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 of contractility in the absence of added endothelin. To address this question, the changes in contractility of isolated rat ventricular trabeculae produced by endothelin and by BQ-123, an endothelin receptor A antagonist, were measured in tissues with different levels of contractility 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-123 also depended on the extent to which force had declined. The effects of the addition of endothelin or BQ-123 indicate the presence of substantial regulation of contractility due to basal secretion of endothelin: the degree of endothelin activity is greater in cardiac tissue generating more tension. Damage to the endocardial endothelium from a brief exposure to Triton X-100 reduced the response to BQ-123. The response 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 sensitive to endothelin produced by the endothelial cells in the isolated heart. This stimulation of contractility is gradually lost in the isolated cardiac tissue, contributing to the progressive decline in developed force with time.