EFFECTS OF CYCLIC ADENOSINE-MONOPHOSPHATE (CAMP) ON SARCOPLASMIC-RETICULUM CA2-LOADING IN FAILING RABBIT AND HUMAN CARDIAC TRABECULAE()

The response of cardiac SR Ca2+-loading to cAMP in failing rabbit and human myocardium was examined. Right ventricular (RV) trabeculae were isolated and mounted for isometric tension measurement. They were trea ted with saponin to permeabilise the sarcolemma but retain SR function , and bathed in a mock intracellular solution including adenosine trip hosphate (ATP) and buffered calcium. Caffeine (10 mM) was used to rele ase calcium from the SR. The amplitude of the caffeine-induced contrac ture was used as a quantitative gauge of the calcium content of the SR . Trabeculae were isolated from rabbits with coronary ligation-induced heart failure (LIG, n = 11), sham operated controls (SW, n = 10), iso prenaline-infused rabbits (ISO, 7 days mini-osmotic pump 100 mu g/kg.h ; n = 7) and saline-infused controls (SAL, n = 7). Failing human RV tr abeculae were obtained at the time of cardiac transplantation. Failing rabbit trabeculae demonstrated increased baseline caffeine-induced co ntractures compared with controls, the response to cAMP was similar in the two groups (LIG 9.3 +/- 2.8 vs SH 10.6 +/- 3.2 % F-max; P = 0.55) , There was no difference in the baseline SR Ca2+-loading in ISO trabe culae compared with SAL controls but there was a marked difference in the response to cAMP (11.1 +/- 5.4 vs 4.2 +/- 2.1 % F-max, P = 0.02). SR Ca2+-loading in failing human RV trabeculae was related to the seve rity of LV dysfunction (r = 0.59, P = 0.04) and demonstrated a marked cAMP-induced enhancement of caffeine-contracture (20.2 +/- 4.7 % incre ase of F-max) which was greater in patients with low compared with hig h ejection fraction. While beta-receptors are known to be down regulat ed in heart failure these results suggest that the scope for cAMP-medi ated enhancement of SR Ca2+-loading is maintained.