Mineralocorticoid and AT₁ receptors in the paraventricular nucleus contribute to sympathetic hyperactivity and cardiac dysfunction in rats post myocardial infarct

Key points Central mineralocorticoid receptor (MR) and angiotensin II type 1 receptor (AT 1 R) activation play a critical role in sympathetic hyperactivity and progressive left ventricle (LV) remodelling and dysfunction after a myocardial infarction (MI). Intra‐paraventricular nucleus (PVN) infusion of adeno‐associated virus (AAV) carrying small interfering RNA (siRNA) against MR (AAV‐MR‐siRNA) markedly decreases both MR and AT 1 R expression in the PVN post MI, whereas AAV‐AT 1a R‐siRNA only decreases AT 1 R expression. Both AAVs largely prevent sympathetic hyperactivity and inhibit part of LV remodelling and dysfunction post MI. These findings indicate that enhanced MR–AT 1 R signalling in the PVN is critical for sympathetic hyperactivity post MI, and contributes to part of LV dysfunction post MI. Abstract Intracerebroventricular infusion of a mineralocorticoid receptor (MR) or angiotensin II type 1 receptor (AT 1 R) blocker in rats attenuates sympathetic hyperactivity and progressive left ventricular (LV) dysfunction post myocardial infarction (MI). The present study examined whether knockdown of MRs or AT 1 Rs specifically in the paraventricular nucleus (PVN) contributes to these effects, and compared cardiac effects with those of systemic treatment with the β 1 ‐adrenergic receptor blocker metoprolol. The PVN of rats was infused with adeno‐associated virus carrying small interfering RNA against either MR (AAV‐MR‐siRNA) or AT 1 R (AAV‐AT 1 R‐siRNA), or as control scrambled siRNA. At 4 weeks post MI, AT 1 R but not MR expression was increased in the PVN, excitatory renal sympathetic nerve activity and pressor responses to air stress were enhanced, and arterial baroreflex function was impaired; LV end‐diastolic pressure (LVEDP) was increased and LV peak systolic pressure (LVPSP), ejection fraction (EF) and d P /d t max decreased. AAV‐MR‐siRNA and AAV‐AT 1 R‐siRNA both normalized AT 1 R expression in the PVN, similarly ameliorated sympathetic and pressor responses to air stress, largely prevented baroreflex desensitization, and improved LVEDP, EF and d P /d t max as well as cardiac interstitial (but not perivascular) fibrosis. In a second set of rats, metoprolol at 70 or 250 mg kg −1 day −1 in the drinking water for 4 weeks post MI did not improve LV function except for a decrease in LVEDP at the lower dose. These results suggest that in rats MR‐dependent upregulation of AT 1 Rs in the PVN contributes to sympathetic hyperactivity, and LV dysfunction and remodelling post MI. In rats, normalizing MR–AT 1 R signalling in the PVN is a more effective strategy to improve LV dysfunction post MI than systemic β 1 blockade.