Endocardial endothelium has been shown to modulate the contractile characteristics and alpha-1-adrenergic responsiveness of its adjacent myocardium. This study was designed to evaluate whether this was also the case in the pacing-overdrive model of heart failure in the dog, a model in which changes in contractile characteristics and changes in alpha-1-adrenergic responsiveness similar to those caused by endocardial endothelial removal, occur prior to endocardial endothelial removal. Pacing-overdrive heart failure caused a decrease in total tension (TT) (5.1 +/- 0.5 g/mm2 in controls to 2.2 +/- 0.4 g/mm2 in pacing-overdrive, P < 0.01) and twitch configuration (time to 1/2 tension decline [RT1/2] 659 +/- 23 to 517 +/- 41 ms P < 0.01) to occur in isolated papillary muscles. Endocardial endothelial removal in control muscles caused similar but less marked changes (TT to 3.8 +/- 0.3 g/mm2, and RT1/2 to 563 +/- 21 ms). Endocardial endothelium removal also decreased TT (to 1.6 +/- 0.3 g/mm2) and RT1/2 (459 +/- 28 ms) in pacing-overdrive muscles indicating that even in this model of heart failure, endocardial endothelium continued to modulate the contractile characteristics of its adjacent myocardium. The addition of phenylephrine caused proportionately similar changes in contractile characteristics in both control and pacing-overdrive muscles prior to and after endocardial endothelial removal. However, in control muscles, endocardial endothelial removal caused a rightward shift in phenylephrine concentration-response curve (EC50 0.6 +/- 0.2 x 10(-6)M to 3.4 +/- 1.0 x 10(-6)M, P < 0.05). Pacing-overdrive muscles already had a rightward shift (EC50 = 4.1 +/- 1.0 x 10(-6)M) prior to endocardial endothelium removal, such that endocardial endothelial removal caused no further shift in EC50 (2.8 +/- 1.0 x 10(-6)M) indicating that the decrease in alpha-1-adrenergic responsiveness in this model was endocardial endothelium dependent. Taken together, these results suggest that the direct modulating effects of the endocardial endothelium on its adjacent myocardium are not necessarily related to its modulatory role on the myocardial effects of circulating substances in the plasma and, that in heart failure, the decrease in alpha-1-adrenergic responsiveness that occurs is related to endocardial endothelium dysfunction.