6533b7d9fe1ef96bd126d783

RESEARCH PRODUCT

Endothelial kinin B1‐receptors are induced by myocardial ischaemia‐reperfusion in the rabbit

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Kinin B1-receptors are induced by various inflammatory stimuli. Since myocardial ischaemia-reperfusion results in inflammation, we questioned whether it could induce B1-receptor-dependent responses to des-Arg9-bradykinin (DBK). Thirty-six rabbits were submitted either to a 30 min coronary occlusion followed by a 3 h reperfusion or to a sham operation. The response to DBK was then tested in vivo on mean arterial pressure (MAP) and in vitro on isolated hearts and arterial rings. DBK induced a dose-dependent decrease in MAP in the ischaemia-reperfusion group (DBK, 10 μg kg−1, intra-arterial: -12 ± 2 vs. -5 ± 2 mmHg in the sham group, P < 0.02), which was significantly antagonised by [Leu8]-des-Arg9-bradykinin (LBK), a B1-receptor antagonist. Following ischaemia-reperfusion, isolated hearts responded to DBK by a decrease in coronary perfusion pressure greater than that of the sham group. DBK dose-dependently decreased the isometric force of isolated carotid rings (DBK, 10−5m: -9 ± 2 vs. -1 ± 2 % in the sham group, P < 0.02) and mesenteric arteries (DBK, 10−6m: -38 ± 7 %vs. -3 ± 2 % in the sham group, P < 0.001). The vascular effects of DBK seen after ischaemia-reperfusion were significantly antagonised by LBK. The presence of B1-receptors in ischaemia-reperfusion animals was confirmed by immunolocalisation and Western blot analysis. This study demonstrates that myocardial ischaemia-reperfusion induces a global induction of functional kinin B1-receptors in the endothelium. B1-receptors are inducible receptors. They were first described by Regoli et al. (1977) who showed that large rabbit arteries, which normally do not respond to des-Arg9-bradykinin (DBK), gradually increased their sensitivity to this B1-receptor agonist when incubated in vitro in normal conditions. These authors also demonstrated that intravenous administration of bacterial lipopolysaccharide (LPS) 5 or 20 h earlier is able to induce hypotension or vasorelaxation in response to DBK by promoting the de novo formation of B1-receptors (Regoli et al. 1981). Various inflammatory stimuli are able to induce B1-receptors (Marceau et al. 1997). In particular, cytokines such as interleukin-1 (IL-1) have been shown to enhance the development of the response to DBK (de Bloiset al. 1988) and could be one of the mediators of the effect of LPS. The induction of B1-receptors is also enhanced by angiotensin converting enzyme (ACE) inhibition or bradykinin (BK) administration, possibly because of the inflammatory effect of the increase in kinin concentrations (Nwator et al. 1989). Ischaemia-reperfusion is known to induce an inflammatory response that contributes to tissue injury; it is associated with the activation of monocytes and neutrophils, and the production of cytokines (Entman et al. 1991). In particular, IL-1 is released by endothelial cells upon hypoxia-reoxygenation (Ala et al. 1992), and its mRNA expression is increased in ischaemic myocardium (Herskowitz et al. 1995). Also, kinins are released during ischaemia in different species (Hashimoto et al. 1978; Matsuki et al. 1987; Baumgarten et al. 1993) and could contribute to the inflammatory response. Thus, the aim of this study was to investigate whether myocardial ischaemia-reperfusion could induce B1-receptor-dependent responses. The effect of DBK following myocardial ischaemia-reperfusion was evaluated in vivo in anaesthetised rabbits and in vitro on isolated rabbit hearts and arterial rings. The presence of cardiovascular B1-receptors was also confirmed by Western blot analysis and immunohistochemical localisation.