title: Acquisition of brain Na sensitivity contributes to salt-induced sympathoexcitation and cardiac dysfunction in mice with pressure overload.
abstract: In animal models of salt-sensitive hypertension, high salt augments sympathetic outflow via central mechanisms. It is not known, however, whether pressure overload affects salt sensitivity, thereby modifying central sympathetic outflow and cardiac function. We induced left ventricular hypertrophy with aortic banding in mice. Four weeks after aortic banding (AB-4), the left ventricle wall thickness was increased without changing the percentage fractional shortening. AB-4 mice were then fed either a high-salt (8%) diet or regular-salt diet for additional 4 weeks. Cardiac dysfunction, wall thickness, and 24-hour urinary catecholamine excretion were increased with high-salt diet compared with regular-salt diet. We then examined brain Na sensitivity. Intracerebroventricular infusion of high-Na (0.2 mol/L) artificial cerebrospinal fluid into AB-4 mice and mice Sham-4 increased urinary catecholamine excretion, arterial pressure, and heart rate more in AB-4 mice than in Sham-4 mice. Intracerebroventricular infusion of an epithelial Na channel blocker (benzamil) into mice with high-salt diet significantly decreased urinary catecholamine excretion and improved cardiac function. Infusion of either an angiotensin II type 1 receptor blocker or a Rho-kinase inhibitor also attenuated the salt-induced sympathetic hyperactivation and cardiac dysfunction in mice with high-salt diet. The levels of angiotensin II type 1 receptor and phosphorylated moesin, a substrate of Rho-kinase, were significantly greater in AB-4 mice than in Sham-4 mice. These results suggest that mice with pressure overload acquire brain Na sensitivity because of the activation of epithelial Na channel via Rho-kinase and angiotensin II, and this mechanism contributes to salt-induced sympathetic hyperactivation, further pressure overload, and cardiac dysfunction.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ito
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hirooka
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000768:Anesthesia, General; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000818:Animals; D001794:Blood Pressure; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004195:Disease Models, Animal; D004837:Epinephrine / Q000652:urine; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006321:Heart / Q000294:innervation*; D006339:Heart Rate; D006973:Hypertension / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D007263:Infusions, Parenteral; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008840:Microfilament Proteins / Q000378:metabolism; D009200:Myocardial Contraction; D009638:Norepinephrine / Q000652:urine; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000008:administration & dosage; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D013686:Telemetry; D013997:Time Factors; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D053503:Epithelial Sodium Channels; D008840:Microfilament Proteins; D047428:Protein Kinase Inhibitors; D044140:Receptor, Angiotensin, Type 1; D026941:Sodium Channel Blockers; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; C071058:moesin; D054460:rho-Associated Kinases; D009638:Norepinephrine; D004837:Epinephrine