Abnormal vascular responsiveness to ligands has been frequently observed in cirrhosis and portal hypertension, but its existence is not proven. The signaling pathways in vascular smooth muscle cells ...(VSMCs) have been studied only in animal models of cirrhosis and portal hypertension. Emerging evidence suggests that active relaxation, expressed as augmented content or activity of effectors within the cyclic AMP signaling pathway and suppressed content or activity of effectors in the inositol 1,4,5-trisphosphate/1,2-diacylglycerol signaling pathway, may be occurring in VSMCs of the splanchnic circulation in portal hypertension. The evidence supporting the existence of this phenomenon in the VSMCs of extrasplanchnic circulations in portal hypertension, as well as in the splanchnic circulation when chronic cellular damage is present, is very limited. The status of the other signaling pathways associated with contractile functions of the VSMCs, viz., cyclic GMP and tyrosine kinase-linked pathways, is unknown. The status of all the signaling pathways in non-contractile functions of VSMCs, such as growth and remodeling, has not been studied. As our overall understanding on the signaling pathways in VSMCs is only emerging, it is premature to implicate altered activity of the signaling pathways as the underlying basis of vascular hyporesponsiveness in cirrhosis and portal hypertension, and to extrapolate these limited observations to the human condition.
Cholecystokinin (CCK) is considered to simply contract the gallbladder and relax the sphincter of Oddi with meals. In this study, we examined this hypothesis by investigating the action of CCK on the ...sphincter of Oddi and gallbladder of the guinea pig. The experimental design used an in vitro preparation of the sphincter of Oddi to measure contraction of the circular muscle. CCK increased tone in both the gallbladder and the sphincter of Oddi in a concentration-dependent manner. The normalized concentration-response curves for CCK, however, revealed that the gallbladder had a greater sensitivity to CCK (ED50 7 nM) than the sphincter of Oddi (ED50 22 nM; p < 0.01). Conversely, the sphincter was more sensitive to bethanechol than was the gallbladder. When the sphincter of Oddi was stimulated maximally with CCK in the presence of atropine (10(-6) M) or tetrodotoxin (10(-6) M), the contractile response was significantly reduced (p < 0.05) although not abolished. Conversely, atropine completely abolished the responses to bethanechol (10(-3) M) and transmural field stimulation (70 V, 10 Hz, 1 ms, for 20 s). Transmural field stimulation of the sphincter that had been precontracted with CCK (26 nM) caused a transient, initial relaxation followed by contraction. Pretreatment with atropine augmented the duration of this relaxation, which could be completely abolished by tetrodotoxin. Thus, CCK contracts the sphincter of Oddi in the guinea pig by a direct (myogenic) and a neural (likely cholinergic) mechanism. Relaxation of the sphincter of Oddi also occurs in the guinea pig via noncholinergic inhibitory nerves.
Patients with obstructive jaundice are more susceptible to post-operative shock than are nonjaundiced patients. This paper reviews the presently available experimental information, and concludes that ...jaundice blunts the contractile response of cardiac and vascular smooth muscle to sympathetic stimulation. Moreover, the experimental studies indicate that altered peripheral catecholamine metabolism may account for these attenuated responses.
Patients with obstructive jaundice are susceptible to postoperative shock. To clarify the mechanism of this phenomenon, we compared the contractile response to isoprenaline of isolated ventricular ...preparations from three groups of dogs: (a) dogs with chronic bile-duct ligation (CBDL), (b) dogs with choledochocaval anastomosis (CDCA) and (c) sham-operated dogs (SO). Isolated ventricular muscles from CBDL and CDCA dogs showed a depressed contractile response to isoprenaline as compared with SO dogs. Mechanical performance was spared in the CBDL and CDCA dogs. There were no differences in the contractile responses of SO and CBDL dogs, either to ouabain or to changes in the rates of stimulation (force-frequency relationships). These data demonstrate that, in the dog, obstructive jaundice and/or cholaemia are associated with blunted contractile response to beta-adrenoreceptor stimulation in the face of intact basic mechanical performance. Similar inotropic refractoriness to beta-adrenoreceptor stimulation could contribute to the susceptibility to postoperative shock in patients with obstructive jaundice.
It has been postulated that loss of response to norepinephrine accounts in part for the portal hypertension, systemic hypotension, and generalised vascular dilatation of chronic liver disease. The in ...vitro vascular responsiveness to norepinephrine was measured in aortic rings and portal veins excised from four different rat models of hepatic disease with and without portal hypertension, hepatocellular damage, and hyperbilirubinemia--the carbon tetrachloride (CCl4) cirrhotic rat with portal hypertension, the five-week chronic bile duct ligated and resected (CBDL) cirrhotic rat with portal hypertension and hyperbilirubinemia, the 10-day partial ligated portal vein (PVL) portal hypertensive rat without hepatocellular damage and hyperbilirubinemia, and the three-day bile duct ligated (ABDL) rat with acute hepatocellular damage and hyperbilirubinemia but without portal hypertension. Sham-treated or operated groups for each model were also prepared. Vascular reactivity of the aortic rings to norepinephrine was potentiated in the three portal hypertensive groups, and attenuated in the model of acute cholestasis. No consistent pattern of response to norepinephrine was evident in the portal veins. Based upon the presented in vitro data and the discussed limitations of an in vitro study, we conclude that it is unlikely that the loss of response to norepinephrine accounts for the portal hypertension, systemic hypotension, and generalised vascular dilatation of chronic liver disease.
On the in vitro vasoactivity of bile acids Ljubuncic, Predrag; Said, Omar; Ehrlich, Yaron ...
British journal of pharmacology,
October 2000, Letnik:
131, Številka:
3
Journal Article
Recenzirano
Odprti dostop
We compared the vasorelaxant action of nine different bile acids and correlated their vasorelaxant activity with their individual indices for hydrophobicity or lipophilicity.
Vasorelaxant activity ...correlated with the relative lipid solubility of bile acids with lipophilic bile acids exhibiting the greatest vasorelaxant activity with modest to no vasorelaxant activity exhibited by hydrophilic bile acids.
We also investigated whether bile acid‐induced vasorelaxation is mediated by antagonism of a prototypal contractile receptor, the α1‐adrenoceptor, by stimulation of a bile acid surface membrane receptor, by the release of endothelium‐derived relaxant factors, by promoting the generation of reactive oxygen species and increasing the extent of lipid peroxidation, or by modifying membrane fluidity.
Lipophilic bile acids induce vasorelaxation possibly by antagonizing α1‐adrenoceptors, a phenomenon that manifests itself as a lowering of the affinity of vascular α1‐adrenoceptors. Bile acid‐induced vasorelaxation was not dependent upon stimulation of a bile acid surface membrane receptor or the release of endothelium‐derived relaxant factors.
Lipophilic bile acids can also increase the extent of lipid peroxidation with a subtle reduction in the fluidity of rat vascular smooth muscle membranes not associated with loss of membrane cholesterol or phospholipid.
We have concluded that lipophilic bile acids are non‐selective vasorelaxants whose mechanism of action is a multifaceted process involving antagonism of contractile surface membrane receptors possibly effected by an increased extent of lipid peroxidation and/or membrane fluidity but occurs independent of the release of endothelial‐derived relaxant factors or stimulation of a surface membrane bile acid binding site.
British Journal of Pharmacology (2000) 131, 387–398; doi:10.1038/sj.bjp.0703554
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