title: The renin-angiotensin-aldosterone system excites hypothalamic paraventricular nucleus neurons in heart failure.
abstract: The paraventricular nucleus (PVN) of the hypothalamus has critical homeostatic functions, including the regulation of fluid balance and sympathetic drive. It has been suggested that altered activity of this nucleus contributes to the progression of congestive heart failure (HF). We hypothesized that forebrain influences of the renin-angiotensin-aldosterone system augment the activity of PVN neurons in HF. The rate of PVN neurons (n = 68) from rats with ischemia-induced HF was higher than that of PVN neurons (n = 42) from sham-operated controls (8.7 +/- 0.8 vs. 2.7 +/- 0.3 spikes/s, P < 0.001, HF vs. SHAM). Forebrain-directed intracarotid artery injections of the angiotensin type 1 receptor antagonist losartan, the angiotensin-converting enzyme inhibitor captopril, and the mineralocorticoid receptor antagonist spironolactone all significantly (P < 0.05) reduced PVN neuronal activity in HF rats. These findings demonstrate that the renin-angiotensin-aldosterone system drives PVN neuronal activity in HF, likely resulting in increased sympathetic drive and volume accumulation. This mechanism of neurohumoral excitation in HF is accessible to manipulation by blood-borne therapeutic agents.
authors.affiliation: Department of Internal Medicine and Cardiovascular Center, University of Iowa, Iowa City, 52242, USA.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Joseph
authors.initials: J
authors.lastname: Francis
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Robert B
authors.initials: RB
authors.lastname: Felder
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D003714:Denervation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D019808:Losartan / Q000494:pharmacology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000503:physiopathology*; D011311:Pressoreceptors / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013148:Spironolactone / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D002216:Captopril; D019808:Losartan