NOVEL CARDIAC MYOFILAMENT DESENSITIZING FACTOR RELEASED BY ENDOCARDIAL AND VASCULAR ENDOTHELIAL-CELLS

Background Recent studies suggest that both endocardial endothelium an d coronary vascular endothelium influence myocardial contraction, but the mediators responsible and their mechanisms of action are not well defined. Methods and Results We investigated the effects of cultured e ndocardial endothelial and vascular endothelial cell superfusate on co ntraction and intracellular calcium transients of isolated rat cardiac myocytes. Endothelial cell superfusate induced a potent negative inot ropic effect, with a rapid reversible decrease in myocyte twitch ampli tude, earlier twitch relaxation, and a significant increase in diastol ic length. This effect was not associated with significant changes in intracellular calcium or pH; was not attributable to nitric oxide, pro stanoids, cGMP, or protein kinase C activation; and did not pertussis toxin-sensitive G proteins. The activity was stable at 37 degrees C fo r several hours, was not destroyed by protease treatment, and was foun d in low-molecular-weight (<<1 kD) superfusate fractions. Conclusions These data suggest the tonic release by endothelial cells of a novel, stable factor that acts predominantly by reducing the response of card iac myofilaments to calcium (ie, ''desensitizes'' them). This ''desens itizing factor'' could rapidly modulate cardiac contraction-relaxation coupling and diastolic tonus and exert distant effects because of its stability.