Direct effects of thrombin on myocyte contractile function.

Abstract

Cardiopulmonary bypass activates the clotting cascade, resulting in elevated circulating levels of thrombin. In light of the fact that the function of a wide variety of cell types is modulated by thrombin, we hypothesized that thrombin may have a direct effect on myocyte function. Isolated left ventricular myocyte contractile function was measured from 6 adult dogs using videomicroscopy at baseline and after increasing concentrations of thrombin (1 to 10 U/mL). Indices of myocyte contractile function were reduced in a dose-dependent manner in the presence of increasing concentrations of thrombin. For example, myocyte percent shortening fell by 18% with 1 U/mL thrombin and by 43% with 2 U/mL thrombin. The addition of hirudin, a highly selective thrombin inhibitor, completely blocked the effects of thrombin on myocyte contractile function. beta-Adrenergic agonists are commonly used in the early post-cardiopulmonary bypass period. Accordingly, a final set of experiments examined the effects of thrombin on myocyte beta-adrenergic responsiveness using isoproterenol (25 nmol/L). In myocytes preincubated with 1 U/mL thrombin, myocyte beta-adrenergic responsiveness was significantly reduced. For example, in the presence of 1 U/mL thrombin, myocyte velocity of shortening fell by 25% from isoproterenol alone values. The results from the present study provide evidence that thrombin has a direct negative effect on steady-state contractile function and beta-adrenergic responsiveness in adult mammalian ventricular myocytes. These findings suggest that thrombin may be an additional contributory factor toward the transient left ventricular dysfunction that has been observed after cardiopulmonary bypass.