Inhibition of Na+/H+-exchanger with sabiporide attenuates the downregulation and uncoupling of the myocardial beta-adrenoceptor system in failing rabbit hearts.

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.