Serotonin-induced coronary contraction increases after blood cardioplegia-reperfusion - Role of COX-2 expression

Background-Coronary contraction has been implicated in causing suboptimal m yocardial function after coronary bypass surgery. Addition of blood to card ioplegic solutions has been shown to improve endothelial function after car dioplegia. In this study, the effects of blood cardioplegia and brief reper fusion on vascular reactivity in patients with coronary artery disease and the expression (mRNA and protein) of enzymes involved in vasomotor regulati on were examined. Methods and Results-The atrial appendages of patients undergoing coronary a rtery surgery were harvested before cardiopulmonary bypass (control, n = 8) and after bypass from a nonischemic tissue atrial segment exposed to cold, hyperkalemic blood cardioplegia (mean, 60 minutes) and a brief period (10 minutes) of reperfusion (CP-Rep, n = 8). Responses of atrial arterioles wer e studied in vitro with video-microscopy. Reverse-transcriptase polymerase chain reaction and Western blotting were used to examine the expressions an d protein content, respectively, of enzymes involved in vasomotor regulatio n. Serotonin caused a minimal dilation under baseline conditions but after CP-Rep elicited a potent contractile response that was inhibited in the pre sence of the selective inducible cyclooxygenase (COX-2) inhibitor NS398. Su bstance P caused an endothelium-dependent relaxation of atrial arterioles t hrough release of nitric oxide, and ADP caused relaxation mediated through release of prostaglandins. After CP-Rep, relaxation to substance P was impa ired, whereas endothelium-independent relaxation to nitroprusside and respo nse to ADP were unchanged. Expression and protein level of COX-2 were signi ficantly increased after CP-Rep. In contrast, expression of inducible (nitr ic oxide synthase-2) or constitutive endothelial (nitric oxide synthase-3) nitric oxide synthase, prostacyclin synthase, and constitutive cyclooxygena se (COX-1) were not altered after CP-Rep. Conclusions-CP-Rep increases serotonin-induced contraction of human microve ssels caused by the release of products of COX-2 and the impaired release o f nitric oxide. These findings have implications regarding altered coronary microvascular regulation and the cause of coronary spasm after cardiac sur gery.