Effect Of Nitric Oxide And Endothelin On Hepatic Microcirculation During Ischemia-Preconditioning In Rats

Hepatic injury secondary to ischemia and reperfusion is an important clinical issue. It has been implicated in the pathogenesis of a variety of clinical conditions including trauma, thermal injury, and shock, reconstructive vascular surgery, liver transplantation, and liver resectional surgery. The hepatic microvasculature, i.e., the sinusoidal space with the lining endothelium is vulnerable to the deleterious consequences. Microvascular dysfunction results from a series of events that involve the interaction of intravascular blood cells, i.e. neutrophil, with nonparenchymal cells, endothelial and Kupffer cells, and are mediated by the synthesis and release of adhesion proteins, cytokines, reactive oxygen species, nitric oxide, and endothelins. Another mechanism involved in the pathogenesis of the microvascular dysfunction is the local complement activation. Although the mechanism is not clear, ischemia-reperfusion-induced microvascular dysfunction cannot be expained by means of : (i) imbalance between the rate of NO production and the release of endothelin;(ii)alteration of the ratio between NO and superoxide anion;(iii)degree of neutrophil adhesion and activation. Over recent years,a surgical strategy known as ischemic-perconditioning has been developed to reduce ischemia-reperfusion injury.By this procedure,an organ is made resistant to the deleterious effects of sustained ischemia and reperfusion by previous exposure to repeated short periods of ischemia,seperated by intermitent reperfusion.The protective effect of ischemic-preconditioning was first described in the heart,and has since been demonstrated in many other organs.While originally described as an immediate adaptation to bridf vascular occlusion,ischemia preconditioning actually affords two types of protection,which differ in time frame and mechanisms. For this reason ,distinction is made between early and delayed preconditioning.With regard to the liver,adenosine has thus far been consierd the major player in triggering early preconditioning,which has been shown to inhibit neutrophil oxidative metabolism and adhesion to endothelial cells,to increase membrane stability and energy production by promoting glucose transport ,and to reduce Ca2+ influx through the acivation of ATP-dependent K+ channels.While the triggering and amplification of signals for procection seem to be as in early preconditioning, the effectors of this second window are probably different.The time frame within which the second wimdow confers protection lends itself to the theory that altered gene expression,with the consequent synthesis of new proteins,is the protection method. Several proteins have been proposed as possible effectors, including nitric oxide synthase, cyclooxygenase-2, antioxidant enzymes, and heat shock proteins.During delayed preconditioning the rate of NO production and the release of endothelin is considered as significant factor to modulate hepatic microvascular dysfunction. Nitric oxide and endothelin are low-molecular-weight bioactive peptide discoveried by recent decades, which can comprehensively exert various biological effects as cellular messages by means of autocrine, paracrine and circulation. Endothelin is a potent vasoconstrictor, which promotes hematoblastic conglomeration, hyperplasia of vascular smooth muscle and cellular adhesion, but NO exerts adverse action and ameliorate blood flow.Therefore,a endogenous endoself-balanced system is constructed by NO and endothelin ,which play a important role in regulating vasoconstriction and vasodialation , maintaining circulation and hepatic microcirculation.The aim of this research is to observe the level of NO and endothelin and change of hepaeic microcirculation during ischemic preconditioning in ischemia-reperfusion models,and investigate protection of microcirculation after preconditioning .Data indicate that preconditioning can meliorate microvascular dysfunction which is involved with increase of NO and decrease of endothelin.The mechanisms ,by which NO is relesed during ischemic p...