Impaired Contractile Response Of Human Peripheral Arterioles To TXA-2 After Cardiopulmonary Bypass

Abstract

Introduction: Cardiopulmonary bypass (CPB) is often associated with peripheral vasomotor dysfunction. This is thought to lead to decreased vascular tone, hypotension, and an increased need for vasopressor support. We investigated the contractile response to the vasoconstrictor thromboxane A2 (TXA-2), the blockade of TXA-2 receptors and the inhibition of phospholipase-C (PLC) and phospholipase-A2 (PLA-2) in the human peripheral microvasculature pre- and post- CPB. We also examined the effect of CPB on the gene expression of skeletal muscle TXA-2 and TXA-2 synthase. Methods: Chest wall skeletal muscle tissue was harvested pre- and post-CPB from patients undergoing coronary artery bypass grafting. Skeletal muscle arterioles (90-180 micrometer in diameter) were dissected from the harvested tissue and placed in an organ bath containing Krebs solution. Constractile response of the peripheral arterioles to the TXA-2 analog U46619, with and without the highly selective TXA-2 receptor antagonist, SQ 29548, the specific PLC inhibitor U73122 or the selective PLA-2 inhibitor, quinacrine was assessed by videomicroscopy. TXA-2 receptor and TXA-2 synthase gene expression were examined using microarray analysis. Results: The post-CPB contractile response of peripheral arterioles to TXA-2 analog U46619 (10−6M) was significantly impaired compared with pre-CPB (28.5±2% vs. 42.7±3.6 %, P=0.002). The presence of TXA-2 antagonist SQ 29548 (10−6 M) prevented the contractile response to U46619. Pretreatment with the PLC inhibitor U73122 (10−5M) significantly inhibited the U46619-induced contractile response as well. Addition of the PLA-2 inhibitor,quinacrine (10−6M) failed to affect U46619-induced contraction. Microarray analysis showed no significant changes in the gene expression of TXA-2 receptor and TXA-2 synthase. Conclusions: CPB decreases the contractile response of human peripheral arterioles to TXA-2 analog U46619. The contractile response to the TXA-2 analog U46619 is via activation of TXA-2 receptors and PLC, but not of PLA-2. These results provide novel mechanisms for TXA-2-induced contraction and signaling in peripheral vasomotor dysfunction after CPB and cardiac surgery.