ENDOTHELIN REGULATION OF CARDIAC CONTRACTILITY IN ABSENCE OF ADDED ENDOTHELIN

Endothelin has a positive inotropic effect on cardiac muscle, but its role in the regulation of contraction in cardiac tissue is not clear, inasmuch as there has been no demonstration of endothelin regulation o f contractility in the absence of added endothelin. To address this qu estion, the changes in contractility of isolated rat ventricular trabe culae produced by endothelin and by BQ-123, an endothelin receptor A a ntagonist, were measured in tissues with different levels of contracti lity resulting from bathing the tissues for different lengths of time. The effect of endothelin depended on the extent to which tension had declined from its peak level: the greater the decline, the larger the increase in developed force produced by endothelin. The effect of BQ-1 23 also depended on the extent to which force had declined. The effect s of the addition of endothelin or BQ-123 indicate the presence of sub stantial regulation of contractility due to basal secretion of endothe lin: the degree of endothelin activity is greater in cardiac tissue ge nerating more tension. Damage to the endocardial endothelium from a br ief exposure to Triton X-100 reduced the response to BQ-123. The respo nse to BQ-123 depends on the number of functioning endothelial cells. From the extent of the effect of endothelin or BQ-123, it appears that as much as 50% of total force-generating capacity of the tissue is se nsitive to endothelin produced by the endothelial cells in the isolate d heart. This stimulation of contractility is gradually lost in the is olated cardiac tissue, contributing to the progressive decline in deve loped force with time.