Digoxin restores in vitro but not in vivo response to adrenerghc stimulation in experimental volume overload
Digoxin may restore contractile function in volume overload hypertrophy, however the mechanisms are not well understood. To determine the effects of digoxin on the b-receptor system in heart failure, and their effects on in vivo contractile reserve, we induced volume overload in adult male rats by aortocaval fistula. Methods: Fistula animals were treated with digoxin (5ug/kg/d), (FID. n* 6) or saline placebo (Ffê, n-7) via subcutaneous mlnipumps. Sham-operated animals were also studied (S/D, n= 6, and S/S, n-7). Cavity dimensions (LVDs), percent fractional shortening (%FS) and LV weight (LVW) were measured from 2Decho triggered M-mode tracings. After six weeks, in vivo %FS and hemodynamlc responses to dobutamine infusion (1-1 Oug/kg/min) were measured. Myocardial (Weceptor density (Bmax) and adenylate cyclase (AC) response to isoproterenol (Vmax) were measured. Results: 1) Digoxin did not ameliorate the Increase in LVW and LVDs that occurred in fistula animals (see table). 2) The increase in %FS in response to dobutamine was blunted in fistula animals as compared to shams, and was associated with a loss of responsrveness of AC in vitro, but no change in Bmax. 3) Digoxin treatment restored in v/fru responsiveness of AC to stimulation, but did not affect Bmax or improve in vivo res ronse to dobutamine. Group LVW LVDs %FS %FS10ug B-4,(e-13) V-4,(pmol) SCS 86)118 4.2±.2 51+2 86+3 34+3 1.8+.2 S/D 1031+38 4.2±.2 50+2 78+3 35±3 2.41.B F/S 1519+84- 6.4±.3- 44±2 56±3' 47+10 0.5+.2' F/D 1588+69' 6.4+.4' 47+2 62+5- 32+4 1.4+.2 *p<.001 vs sham , p<.OS vs sham Conclusion: Digoxin restores β-receptor function in volume overload but has no effect on LV contractile reserve. This suggests that other factors may be responsible for the contractile dysfunction that results In overload remodeling.
Sullebaraer, JT; D'Ambra, PM; Clark, LC; Thannikary, UJ; Schocken, DD; Fontanet, HL
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