Basic-liver, pancreas, and biliary tractDefective RhoA/Rho-Kinase Signaling Contributes to Vascular Hypocontractility and Vasodilation in Cirrhotic Rats
Section snippets
Animals
For our experiments, male Sprague–Dawley rats with an initial body weight of 180 to 200 g were used and divided into 2 groups. One group (n = 109) underwent bile duct ligation (BDL) as previously described.21 The rats of the other group (n = 118) were sham operated and served as controls. In these rats, the common bile duct was exposed by median laparotomy, but no ligation or resection was performed. In both groups of rats, BDL and sham-operated rats, experiments were carried out after 5 weeks.
Hypocontractility of Isolated Aortic Rings
Contraction of aortic rings from BDL rats induced by the α1-adrenergic receptor agonist methoxamine (10 μmol/L) was reduced on average by 51% compared with contraction of aortic rings from sham-operated rats (Figure 2A), demonstrating the typical hypocontractility of aortic smooth muscle in cirrhosis. Preincubation of the aortic rings with the NOS inhibitor L-NAME (200 μmol/L) increased the contraction in both groups. However, the increase was similar in both groups (Figure 2A). Thus, aortic
Discussion
Vasodilation because of an impaired response to vasoconstrictors is one of the main features of hemodynamic changes occurring in cirrhosis.34 The reasons for this hypocontractility have been the topic of many investigations but are still discussed controversially.9, 10, 35, 36, 37, 38, 39, 40, 41, 42 Vasoconstrictor-induced contraction of vascular smooth muscle is not only mediated by the PLC/IP3 pathway but also in large parts by the RhoA/Rho-kinase pathway.14, 16, 18 Here, evidence is
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2022, Life SciencesCitation Excerpt :For quantification of the results, a decrease in ∆CT value indicated a higher mRNA level and was noted. The efficiency of the real-time PCR was approximately equal for the targeted and internal control genes; therefore, the ∆CT showed a relative quantification [33]. All the experimental data collected were presented as mean ± SEM.
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2021, JHEP ReportsCitation Excerpt :Indeed, in parallel to the increased NO synthesis and bioavailability in these vessels, the vasocontractile pathways are also impaired.3 It has been demonstrated that the RhoA/Rho-kinase pathway is defective and less active.100 This is at least partly due to changes in the post-receptor regulation of vasoconstrictor receptors, such as AT1R, which is desensitised by increased β-Arr2 binding.56
The antifibrotic potential of a sustained release formulation of a PDGFβ-receptor targeted rho kinase inhibitor
2019, Journal of Controlled ReleaseCitation Excerpt :Rho kinase is a major downstream effector protein of Rho GTPase, and is involved in cell migration and contractility of different cell types [6,7]. Inhibition of this protein using rho kinase inhibitors, such as Y27632, reduced portal vascular resistance and thus portal pressure [5,8]. In addition to these hemodynamic effects, Y27632 was shown to possess antifibrotic activity in several animal models of liver fibrosis [9–11].
Portal Hypertension-Molecular Mechanisms
2017, Liver Pathophysiology: Therapies and AntioxidantsAssessment of response to beta-blockers by expression of βarr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients
2016, Journal of HepatologyCitation Excerpt :This dysfunction is, at least partly, a result of an imbalance in vasoconstricting and vasodilating pathways. The defective Ras homolog family member A (RhoA)/Rho-kinase (ROCK) pathway together with upregulated beta-arrestin2 (βArr2) blunts contraction [17–21]. Furthermore, a higher production of nitric oxide (NO) deriving from upregulation of endothelial nitric oxide synthase (eNOS) and iNOS induce exaggerated vasodilatation [22–24].
Supported by grants of the Deutsche Forschungsgemeinschaft (HE 2402/5-1) and the Ernst und Berta Grimmke-Stiftung.