Nitric oxide homeostasis as a target for drug additives to cardioplegia

Abstract

The vascular endothelium of the coronary arteries has been identified as the important organ that locally regulates coronary perfusion and cardiac function by paracrine secretion of nitric oxide (NO) and vasoactive peptides. NO is constitutively produced in endothelial cells by endothelial nitric oxide synthase (eNOS). NO derived from this enzyme exerts important biological functions including vasodilatation, scavenging of superoxide and inhibition of platelet aggregation. Routine cardiac surgery or cardiologic interventions lead to a serious temporary or persistent disturbance in NO homeostasis. The clinical consequences are ''endothelial dysfunction'', leading to ''myocardial dysfunction'': no-or low-reflow phenomenon and temporary reduction of myocardial pump function. Uncoupling of eNOS (one electron transfer to molecular oxygen, the second substrate of eNOS) during ischemia-reperfusion due to diminished availability of L-arginine and/or tetrahydrobiopterin is even discussed as one major source of superoxide formation. Therefore maintenance of normal NO homeostasis seems to be an important factor protecting from ischemia/reperfusion (I/R) injury. Both, the clinical situations of cardioplegic arrest as well as hypothermic cardioplegic storage are followed by reperfusion. However, the presently used cardioplegic solutions to arrest and/or store the heart, thereby reducing myocardial oxygen consumption and metabolism, are designed to preserve myocytes mainly and not endothelial cells. This review will focus on possible drug additives to cardioplegia, which may help to maintain normal NO homeostasis after I/R.

β2-Glycoprotein I inhibits endothelial cell migration through the nuclear factor κB signalling pathway and endothelial nitric oxide synthase activation

“…Moreover, NO synthesized by eNOS in the endothelial cells has been well characterized in maintaining cell homoeostasis in the vasculature [32,33]. Mounting evidence indicates that lack of NO production may cause endothelial dysfunction [33,50].…”

“…NO generated by eNOS is a signalling messenger with beneficial effects on endothelial cell homoeostasis [32,33]. NO production is able to activate the sGC (soluble guanylyl cyclase) and increase the production of cGMP.…”

The ageing population – a challenge for cardiovascular surgery

“…Besides, myocardial protection was limited to intraoperative protection only and did not address the potential benefits of perioperative management [34]. We have shown convincing experimental evidence that pre-and intra-operative priming of the heart with endothelialprotective drugs can improve organ function and postischemic outcome [35][36][37].…”

A prospective, randomized, single-blind, multicentre, phase III study on organ preservation with Custodiol-N solution compared with Custodiol® solution in organ transplantation (kidney, liver and pancreas)

“…Microcirculatory disturbances have been reported following reperfusion of diverse organs. In various experimental models, the troublesome application of the vasodilator nitric oxide or simply the supplementation of L-arginine (the substrate of the endogenous nitric oxideproducing enzymes) has been proven to decrease these microcirculatory disturbances [18][19][20][21]. Therefore, in Custodiol-N, L-arginine is supplemented.…”