Effects of Cardiopulmonary Bypass on Endothelin-1-Induced Contraction and Signaling in Human Skeletal Muscle Microcirculation

Background-We investigated the effects of cardiopulmonary bypass (CPB) on the contractile response of human peripheral microvasculature to endothelin-1 (ET-1), examined the role of specific ET receptors and protein kinase C-alpha (PKC-alpha), and analyzed ET-1 related gene/protein expression in this response. Methods and Results-Human skeletal muscle arterioles (90 to 180 mu m in diameter) were dissected from tissue harvested before and after CPB from 30 patients undergoing cardiac surgery. In vitro contractile response to ET-1 was assessed by videomicroscopy, with and without an endothelin-A (ET-A) receptor antagonist, an endothelin-B (ET-B) antagonist, or a PKC-alpha inhibitor. The post-CPB contractile response of peripheral arterioles to ET-1 was significantly decreased compared with pre-CPB response. The response to ET-1 was significantly inhibited in the presence of the ET-A antagonist BQ123 but unchanged in the presence of the ET-B receptor antagonist BQ788. Pretreatment with the PKC-alpha inhibitor safingol reversed ET-1-nduced response from contraction to relaxation. The total protein levels of ET-A and ET-B receptors were not altered after CPB. Microarray analysis showed no significant changes in the gene expression of ET receptors, ET-1-related proteins, and protein kinases after CPB. Conclusions-CPB decreases myogenic contractile function of human peripheral arterioles in response to ET-1. The contractile response to ET-1 is through activation of ET-A receptors and PKC-alpha. CPB has no effects on ET-1 related gene/protein expression. These results provide novel mechanisms of ET-1 induced contraction in the setting of vasomotor dysfunction after cardiac surgery. (Circulation. 2010;122[suppl 1]:S150S-155.)