title: Inhibition of Na+/H+-exchanger with sabiporide attenuates the downregulation and uncoupling of the myocardial beta-adrenoceptor system in failing rabbit hearts.
abstract: Chronic heart failure (HF) is characterized by left ventricular (LV) structural remodeling, impaired function, increased circulating noradrenaline (NA) levels and impaired responsiveness of the myocardial beta-adrenoceptor (betaAR)-adenylyl cyclase (AC) system. In failing hearts, inhibition of the sodium/proton-exchanger (NHE)-1 attenuates LV remodeling and improves LV function. The mechanism(s) involved in these cardioprotective effects remain(s) unclear, but might involve effects on the impaired betaAR-AC system. Therefore, we investigated whether NHE-1 inhibition with sabiporide (SABI; 30 mg kg(-1) day(-1) p.o.) might affect myocardial betaAR density and AC activity in relation to changes in LV end-diastolic diameter (LVEDD) and LV systolic fractional shortening (LVS-FS) after 3 weeks of rapid LV pacing in rabbits. After 3 weeks of rapid LV pacing LVEDD was significantly increased (Shams 17+/-0.2 mm, n=9 vs 3 wksHF 20+/-0.5 mm, n=8; P<0.05) and LVS-FS decreased (Shams 31+/-1%, n=9 vs 3 wksHF 10+/-1%, n=8; P<0.05). SABI treatment significantly improved LV function independent of whether rabbits were treated after 1 week of pacing (3 wksHF+2 wksSABI (n=7): LVEDD 18+/-1 mm; LVS-FS 16+/-4%) or before pacing (3 wksHF+3wksSABI (n=9): LVEDD 18+/-1 mm; LVS-FS 18+/-6%). After 3 weeks of rapid LV pacing, SABI treatment significantly attenuated increases in serum NA content (Shams 0.83+/-0.19, 3 wksHF 2.68+/-0.38, 3 wksHF+2 wksSABI 1.22+/-0.32, 3 wksHF+3wksSABI 1.38+/-0.33 ng ml(-1)). Moreover, betaAR density (Shams 64+/-5, 3 wksHF 38+/-3, 3 wksHF+2 wksSABI 48+/-4, 3 wksHF+3 wksSABI 55+/-3 fmol mg(-1) protein) and responsiveness (isoprenaline-stimulated AC activity. (Shams 57.6+/-4.9, 3 wksHF 36.3+/-6.0, 3 wksHF+2 wksSABI 56.9+/-6.0, 3 wksHF+3 wksSABI 54.5+/-4.8 pmol cyclic AMP mg(-1) protein(-1) min(-1)) were significantly improved in SABI-treated rabbits. From the present data we cannot address whether the improved betaAR-AC system permitted improved LV function and/or whether the improved LV function resulted in less activation of the sympathetic nervous system and by this in a reduced stimulation of the betaAR-AC system. Accordingly, additional studies are needed to fully establish the cause-and-effect relationship between NHE-1 inhibition and the restoration of the myocardial betaAR system.
authors.affiliation: Institute of Pathophysiology, University of Essen School of Medicine, D-45122 Essen, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Leineweber
authors.forename: Stephanie
authors.initials: S
authors.lastname: Aker
authors.forename: Anja
authors.initials: A
authors.lastname: Beilfuss
authors.forename: Heike
authors.initials: H
authors.lastname: Rekasi
authors.forename: Ina
authors.initials: I
authors.lastname: Konietzka
authors.forename: Claus
authors.initials: C
authors.lastname: Martin
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
authors.forename: Rainer
authors.initials: R
authors.lastname: Schulz
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D015536:Down-Regulation; D004719:Endomyocardial Fibrosis / Q000097:blood / Q000378:metabolism / Q000473:pathology; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine / Q000097:blood; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D006146:Guanidines; D011943:Receptors, Adrenergic, beta; D017923:Sodium-Hydrogen Exchangers; D005576:Colforsin; D000262:Adenylyl Cyclases; C476560:sabiporide; D009638:Norepinephrine