Mesenteric artery responsiveness to acetylcholine and phenylephrine in cirrhotic rats challenged with endotoxin: the role of TLR4

Abstract

Cirrhosis is associated with vascular dysfunction and endotoxemia. These experiments were designed to investigate the hypothesis that the administration of a low-dose of lipopolysaccharide (LPS) worsens vascular dysfunction in rats subjected to bile-duct ligation (BDL), and to determine whether LPS initiates changes in vascular Toll-like receptor 4 (TLR4) expression. Four weeks after BDL, the animals were given an intraperitoneal injection of either saline or LPS (1.0 mg/kg body mass). Three hours later, the superior mesenteric artery was isolated, perfused, and then subjected to the vasoconstriction and vasodilatation effects of phenylephrine and acetylcholine, respectively. Our results show that phenylephrine-induced vasoconstriction decreased in the cirrhotic vascular bed (BDL rats) compared with the vascular bed of the sham-operated animals, and that the LPS injections in the cirrhotic (BDL) rats worsened this response. LPS injection administered to the sham-operated animals had no such effect. On the other hand, both the BDL procedure and the LPS injection increased acetylcholine-induced vasorelaxation, but LPS administration to the BDL rats had no effect on this response. The mRNA levels of TLR4 did not change, but immunohistochemical studies showed that TLR4 localization switched from the endothelium to vascular smooth muscle cells following chronic BDL. In conclusion, acute endotoxemia in cirrhotic rats is associated with hyporesponsiveness to phenylephrine and tolerance to the effects of acetylcholine. Altered localization of TLR4 may be responsible for these effects.

Acute-on-chronic liver disease enhances phenylephrine-induced endothelial nitric oxide release in rat mesenteric resistance arteries through enhanced PKA, PI3K/AKT and cGMP signalling pathways

“…The vasodilator response to ACh is widely used to determine possible alterations in endothelial function. Increases 13,34,52,62 , decreases 63 and no changes 64 in ACh-induced vasodilation have been reported in mesenteric vasculature from different rat models of liver disease. These inconsistencies suggest that the alterations in ACh relaxation depend on the aetiology of the liver pathology, as well as on the vascular bed used.…”

Abnormalities in the 24‐hour rhythm of skin temperature in cirrhosis: Sleep‐wake and general clinical implications

“…Inpatients with cirrhosis vs outpatients with cirrhosis: § P<.05 and § § § P<.001; Inpatients with cirrhosis vs healthy volunteers: ## P<.01 and ### P<.001. circulating endogenous vasodilators 32 and (ii) vascular responsiveness to adrenergic stimulation is significantly impaired 33. In addition to blunted response to adrenergic stimulation, vascular beds from cirrhotic subjects have impaired endothelium-dependent vasodilator response to cholinergic stimulation 34. This indicates that although peripheral vessels in cirrhosis are more dilated than normal individuals, they may not respond well to cholinergic vasodilatatory mechanisms such as sympathetic cholinergic fibres.…”

Physiological network approach to prognosis in cirrhosis: A shifting paradigm

“…The exact mechanism for physiological network disruption in decompensated cirrhosis is not well understood. However, evidence from experimental (in vitro, ex vivo, and in vivo) studies indicate impaired end organ responsiveness to physiologic signals in animal models of decompensated cirrhosis (Castro et al., 1993 ; Haddadian et al., 2013 ; Liu et al., 2022 ; Ostadhadi et al., 2015 ). For example, cardiomyocytes, cardiac pacemaker cells, and vascular smooth muscle cells exhibit a blunted response to adrenergic and cholinergic stimuli in experimentally decompensated cirrhosis (Jaue et al., 1997 ; Liu et al., 2000 ; Mani et al., 2009 ; Ostadhadi et al., 2015 ).…”

“…However, evidence from experimental (in vitro, ex vivo, and in vivo) studies indicate impaired end organ responsiveness to physiologic signals in animal models of decompensated cirrhosis (Castro et al., 1993 ; Haddadian et al., 2013 ; Liu et al., 2022 ; Ostadhadi et al., 2015 ). For example, cardiomyocytes, cardiac pacemaker cells, and vascular smooth muscle cells exhibit a blunted response to adrenergic and cholinergic stimuli in experimentally decompensated cirrhosis (Jaue et al., 1997 ; Liu et al., 2000 ; Mani et al., 2009 ; Ostadhadi et al., 2015 ). Other reports support disruption of the physiological control in decompensated cirrhosis by demonstrating reduced controllability of the physiological subsystems in decompensated cirrhosis using advanced statistical techniques used in the analysis of complex systems (Shirazi et al., 2013 ; Taghipour et al., 2016 ).…”