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

1 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 ( β AR)‐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 β AR‐AC system. 2 Therefore, we investigated whether NHE‐1 inhibition with sabiporide (SABI; 30 mg kg −1  day −1 p.o.) might affect myocardial β AR 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. 3 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, β AR 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. 4 From the present data we cannot address whether the improved β AR‐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 β AR‐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 β AR system.British Journal of Pharmacology (2006) 148 , 137–146. doi: 10.1038/sj.bjp.0706714