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Bradykinin increases BP in endotoxemic rat: functional and biochemical evidence of angiotensin II AT 1 /bradykinin B 2 receptor heterodimerization
Author(s) -
Anton Elaine Leocádia,
Fernandes Daniel,
Assreuy Jamil,
SilvaSantos José Eduardo
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14685
Subject(s) - bradykinin , losartan , angiotensin ii , receptor antagonist , medicine , bradykinin receptor , endocrinology , receptor , vasoconstriction , antagonist , chemistry , prazosin , pharmacology , biology
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 AT 1 /B 2 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 B 2 receptor antagonist Hoe‐140 fully blocked the responses to bradykinin. The pressor effect of bradykinin was not prevented by prazosin, an α 1 ‐adrenoceptor antagonist, but it was inhibited by the AT 1 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‐B 2 or anti‐AT 1 receptor antibodies showed that resistance arteries presented augmented levels of the AT 1 /B 2 receptor complexes at 24 hr after LPS injection. The presence of AT 1 /B 2 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 AT 1 /B 2 receptor heterodimerization in native vessels and shifts the B 2 receptor‐dependent vascular effect of bradykinin to a more complex pathway, which also depends on AT 1 receptors and their intracellular signalling pathways.