title: Inhibition of NHE3-mediated Sodium Absorption in the Gut Reduced Cardiac End-organ Damage Without Deteriorating Renal Function in Obese Spontaneously Hypertensive Rats.
abstract: Increased sodium absorption in the gut is one mechanism contributing to hypertensive blood pressure values. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of intestinal sodium absorption. The compound SAR is a new specific NHE3 inhibitor with extremely low oral absorbability leading to decreased sodium absorption in the gut and substantial systolic blood pressure reduction. The effects of intestinal NHE3 inhibition on cardiac and renal hypertensive end-organ damage are unknown. The effects of SAR (1 mg·kg⁻¹·d⁻¹ in chow) on left ventricular (LV) and renal remodeling processes were studied by magnetic resonance imaging and biochemical and histological analysis in obese spontaneously hypertensive rats (SHR-ob SAR) compared with placebo-treated SHR-ob (SHR-ob PLAC). Inhibition of intestinal NHE3 by SAR lowered blood pressure and reduced LV end-diastolic pressure from 21 ± 3.0 to 15 ± 2.0 mm Hg (P = 0.0016), whereas heart rate kept unchanged. LV mass indices, LV myocyte diameters, and LV fibrosis formation were lower in SHR-ob SAR compared with SHR-ob PLAC. SAR did not influence urinary albumin to creatinine ratio or glomerular filtration rate. Renal interstitial fibrosis formation, as well as podocyte damage and glomerulosclerosis remained unchanged. Reduction of intestinal sodium absorption by selective NHE3 inhibition in the gut lowered high blood pressure and reduced LV remodeling without deteriorating renal functional and structural parameters in SHR-ob.
authors.affiliation: Department of Cardiology, Universitätsklinikum des Saarlandes, Homburg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Linz
authors.forename: Mathias
authors.initials: M
authors.lastname: Hohl
authors.forename: Jan Christian
authors.initials: JC
authors.lastname: Reil
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Dominik
authors.initials: D
authors.lastname: Linz
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000150:complications; D010641:Phenotype; D011918:Rats, Inbred SHR; D012964:Sodium / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D014508:Urea; D012964:Sodium