Altered coronary microvascular serotonin receptor expression after coronary artery bypass grafting with cardiopulmonary bypass

Abstract

Objectives Evaluate the role of serotonin receptors 1B and 2A, thromboxane synthase and receptor and phospholipases A2 and C in response to cardiopulmonary bypass in patients. Methods Atrial tissue was harvested from patients before and after cardiopulmonary bypass with cardioplegia (n=13). Coronary microvessels were assessed for vasoactive response to serotonin with and without inhibitors of 5-HT1B and 5-HT2A receceptors, phospholipase A2 and C. Expression of 5-HT1B and 5-HT2A mRNA was determined by RT-PCR. Expression of 5-HT1B, 5-HT2A, Thromboxane A2 receptor and synthase protein was determined by immunoblotting and immunohistochemistry. Results Exposure of microvessels to serotonin elicited a 7.3 ± 2% relaxation response pre-bypass, changing to a strong contraction response of -19.2 ± 2% after bypass (p<0.001). Addition of either a specific 5-HT1B antagonist or inhibitor of PLA2 resulted in a significant decrease in the contractile response to -8.6 ±1% (p<0.001) and 2.8 ± 3% (p= 0.001), respectively. 5-HT1B receptor mRNA expression increased 1.82 ± 0.34 fold after bypass (p=0.044), while 5-HT2A mRNA expression did not change. 5-HT1B receptor, but not 5-HT2A, protein expression increased after bypass by 1.35 ± 0.7 fold (p=0.0413). Neither thromboxane synthase nor thromboxane receptor expression changed after bypass. Immunohistochemistry demonstrated 5-HT1B receptor increased mainly in the arterial smooth muscle. There was no appreciable difference in arterial expression of either thromboxane synthase or receptor. Conclusion These data indicate that 5-HT-induced vascular dysfunction after cardiopulmonary bypass with cardioplegia may be mediated by increased expression of 5-HT1B receptor and subsequent PLA2 activation in myocardial coronary smooth muscle. Mini Abstract The expression of 5-HT1B receptor protein and mRNA were increased in the atrial myocardium after cardioplegia and cardiopulmonary bypass (CP-CPB). Serotonin elicited a strong contraction response of atrial microvessels after CPB which was mitigated by specific 5-HT1B receptor blockers and phospholipase A2 inhibitors. This suggests that coronary microvascular contraction after CP-CPB is related to increased expression of the 5-HT1B receptor and subsequent phospholipase A2 signaling.

Effects of Selective Cyclooxygenase-2 and Nonselective Cyclooxygenase Inhibition on Myocardial Function and Perfusion

“…After cardiac harvest, coronary arterioles (80-180μm in diameter) from the myocardium supplied by the left anterior descending coronary artery (LAD) were dissected from the surrounding tissue and placed in an isolated microvessel chamber as described previously 14. Response to the vasoconstricting agent serotonin (5-HT, 10 -9 mol/L to 10 -5 mol/L) was assessed in non-precontracted vessels.…”

Microvascular dysfunction in patients with diabetes after cardioplegic arrest and cardiopulmonary bypass

“…(28, 43) Further study shows that 5HT-induced vascular dysfunction after CP/CPB may be mediated by increased expression of 5HT-1B receptor and subsequent phospholipase A2 (PLA-2) activation in myocardial coronary smooth muscle. (44) These findings may have implications regarding the cause of coronary spasm during acute myocardial ischemia. Verma and colleague also reported that diabetic coronary microvessels respond to CP/CPB with greater ET-1-mediated vasoconstriction and diminished nitric oxide-mediated vasodilatation; and 3) these effects are attenuated by ET antagonism.…”

“…(28, 43, 44) CP/CPB enhances contractile response of arterioles to 5-HT may be due to the stimulated prostaglandin release (likely TXA-2) secondary to induction of COX-2 expression. (28, 43) Further study shows that 5HT-induced vascular dysfunction after CP/CPB may be mediated by increased expression of 5HT-1B receptor and subsequent phospholipase A2 (PLA-2) activation in myocardial coronary smooth muscle.…”

Mechanisms Responsible for Serotonin Vascular Reactivity Sex Differences in the Internal Mammary Artery

“…More important, activated platelets liberate serotonin and thromboxane A 2 , both of which are potent vasoactive compounds implicated in several clinical situations, such as angina, acute coronary syndrome, and vasospasm 10, 11, 12. Serotonin and thromboxane A 2 function through their cell surface receptors (serotonin 2A+2B and thromboxane A 2 receptors), coupled to both the G q/11 and G 12/13 families of G‐protein–coupled receptors, respectively.…”