The Mechanism Of Protective Effect Induced By Pharmacological Postconditioning On Mycardical/renal Ischemia Reperfusion Injury

Objective Morphine has been widely used to rescue heart stroke and failure in human for many decades.Relatively little has been known about the role of spinal opioid receptors in morphine cardioprotection.Recent studies have shown that intrathecal morphine postconditioning(IMPOC)can reduce the heart injury caused by ischemia reperfusion(I/R)in rats.However,the molecular and cellular mechanism underlying intrathecal morphine cardioprotection has not been determined.n NOS/s GC/c GMP signaling pathway is a very important pathway on morphine depress the noxious stimulation in primary neuronal cells.This research is to discover the effective of n NOS/s GC/c GMP signaling pathway on IMPOC.Methods Male Sprague-Dawley rats were implanted with intrathecal catheter and subjected to myocardial ischemia and reperfusion injury.IMPOC was achieved by5-min intrathecal infusions of morphine at the end of ischemia.Intrathecally administrated a non speci?c nitric oxide synthase(NOS)inhibitor N?-Nitro-L-arginine methyl ester(L-NAME,30 nmol)and a specific neuronal NOS 7-nitroindazole(7-NI,100nmol),a speci?c guanylate cyclase inhibitor ODQ(11 nmol)10 min before RMPC.Infarct size,as a percentage of the area at risk(AAR),was determined by2,3,5-triphenyltetrazolium staining.The content of NO and c GMP in the thoracic spinal cord was determined by enzyme immunoassay;the expression of pn NOS and n NOS in the thoracic spinal cord were determined by westernblotting.Results We report that intrathecal morphine postconditioning(IMPOC)rescued mean artery pressure(MAP)and reduced the myocardial injury in I/R.Pretreatment with either naloxone(NAL),a selective mu-opioid receptor antagonist,or nitric oxide synthase(NOS)inhibitors via intrathecal delivery completely abolished IMPOC cardioprotection,suggesting that spinal mu-opioid receptor and its downstream NOS signaling pathway are involved in the mechanism of morphine-induced effect.Consistent with this,IMPOC significantly enhanced spinal neural NOS phosphorylation,nitric oxide(NO)and c GMP content in a similar time course.Intrathecal application of ODQ and s GC,completely ablated IMPOC-induced enhancement of cardioprotection and spinal c GMP content.IMPOC rescue of MAP and ischemic injury is correlated with IMPOC enhancement of NOS signaling.Conclusion Collectively,these findings strengthen the concept of spinal mu-opioid receptors as a therapeutic target that mediates morphine-induced cardioprotection.We also provide evidence suggesting that activation of spinal NOS signaling is essential for morphine cardioprotection.Objective: In localized disease,partial nephrectomy(PN)for small tumors continues to be the gold-standard treatment.However,clamped renal vascular pedicle during PN lead to renal ischemic/reperfusion injury(IRI).In this study,we evaluate whether or not dexmedetomidine postconditioning(DPOC)can reduce the renal I/R injury in patients receiving laparoscopic partial nephrectomy(LPN).Methods: Altogether,77 patients receiving LPN were randomly divided into two groups: Control and DPOC group.Each group has 38 or 39 patients respectively and undergoing 6-months follow-up.DPOC was conducted with intravenous administration of dexmedetomidine at 0.6?g/kg for 10 min immediately after unclamping renal artery.The primary outcome was the change of glomerular filtration rate(GFR)in the affected kidney,as revealed by renal scintigraphy in a span of 6 months.The secondary outcomes were hemodynamic data collected during the operation and the data collected postoperative including serum neutrophil gelatinase-associated lipocalin(NGAL)levels measured at 2 and 6h;retinol-binding protein(RBP)levels at 24 h and 48 h,serum creatinine,and estimated GFR(e GFR)at 1and 6 months.Results GFR was substantially reduced 1 and 6 month after LPN in affected kidney respectively.DPOC treatment restored LPN-induced reduction of GFR from 33.2±5.4m L/ min/1.73m2(control group)to 35.7±4.9 m L/ min/1.73m2(p<0.05)1 month after LPN and from36.1±5.1 m L/ min/1.73m2(control group)to37.9±4.0 m L/ min/1.73m2 6month after LPN.DPOC treatment accelerated the recovery of mean artery pressure(MAP)by 5-6% 10 min and 30 min after release of vascular pedicle occlusion(p<0.05).The levels of serum NGAL and urinary RBP of DPOC group were significantly lower than that of control group after LPN(NGAL: 1027.0±72.8?g/L vs.837.9±79.0 ?g/L at2 h,1225.0±90.0 ?g/L vs.922.1±106.4 ?g/L at 6 h,p<0.0001;RBP: 0.44±0.17 vs.0.67±0.2mg/L at 24 h,p< 0.0001).Furthermore,the value of GFR at 1 month after LPN is inversely correlated with the levels of NGAL at 6h(?=-0.43,p<0.01)and RBP at 24h(?=-0.39,p<0.05)after LPN in affected kidney.Conculsions We conclude that dexmedetomidine postconditioning provides therapeutic benefit in LPN patients by alleviating renal IRI at least in a short-term basis.