Mineralocorticoid and AT1 receptors in the paraventricular nucleus contribute to sympathetic hyperactivity and cardiac dysfunction in rats post myocardial infarct. (14th July 2014)

• Record Type: Journal Article
• Authors: Huang, Bing S.; Chen, Aidong; Ahmad, Monir; Wang, Hong‐Wei; Leenen, Frans H. H.
• Is Part Of: Journal of physiology. Volume 592:Number 15(2014:Aug.)
• Page Start: 3273
• Page End: 3286
• Publication Date: 2014-07-14
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2014.276584
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="tjp6256-sec-0010" sec-type="section"> <title>Key points</title> <p> <list id="tjp6256-list-0001" list-type="bullet"> <list-item> <p>Central mineralocorticoid receptor (MR) and angiotensin II type 1 receptor (AT<sub>1</sub>R) activation play a critical role in sympathetic hyperactivity and progressive left ventricle (LV) remodelling and dysfunction after a myocardial infarction (MI).</p> </list-item> <list-item> <p>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<sub>1</sub>R expression in the PVN post MI, whereas AAV‐AT<sub>1a</sub>R‐siRNA only decreases AT<sub>1</sub>R expression. Both AAVs largely prevent sympathetic hyperactivity and inhibit part of LV remodelling and dysfunction post MI.</p> </list-item> <list-item> <p>These findings indicate that enhanced MR–AT<sub>1</sub>R signalling in the PVN is critical for sympathetic hyperactivity post MI, and contributes to part of LV dysfunction post MI.</p> </list-item> </list> </p> </sec> <sec id="tjp6256-sec-0020" sec-type="section"> <title>Abstract</title> <p>Intracerebroventricular infusion of a mineralocorticoid receptor (MR) or angiotensin II type 1 receptor (AT<sub>1</sub>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<sub>1</sub>Rs specifically in the paraventricular nucleus (PVN) contributes to these effects, and compared cardiac effects with those of systemic treatment with the β<sub>1</sub>‐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<sub>1</sub>R (AAV‐AT<sub>1</sub>R‐siRNA), or as control scrambled siRNA. At 4 weeks post MI, AT<sub>1</sub>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<italic>P</italic>/d<italic>t</italic><sub>max</sub> decreased. AAV‐MR‐siRNA and AAV‐AT<sub>1</sub>R‐siRNA both normalized AT<sub>1</sub>R expression in the PVN, similarly ameliorated sympathetic and pressor responses to air stress, largely prevented baroreflex desensitization, and improved LVEDP, EF and d<italic>P</italic>/d<italic>t</italic><sub>max</sub> as well as cardiac interstitial (but not perivascular) fibrosis. In a second set of rats, metoprolol at 70 or 250 mg kg<sup>−1</sup> day<sup>−1</sup> 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<sub>1</sub>Rs in the PVN contributes to sympathetic hyperactivity, and LV dysfunction and remodelling post MI. In rats, normalizing MR–AT<sub>1</sub>R signalling in the PVN is a more effective strategy to improve LV dysfunction post MI than systemic β<sub>1</sub> blockade.</p> </sec> </abstract>