| Preconditioning has been documented in multiple experimental models and clinical scenarioes, whereby a seemingly noxious stimulus seems to confer resistance to a subsequent, related insult. The phenomenon is useful to the self-protection of host. A great deal of studies have shown that the ATP-sensitive potassium channel opener (KCO) can mimic the preconditioning induced by ischemia. For example, pinacidil, nicorandil, bimakalim, aprikalim, all these of ATP-sensitive potassium channel openers as pharmacologic preconditioning can significantly reduce myocardial damage, or improve cardiac contractile function. In the parallel investigation using the endotoxin, lipopolysaccaride (LPS) in whole animals or cell cultures, this decreased response to a second exposure was termed endotoxin tolerance. The mechanism of endotoxin tolerance is similar to ischemia-preconditioning's, both of them exist cross-tolerance.These investigations showed that LPS, monophosphoryl lipid A (MLA) as inducers of endotoxin tolerance could decrease the injuries of heart, liver and kidney induced by ischemia-reperfusinon. Based on these results, we used pinacidil as a pharmacological preconditioning tool on experimental models, to explore the effects of pharmacological preconditioning on endotoxemia and resuscitation, and its mechanisms.In the present study we evaluated the protection effects of pinacidil on endotoxemia and its mechanisms. In order to elucidate the mechanisms of preconditioning of pinacidil, following three protocols were conducted: (1) the effect of pinacidil pretreatment on blood coagulation; (2) the effect of pinacidilinpretreatment on cytokine generation and modulation of signal transduction; (3) the effect of pinacidil pretreatment on respiratory burst of polymorphonuclear neutrophil(PMN).The main results and conclusions were as follows;Firstly, in the endotoxemia mice, the survival rate in pinacidil pretreatment was higher than that in LPS control group. The survival rate in glyburide, a antagonist of pinacidil, was reduced markedly than that in pinacidil pretreatment.In the endotoxemia rats,metabolic acidosis, respiratory acidosis, hyperkalemia were appeared, the blood levels of natriumCNa*), chlorine(Cl') and calcium (Ca2+) were decreased markedly. Following the pretreatment with pinacidil, it seems that metabolic acidosis, hyperkalemia, hyponatremia, hypochloraemia and hypocalcemia were aggraved, but respiratory acidosis was reduced. The effect of the pinacidil pretreatment was partly blocked by glyburide. These results indicated that pinacidil pharmacologically preconditioned to endotoxemia, but had no significant effect on metabolism disorder caused by endotoxemia.Secondly, Through detecting coagulation factors II, V, VQ, X and fibrinogen with sedimentation, we discovered that pinacidil pretreatment delayed the decrease of coagulation factors II,V,Vfl and X, and caused fibrinogen increase in pinacidil-group remarkedly increase compared with LPS-group. Glyburide had antagonistic action to pinacidil pretreatment. These results suggested that pinacidil pretreatment could delay the occurance of blood coagulation and decrease the microthrombus in endotoxemia.Thirdly, TNF-a and IL-6 in blood of rats were detected by ELISA. The result indicated that pinacidil pretreatment significantly decreased TNF-a and IL-6 level in endotoxemia When human monocyte THP-1 was stimulated by LPS, pinacidil pretreatment significantly reduced TNF-a and EL-6 secreted by THP-1. Glyburide had antagonistic action to pinacidil pretreatment. These results suggested thatIVpinacidil pretreatment could decrease TNF-a and IL-6 release of monocyte/ macrophage during SIRS, and then reduced TNF-a and IL-6 level in circulation.Forthly, through detecting TLR4 expression on THP-1 with flow cytometer, we discovered that TLR4, transmembrane receptor of LPS, induciblely expressed after being stimulated with LPS.We firstly discorvered that pinacidil pretreatment significantly downregulated TLR4 expression of THP-1 af...
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