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Bradykinin increases BP in endotoxemic rat: functional and biochemical evidence of angiotensin II AT1 /bradykinin B2 receptor heterodimerization.

ABSTRACT: BACKGROUND AND PURPOSE:Bradykinin may induce vasoconstriction in selected vessels or under specific experimental conditions. We hypothesized that inflammatory stimuli, such as endotoxin challenge, may induce the dimerization of AT1 /B2 receptors, altering the vascular effects of bradykinin. EXPERIMENTAL APPROACH:Wistar rats received LPS (1 mg·kg-1 , i.p.) and were anaesthetized for assessment of BP. Mesenteric resistance arteries were used in organ baths and subjected to co-immunoprecipitation and Western blot analyses. KEY RESULTS:At 24 and 48 hr after LPS, bradykinin-induced hypotension was followed by a sustained increase in BP, which was not found in non-endotoxemic animals. The B2 receptor antagonist Hoe-140 fully blocked the responses to bradykinin. The pressor effect of bradykinin was not prevented by prazosin, an ?1 -adrenoceptor antagonist, but it was inhibited by the AT1 receptor antagonist losartan or the Rho-kinase inhibitor Y-27632. Endotoxemic rats also displayed enhanced pressor responses to angiotensin II, which were blocked by Hoe-140. Co-immunoprecipitation isolated using anti-B2 or anti-AT1 receptor antibodies showed that resistance arteries presented augmented levels of the AT1 /B2 receptor complexes at 24 hr after LPS injection. The presence of AT1 /B2 receptor heterodimers did correlate with the development of losartan-sensitive contractile responses to bradykinin and potentiation of angiotensin II-induced contraction, which was prevented by Hoe-140. CONCLUSIONS AND IMPLICATIONS:Endotoxin challenge is a stimulus for AT1 /B2 receptor heterodimerization in native vessels and shifts the B2 receptor-dependent vascular effect of bradykinin to a more complex pathway, which also depends on AT1 receptors and their intracellular signalling pathways.

SUBMITTER: Anton EL

PROVIDER: S-EPMC6592862 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Bradykinin increases BP in endotoxemic rat: functional and biochemical evidence of angiotensin II AT<sub>1</sub> /bradykinin B<sub>2</sub> receptor heterodimerization.

Anton Elaine Leocádia EL Fernandes Daniel D Assreuy Jamil J da Silva-Santos José Eduardo JE

British journal of pharmacology 20190513 14

<h4>Background and purpose</h4>Bradykinin may induce vasoconstriction in selected vessels or under specific experimental conditions. We hypothesized that inflammatory stimuli, such as endotoxin challenge, may induce the dimerization of AT<sub>1</sub> /B<sub>2</sub> receptors, altering the vascular effects of bradykinin.<h4>Experimental approach</h4>Wistar rats received LPS (1 mg·kg<sup>-1</sup> , i.p.) and were anaesthetized for assessment of BP. Mesenteric resistance arteries were used in organ ...[more]

PMID: 30945263

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Project description:UnlabelledAngiotensin II (AT-II) is a pro-fibrotic compound that acts via membrane-bound receptors (AT-1R/AT-2R) and thereby activates hepatic stellate cells (HSCs). AT-II receptor blockers (ARBs) are thus important candidates in the treatment of liver fibrosis. However, multiple case reports suggest that AT-1R blockers may induce hepatocyte injury. Therefore, we investigated the effect of AT-II and its receptor blockers on cytokine-, oxidative stress- and bile salt-induced cell death in hepatocytes. Primary rat hepatocytes were exposed to TNF-?/Actinomycin D, the ROS-generating agent menadione or the bile salts: glycochenodeoxycholic acid (GCDCA) and tauro-lithocholic acid-3 sulfate (TLCS), to induce apoptosis. AT-II (100 nmol/L) was added 10 minutes prior to the cell death-inducing agent. AT-1R antagonists (Sartans) and the AT-2R antagonist PD123319 were used at 1 µmol/L. Apoptosis (caspase-3 activity, acridine orange staining) and necrosis (Sytox green staining) were quantified. Expression of CHOP (marker for ER stress) and AT-II receptor mRNAs were quantified by Q-PCR. AT-II dose-dependently reduced GCDCA-induced apoptosis of hepatocytes (-50%, p<0.05) without inducing necrosis. In addition, AT-II reduced TLCS-induced apoptosis of hepatocytes (-50%, p<0.05). However, AT-II did not suppress TNF/Act-D and menadione-induced apoptosis. Only the AT-1R antagonists abolished the protective effect of AT-II against GCDCA-induced apoptosis. AT-II increased phosphorylation of ERK and a significant reversal of the protective effect of AT-II was observed when signaling kinases, including ERK, were inhibited. Moreover, AT-II prevented the GCDCA-induced expression of CHOP (the marker of the ER-mediated apoptosis).ConclusionAngiotensin II protects hepatocytes from bile salt-induced apoptosis through a combined activation of PI3-kinase, MAPKs, PKC pathways and inhibition of bile salt-induced ER stress. Our results suggest a mechanism for the observed hepatocyte-toxicity of Sartans (angiotensin receptor blockers, ARBs) in some patients with chronic liver injury.

Dataset Information

Bradykinin increases BP in endotoxemic rat: functional and biochemical evidence of angiotensin II AT1 /bradykinin B2 receptor heterodimerization.

Publications

Bradykinin increases BP in endotoxemic rat: functional and biochemical evidence of angiotensin II AT<sub>1</sub> /bradykinin B<sub>2</sub> receptor heterodimerization.

Similar Datasets

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