Antispastic Management in Arterial Grafts in Coronary Artery Bypass Grafting Surgery  Guo-Wei He, MD, DSc, David P. Taggart, FRCS  The Annals of Thoracic Surgery  Volume 102, Issue 2, Pages 659-668 (August 2016) DOI: 10.1016/j.athoracsur.2016.03.017 Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 Schema of molecular mechanisms of smooth muscle contraction and relaxation. Contraction is the summation of myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) activity. Ca2+ influx through calcium channels in the membrane (voltage-operated channel [VOC] and receptor-operated channel [ROC]) and Ca2+ release from intracellular stores in the sarcoplasmic reticulum (SR) through phospholipase C (PLC)-mediated hydrolysis of phosphotidyl inositol bisphosphate, yielding inositol triphosphate (IP3) result an increase in intracellular Ca2+. The Ca2+ interacts with calmodulin, forming a Ca2+-calmodulin complex, which activates MLCK that phosphorylates myosin light chain, allowing for force generation. Vasoconstrictors such as the agonists of alpha-adrenoceptor (α), thromboxane A2 (TXA2), endothelin-1 (ET), and so forth, stimulate G-protein coupled receptors (GPCRs) directly opening the ROC causing Ca2+ influx, or through the production of second messengers such as IP3 causing release of the stored Ca2+. Contraction can also be mediated in Ca2+-sensitization mechanism. Rho kinase becomes activated through the activated RhoA protein, which subsequently phosphorylates MLCP, rendering the enzyme inactive and incapable of dephosphorylating MLC. Relaxation occurs with MLCP dephosphorylating MLC. That can be fulfilled through various mechanisms. For example, it can be through blockage of Ca2+ influx by calcium channel blocker to decrease the intracellular Ca2+. The antagonists of specific vasoconstrictors such as the antagonists of alpha-adrenoceptor, TXA2, ET, and so forth, inhibit the ROC associated with GPCRs. Nitrovasodilators by releasing nitric oxide (NO) stimulate soluble guanylate cyclose (sGCs), which increases synthesis of cyclic guanosine monophosphate (cGMP) from guanosine-5′-triphosphate (GTP). Increased cGMP level inhibits VOC and ROC through protein kinase G (PKG) pathways. NO-cGMP also interacts with the Rho kinase pathway through cGMP-regulated protein kinases (cGK), interferes with the MLC and phospho-MLC activity, and finally, relaxes the smooth muscle. The Rho kinase inhibitor inhibits the Rho kinase pathway and the phosphodiesterase (PDE) inhibitors increase cGMP level through inhibiting cGMP–5′GMP activity, relaxing the vessel. Potassium channel openers (K+ openers) open the potassium channels such as calcium-sensitive potassium channels (KCa), cause efflux of K+, and hyperpolarize the membrane potential (Em). The membrane hyperpolarization decreases intracellular Ca2+ levels by inhibiting Ca2+ influx through VOC and favors the reuptake of Ca2+ into intracellular stores and extrusion of Ca2+ from the cell, resulting in relaxation. Prostacyclin (PGI2) raises cyclic adenosine monophosphate (cAMP) levels in the cytosol, and through activation of the protein kinase A pathway, leads to relaxation. This schema also shows that each vasodilator relaxes a blood vessel in a specific pathway, although there are some interactions between the pathways. A possible protocol for relaxation of coronary artery bypass grafts is to combine two vasodilators that relax the vessel using different pathways. The Annals of Thoracic Surgery 2016 102, 659-668DOI: (10.1016/j.athoracsur.2016.03.017) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions