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- Title
Inhibition of Na+/H+-exchanger with sabiporide attenuates the downregulation and uncoupling of the myocardial beta-adrenoceptor system in failing rabbit hearts.
- Authors
Leineweber, Kirsten; Aker, Stephanie; Beilfuß, Anja; Rekasi, Heike; Konietzka, Ina; Martin, Claus; Heusch, Gerd; Schulz, Rainer; Beilfuss, Anja
- 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 β-adrenoceptor (βAR)-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 βAR-AC system.Therefore, we investigated whether NHE-1 inhibition with sabiporide (SABI; 30 mg kg−1 day−1 p.o.) might affect myocardial βAR 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 3wksHF 20±0.5 mm, n=8; P<0.05) and LVS-FS decreased (Shams 31±1%, n=9 vs 3wksHF 10±1%, n=8; P<0.05). SABI treatment significantly improved LV function independent of whether rabbits were treated after 1 week of pacing (3wksHF+2wksSABI (n=7): LVEDD 18±1 mm; LVS-FS 16±4%) or before pacing (3wksHF+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, 3wksHF 2.68±0.38, 3wksHF+2wksSABI 1.22±0.32, 3wksHF+3wksSABI 1.38±0.33 ng ml−1). Moreover, βAR density (Shams 64±5, 3wksHF 38±3, 3wksHF+2wksSABI 48±4, 3wksHF+3wksSABI 55±3 fmol mg−1 protein) and responsiveness (isoprenaline-stimulated AC activity. (Shams 57.6±4.9, 3wksHF 36.3±6.0, 3wksHF+2wksSABI 56.9±6.0, 3wksHF+3wksSABI 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 βAR-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 βAR-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 βAR system.British Journal of Pharmacology (2006) 148, 137–146. doi:10.1038/sj.bjp.0706714; published online 6 March 2006
- Subjects
NORADRENALINE; HEART failure; SYSTOLIC array circuits; BLOOD plasma; CARDIAC arrest; HEART biopsy
- Publication
British Journal of Pharmacology, 2006, Vol 148, Issue 2, p137
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1038/sj.bjp.0706714