| Vascular hyporesponsiveness is an important mechaniam of high complication rates and increased mortality in obstructive jaundice. The reduced response or no reaction to vascular active drugs in clinical practice is associated with vascular hyporeactivity and seriously influence the treatment effect. The reasons resulting in it may include endotoxemia, increased serum levels of sodium taurocholate and endogenous opioid peptide as well as prostaglandin, excessive production of nitric oxide in serum,and so on.In addition, the vascular hyporeactivity to alpha-epinephrine agonists in obstructive jaundice may be connected with the dysfunction of alpha-1 adrenergic receptor.And the alpha-2 adrenergic receptor desensitization may also occur in obstructive jaundice. There is currently no retrieval of clinical studies reported at home and abroad of vascular hyporeactivity to alpha-epinephrine agonists in obstructive jaundice. In recent decades,many studies have shown that obstructive jaundice can lead to the increase of nitric oxide synthesis in vivo. In addition, there is evidence that NO worked in vascular hyporeactivity induced by cholestasis.In this paper,we firstly studied whether vascular hyporeactivity to norepinephrine, phenylephrine and dexmedetomidine in patients with obstructive jaundice,evaluated by Swan-Ganz floating catheter,have been changed and to evaluate the relation between vascular reactivity and alpha-adrenaline receptor subtypes.Different numbers of patients with obstructive jaundice (serum total bilirubin>20? mol/L) induced by tumour of biliary tract or the head of the pancreas were included in this reaearch.While the corresponding number of nonjaundice patients who suffered primary liver cancer or hepatic hemangioma served as controls. Seven nonjaundice patients were selected to assess the hemodynamic response to a lower concentration dexmedetomidine.And the changement of the mean arterial pressure (MAP), cardiac index(CI), systemic vascular resistance(SVR) and systemic vascular resistance index(SVRI) was used to evaluate the vascular responsiveness.Secondly, the isometric tension recording of aorta strip was adopted to explore the role of nitric oxide in the mechanism of vascular hyporeactivity.To begin with,the role of vascular endothelium and L-NAME in the vascular contractile reactivity was examined.Then the mechanism of vasodilation to nitric oxide in obstructive jaundice was studied. Sodium nitroprusside dose-response curves were generated in aortas preconstricted with phenylephrine that were pre-incubated respectively for 30 minutes with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-l-one (ODQ, a guanylate cyclase inhibitor), the K+ channel blockers(4-AP, TEA, IbTX and ChTX), glibenclamide(ATP-dependent potassium (KATP) channel blocker) or barium chloride (BaC12) (a inwardly rectifying potassium (Kir) channels blocker).Thirdly, we examined the global metabolic and some biochemical changes in rats with cholestasis induced by bile duct ligation (BDL). BDL was carried out in male Wistar rats (n=8). A group of rats receiving sham surgery was used as a control. Serum samples were collected at day 3 after the surgery for metabolomics analysis using a combination of reversed phase chromatography and hydrophilic interaction chromatography (HILIC) and quadrupole-time-of-flight mass spectrometry (Q-TOF MS). The levels of malondialdehyde (MDA), total antioxidative capacity (T-AOC),glutathione (GSH) and glutathione disulfide (GSSG), the activities of superoxide dismutase (SOD) and glutathion peroxidase (GSH-Px) in serum were measured to estimate the oxidative stress state.The main results are as follows:1.Clinical investigation:(1) The blood pressure response(MAP) to norepinephrine (with a injection rate of 60ng.kg-1min-1 for 5 minutes)in patients with obstructive jaundice (added value:14.77±6.37mmHg) were significantly less than that observed for the control group(added value:18.12±7.35mmHg,p<0.05). There was no significant difference between the added value of SVR and SVRI for the two groups.And we found the CI value remarkably unchanged.(2)The MAP,SVR,and SVRI to phenylephrine (with a injection rate of 320ng.kg-1min-1 for 5 minutes)in patients with obstructive jaundice were significantly less than that observed for the control group(added value:MAP 10.11±7.10mmHg VS 16.78± 5.71mmHg,p<0.05; SVR 123.67±99.18 dyn.s.cm-5 m2 VS 211.83±91.98 dyn.s.cm-5m2, p<0.05;SVRI 206.50±159.67 dyn.s.cm-5 m2 VS 369.83± 168.92dyn.s.cm-5 m2, p<0.05). And there was no significant changements of the CI value.(3) With the injection of dexmedetomidine (0.5?g.kg-1h-1 for 5 minutes),the levels of MAP(p<0.05) and CI (p<0.01)increased as well as the levels of SVR and SVRI dropped significantly in seven nonjaundiced patients(p<0.05).And the MAP,SVR,and SVRI to dexmedetomidine (with a injection rate of 2 ? g.kg-1h-1for 5 minutes)in patients with obstructive jaundice were significantly less than that observed for the control group(added value:MAP 8.13±5.80mmHg VS 11.83± 4.44mmHg, p<0.05; SVR 115.94±132.19 dyn.s.cm-5m2 VS 244.70±171.58 dyn.s.cm-5m2, p<0.05;SVRI 192.53±206.94 dyn.s.cm-5m2 VS 413.00± 287.96dyn.s.cm-5m2, p<0.01).2.Studies of underlying mechanisms:(1) The maximum contraction evoked by NA was significantly attenuated in aorta pectoralis with endothelium obtained from 3 day BDL rats when compared with those from sham-operated controls (SO)(p<0.01). However, the reduction almost disappeared when the endothelium was removed or incubated with L-NAME. (2) The maximum relaxation evoked by SNP was not significantly enhanced in aorta pectoralis with endothelium obtained from 7 day BDL rats when compared with those from sham-operated controls (SO)(p>0.05). Endothelium-dependent relaxations produced by SNP in two groups were both disappeared after incubation with ODQ (p<0.001). The relaxations in two groups were both decreased after incubation with TEA, IbTX and ChTX, but there was only significant difference of the degree of relaxation decreased in sham groups incubated with TEA and ChTX.There were no significant changement of the relaxation after incubation with 4-AP and BaCl2. The relaxations produced by SNP in two groups were both enhanced after incubation with Gly, and there were only significant changement of the relaxation in the control group (P<0.05).3.Metabolomic research:Key changes after BDL included increased levels of L-phenylalanine, L-glutamate, L-tyrosine, kynurenine, L-lactic acid, LysoPCc (14:0), glycine and succinic acid and decreased levels of L-valine, PCb (19:0/0:0), taurine, palmitic acid, L-isoleucine and citric acid metabolism products. And treatment with BDL significantly decreased the levels of GSH, T-AOC as well as SOD, GSH-Px activities, and upregulated MDA levels.Conclusion:1.The vascular reactivity of alpha-1 and alpha-2 B adrenaline receptor in patients with obstructive jaundice significantly decreased compared with that of nojaundiced patients,which may partly due to the decline response of the small resistance arteries. Our study show that there were very small changes in blood pressure, with enhanced cardiac function and decreased peripheral vascular resistance after exciting alpha-2 adrenergic receptor.2. Endothelium-derived NO may play an important role in vascular hyporesponsiveness of obstructive jaundice. And the non Kca pathway may play a main role in the vasodilatation of thoracic aorta in BDL rats induced by NO.3.The changes could be mapped to metabolism of amino acids and lipids, Krebs cycle and glycolysis, as well as increased oxidative stress and decreased antioxidant capability. Our study indicated that BDL induces major changes in the metabolism of all 3 major energy substances, as well as oxidative stress. |
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