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The response of cardiac SR Ca(2+)-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 treated with saponin to permeabilise the sarcolemma but retain SR function, and bathed in a mock intracellular solution including adenosine triphosphate (ATP) and buffered calcium. Caffeine (10 mM) was used to release calcium from the SR. The amplitude of the caffeine-induced contracture 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 (SH, n = 10), isoprenaline-infused rabbits (ISO, 7 days mini-osmotic pump 100 micrograms/kg.h; n = 7) and saline-infused controls (SAL, n = 7). Failing human RV trabeculae were obtained at the time of cardiac transplantation. Failing rabbit trabeculae demonstrated increased baseline caffeine-induced contractures compared with controls, the response to cAMP was similar in the two groups (LIG 9.3 +/- 2.8 vs SH 10.6 +/- 3.2% Fmax; P = 0.55), There was no difference in the baseline SR Ca(2+)-loading in ISO trabeculae compared with SAL controls but there was a marked difference in the response to cAMP (11.1 +/- 5.4 vs 4.2 +/- 2.1% Fmax, P = 0.02). SR Ca(2+)-loading in failing human RV trabeculae was related to the severity of LV dysfunction (r = 0.59, P = 0.04) and demonstrated a marked cAMP-induced enhancement of caffeine-contracture (20.2 +/- 4.7% increase of Fmax) which was greater in patients with low compared with high ejection fraction. While beta-receptors are known to be down regulated in heart failure these results suggest that the scope for cAMP-mediated enhancement of SR Ca(2+)-loading is maintained.