Impaired contractile response of human peripheral arterioles to thromboxane A-2 after cardiopulmonary bypass.

Abstract

We studied the contractile response of human peripheral microvasculature to thromboxane A-2 (TXA-2) before and after cardiopulmonary bypass (CPB), with and without the blockade of TXA-2 receptors, or the inhibition of phospholipase C (PLC), phospholipase A-2 (PLA-2) or protein kinase C (PKC)-α. We also examined the protein/gene expression and localization of TXA-2 receptors, TXA-2 synthase, PLC, and other TXA-2-related proteins. Skeletal muscle arterioles (90-180 μm in diameter) were harvested pre- and post-CPB from patients (n = 28) undergoing cardiac surgery. The post-CPB contractile response of skeletal muscle arterioles to TXA-2 analog U-46619 was impaired compared with pre-CPB (P < .05). The presence of TXA-2 receptor antagonist SQ-29548 (10(-6)mol/L) prevented the contractile response to U-46619 (P < .05). Pretreatment with the PLC inhibitor U-73122 (10(-6)mol/L) significantly inhibited the U-46619-induced contractile response (P < .01). Administration of the PLA-2 inhibitor quinacrine (10(-6)mol/L) or PKC-α inhibitor safingol (2 × 10(-5)mol/L), however, failed to affect U-46619-induced contraction. Total protein levels and gene expression of TXA-2 receptors, and TXA-2 synthase of skeletal muscle, were not altered post-CPB. Confocal microscopy showed no differences in the expression of PLCβ-3 in the microcirculation. PLCβ-3 was localized to both smooth muscle and endothelium. CPB decreases the contractile response of human peripheral arterioles to TXA-2 soon after cardiac surgery. This response may be in part responsible for the decrease in vascular tone, and accompanying hypotension sometimes observed after cardiac operations utilizing CPB.