anandamide and Liver-Cirrhosis--Biliary

Increased anandamide, an endocannabinoid that interacts with both cannabinoid CB(1) and CB(2) receptors, can induce hepatic vasoconstrictive responses that contribute to the increased intrahepatic resistance (IHR) in cirrhotic rats. Chronic endotoxaemia and the subsequent release of tumour necrosis factor-alpha (TNF-alpha) are suggested to result in increased anandamide in cirrhotic livers. Thalidomide, which inhibited TNF-alpha effectively, has been used clinically in states of chronic TNF-alpha elevation with encouraging results.. This study explores the possible effects of thalidomide on hepatic endocannabinoids and microcirculation of cirrhotic rats.. Portal venous pressure (PVP), superior mesenteric arterial blood flow (SMA BF), hepatic TNF-alpha, interleukin (IL-6), protein expression of CB(1) and CB(2) receptor and thromboxane synthase (TXS) were measured in bile duct-ligated (BDL) rats receiving 1-month of vehicle (BDL-V) or thalidomide (BDL-thalido). The degree of hepatic fibrosis was also assessed. In the liver perfusion system, IHR and concentration-response curves of the portal perfusion pressure to anandamide were evaluated.. In BDL-thalido rats, PVP, IHR and hepatic levels of TNF-alpha and IL-6, protein expression of CB(1) receptors, TXS and hepatic fibrosis were lower than in BDL-V rats. In BDL-thalido rat livers, the attenuation of the vasoconstrictive response to anandamide was associated with an upregulation of the CB(2) receptor and a downregulation of the CB(1) receptor. Nevertheless, SMA BF was not different between BDL-thalido and BDL-V rats.. Thalidomide decreased the PVP and IHR through the attenuation of anandamide-induced constrictive response, decreasing the production of TNF-alpha, IL-6 and TXA(2) in the liver and the suppression of hepatic fibrogenesis of rats with biliary cirrhosis of this study.

Topics: Animals; Arachidonic Acids; DNA Primers; Endocannabinoids; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Liver; Liver Cirrhosis, Biliary; Microcirculation; Polyunsaturated Alkamides; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reverse Transcriptase Polymerase Chain Reaction; Statistics, Nonparametric; Thalidomide; Tumor Necrosis Factor-alpha; Vasoconstriction

Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non-adrenergic non-cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC-mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model.. Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, strips of corpus cavernosum were mounted in a standard organ bath and NANC-mediated relaxations were obtained by applying electrical field stimulation.. The NANC-mediated relaxation was enhanced in corporal strips from cirrhotic animals. Anandamide potentiated the relaxations in both groups. Either AM251 (CB(1) antagonist) or capsazepine (vanilloid VR(1) antagonist), but not AM630 (CB(2) antagonist), prevented the enhanced relaxations of cirrhotic strips. Either the non-selective NOS inhibitor L-NAME or the selective neuronal NOS inhibitor L-NPA inhibited relaxations in both groups, but cirrhotic groups were more resistant to the inhibitory effects of these agents. Relaxations to sodium nitroprusside (NO donor) were similar in tissues from the two groups.. Cirrhosis potentiates the neurogenic relaxation of rat corpus cavernosum probably via the NO pathway and involving cannabinoid CB(1) and vanilloid VR(1) receptors.

Topics: Animals; Arachidonic Acids; Arginine; Blotting, Western; Cannabinoid Receptor Modulators; Cannabinoids; Electric Stimulation; Endocannabinoids; Enzyme Inhibitors; In Vitro Techniques; Liver Cirrhosis, Biliary; Male; Muscle Relaxation; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type I; Nitroprusside; Penis; Phenylephrine; Polyunsaturated Alkamides; Rats; Signal Transduction; TRPV Cation Channels; Vasoconstrictor Agents

Anandamide can activate potassium (K(+)) channels to induce an endothelium-dependent vasorelaxation in normal rat mesenteric arteries. Cannabinoids contribute partly to the splanchnic vasodilation in cirrhosis. This study investigated the roles of vascular K(+) channels in anandamide-induced mesenteric vasorelaxation in isolated rat cirrhotic vessels.. The effects of the pretreatment of AM251, a specific CB(1) receptor antagonist, were assessed on the vascular reactivity to phenylephrine (PE), potassium chloride (KCl), acetylcholine (ACh) and sodium nitroprusside (SNP). Additionally, cannabinoid (CB(1) and CB(2)) receptors' protein expression and the effects of different K(+) channel blockers on vascular reactivity to anandamide were also studied.. Cirrhotic mesenteric arteries showed an overexpression of CB(1) receptor associated with hyporeactivity to PE and KCl, and hyper-response to ACh, SNP and anandamide. Pretreatment with AM251 significantly improved the hyporeactivity to KCl and ameliorated the hyper-response to ACh in cirrhotic vessels. Increased relaxation response to anandamide was suppressed by combinations of vascular Ca(2+)-dependent K(+) channel blockers (including apamin+charybdotoxin+iberiotoxin or apamin+TRAM-34+iberiotoxin) (TRAM-34, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole).. In cirrhotic mesenteric arteries, vascular CB(1) receptor and anandamide contribute to the in vitro hyporeactivity to KCl. In addition, hyper-response to ACh may probably act through the modulation of vascular Ca(2+)-dependent K(+) channels.

Topics: Acetylcholine; Animals; Apamin; Arachidonic Acids; Cannabinoid Receptor Modulators; Charybdotoxin; Common Bile Duct; Dose-Response Relationship, Drug; Endocannabinoids; Glyburide; Ligation; Liver Cirrhosis, Biliary; Liver Cirrhosis, Experimental; Male; Mesenteric Artery, Superior; Nitroprusside; Peptides; Phenylephrine; Piperidines; Polyunsaturated Alkamides; Potassium; Potassium Channel Blockers; Potassium Channels, Calcium-Activated; Potassium Chloride; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Hyperdynamic circulation and mesenteric hyperaemia are found in cirrhosis. To delineate the role of endocannabinoids in these changes, we examined the cardiovascular effects of anandamide, AM251 (CB(1) antagonist), AM630 (CB(2) antagonist) and capsazepine (VR1 antagonist), in a rat model of cirrhosis.. Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, diameters of mesenteric arteriole and venule (intravital microscopy), arterial pressure, cardiac output, systemic vascular resistance and superior mesenteric artery (SMA) flow were measured after anandamide, AM251 (with or without anandamide), AM630 and capsazepine administration. CB(1), CB(2) and VR1 receptor expression in SMA was assessed by western blot and RT-PCR.. Anandamide increased mesenteric vessel diameter and flow, and cardiac output in cirrhotic rats, but did not affect controls. Anandamide induced a triphasic arterial pressure response in controls, but this pattern differed markedly in cirrhotic rats. Pre-administration of AM251 blocked the effects of anandamide. AM251 (without anandamide) increased arterial pressure and systemic vascular resistance, constricted mesenteric arterioles, decreased SMA flow and changed cardiac output in a time-dependent fashion in cirrhotic rats. Capsazepine decreased cardiac output and mesenteric arteriolar diameter and flow, and increased systemic vascular resistance in cirrhotic rats, but lacked effect in controls. Expression of CB(1) and VR1 receptor proteins were increased in cirrhotic rats. AM630 did not affect any cardiovascular parameter in either group.. These data suggest that endocannabinoids contribute to hyperdynamic circulation and mesenteric hyperaemia in cirrhosis, via CB(1)- and VR1-mediated mechanisms.

Topics: Animals; Arachidonic Acids; Bile Ducts; Blood Flow Velocity; Blood Pressure; Blotting, Western; Capsaicin; Cardiac Output; Disease Models, Animal; Endocannabinoids; Hyperemia; Indoles; Liver Circulation; Liver Cirrhosis, Biliary; Male; Mesenteric Artery, Superior; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Splanchnic Circulation; Time Factors; TRPV Cation Channels; Vascular Resistance; Vasodilation; Vasodilator Agents