Cardiomyocyte mineralocorticoid receptor regulates cardiac functional responses to ischaemia; the role of sex and NOS inhibition

Abstract

Mineralocorticoid receptor (MR) antagonists are protective in patients post-myocardial infarction and are beneficial even when plasma aldosterone levels are normal. Moreover, experimental and clinical evidence suggests that sex differences observed in heart failure may have an MR-dependent mechanism. The aim of this study was to characterise the role of cardiomyocyte MR signalling in ischaemia/reperfusion (I/R) injury and recovery in a model of a mineralocorticoid-independent insult, i.e. chronic nitric oxide deficiency. Male and female (8 weeks of age), wild type (WT) and cardiomyocyte MR knockout (myo-MRKO) mice were uninephrectomised and given (i) high salt (VEH: 0.9%NaCl, 0.4%KCl) or (ii) high salt plus the nitric oxide synthase (NOS) inhibitor L-NG-Nitroarginine methyl ester (L-NAME) (L-NAME: 150mg/kg/day, 0.9%NaCl, 0.4%KCl) to drink. At 8 weeks of treatment hearts were Langendorff-perfused, subjected to 20 minutes global ischaemia plus 45 minutes reperfusion (n=7-9 per group). Basal left ventricular developed pressure (LVDevP) was increased by L-NAME/salt treatment in female but not male hearts. During ischaemia, peak contracture was increased only in female WT and myo-MRKO hearts by NOS inhibition and time to contracture was shorter in female WT vs. myo-MRKO suggesting worse injury. At the end of reperfusion, recovery of LVDevP was significantly greater in myo-MRKO hearts compared to WT in both sexes (% basal LVDevP (mmHg): female WT;VEH:73±6, L-NAME/salt:56±4, female myo-MRKO;VEH:91±5, L-NAME/salt:85±7, p<0.05). These data indicate that cardiomyocyte MR contribute to cardiac dysfunction post-ischaemia/reperfusion following chronic, aldosterone-independent activation of MR. Further studies are investigating the molecular mechanisms involved in sex-and MR-regulation of cardiac function and injury.