolated cardiac function following stimulation with increasing doses of the non-specific beta-agonist isoproterenol. Baseline heart rates were similar in control and MLP-fed offspring. With significant diet x sex interactions (P < 0.01) maximum heart rate response following isoproterenol infusion was significantly longer in MLP than control. Prenatal diet had no effect on maximal left ventricular developed pressure (LVDP) response, but the LVDP isoproterenol response was significantly longer in duration in MLP-exposed male offspring (diet x sex P < 0.001). Myocardial mRNA expression of beta2-adrenergic receptors was increased in 2-week-old female MLP offspring only (P < 0.049). In conclusion, maternal protein restriction programmes cardiac sympathetic activity in a sex-specific manner, and may explain increased susceptibility to ischaemia-reperfusion injury in males subject to fetal undernutrition.