Presence Of B1 Receptors Research Articles

Switching of bradykinin-mediated nociception following partial sciatic nerve injury in mice.

Bradykinin (BK) is well known as a potent mediator of pain and hyperalgesia. Using a highly sensitive nociception test, we found that intraplantar (i.pl.) injection of BK produced nociceptive hyper-responses in partial sciatic nerve-injured mice, compared with the control sham-operated animals. By use of selective agonists and antagonists, we revealed that BK nociception in sham-operated mice was mediated through B2 receptor, whereas that in injured mice was mediated through B1 receptor. When we examined the activation of extracellular signal-regulated protein kinase (ERK) in dorsal root ganglion (DRG) neurons upon i.pl. injection of BK, phosphorylated ERK was mainly observed in unmyelinated neurons in sham-operated mice, and in case of nerve-injured mice, ERK was mainly activated in myelinated neurons and satellite cells. The B1 receptor agonist, [Lys-des-Arg(9)]-BK also produced nociceptive response and activated ERK only in nerve-injured mice. BK or B1 agonist-induced activation of ERK in DRG neurons of nerve-injured mice was completely blocked by pretreatment with antisense oligodeoxynucleotide (AS-ODN) for B1 receptor. We found that in sham-operated mice mainly B2 receptors were expressed in unmyelinated DRG neurons with a very little presence of B1 receptor. After nerve injury, B2 receptor expression drastically decreased, whereas B1 receptors were newly expressed mainly in myelinated DRG neurons and satellite cells. Finally, BK nociception in sham-operated mice was blocked by AS-ODN for B2 receptors and that in injured mice by AS-ODN for B1 receptors. Altogether, these findings confirm a switching of receptor and fiber subtype for BK nociception after peripheral nerve injury, which might contribute to the pathobiology of neuropathic pain.

Endothelial kinin B(1)-receptors are induced by myocardial ischaemia-reperfusion in the rabbit.

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 microg kg(-1), intra-arterial: -12 +/- 2 vs. -5 +/- 2 mm Hg 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(-5) M: -9 +/- 2 vs. -1 +/- 2% in the sham group, P < 0.02) and mesenteric arteries (DBK, 10-6 M: -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.

Hypertension in transgenic (mREN2)27 rats is not associated with the presence of B1 receptors.

B1 receptors are inducible receptors expressed only in stressful conditions. The aim of this study was to determine if, in (mREN2)27 transgenic rats, hypertension is associated with the presence of B1 receptors in the cardiovascular system and if a heat stress inducible effect is preserved during hypertension. Age-matched (16 weeks old) heterozygous hypertensive transgenic (mREN2)27 rats (HT rats) and the normotensive control animals (homozygous Sprague-Dawley rats, NT rats) were used. The study was conducted in two parts: in the first part the responsiveness of B1 receptors was studied in rats submitted to heat stress (42 degrees C rectal temperature, 20 min) or sham anaesthesia 24 h before, by recording changes in isometric tension in aortic rings in response to [des-Arg9]-bradykinin, a B1 receptor agonist. In the second part, we studied whether B1 receptor mRNA was present in aorta, heart and kidneys, using a semi-quantitative RT-PCR technique. [des-Arg9]-Bradykinin induced a concentration-dependent relaxation of aortic rings only from animals submitted to prior heat stress. This response was significantly higher in aortic rings from heat stressed HT rats than from heat stressed NT ones. B1 receptor mRNA was undetectable in organs from rats not submitted to heat stress but they were present 5 h after heat stress in aorta, heart and kidneys from both NT and HT rats. In conclusion, arterial hypertension observed in (mREN2)27 rats is not associated with the presence of B1 receptors. However, after heat stress, we observed an increase in responsiveness from HT rat aortas compared to NT ones.

Action and metabolism of des(Arg)kinins in mesenteric arteries.

Kallidin and bradykinin can be hydrolyzed at their C-termini to produce des(Arg10)kallidin and des(Arg9)bradykinin respectively. These des(Arg)kinins, previously thought to be biologically inactive, are now known to have potent effects on B1 receptors. Although stimulation of B1 receptors has been reported to produce peripheral vasodepressor responses in certain experimental states, only constriction has been reported in isolated vessels (i.e., rabbit aorta, basilar artery, mesenteric vein). In the present study, we have investigated the biologic activity of des(Arg) kinins on a peripheral resistance vessel (rabbit mesenteric artery). We found that des(Arg)bradykinin relaxes mesenteric arteries, and that its potency relative to kallidin and bradykinin is consistent with the presence of B1 receptors. Further, intact mesenteric arteries, and a plasma membrane fraction purified from these arteries, contained a carboxypeptidase activity which was capable of producing des(Arg)kinins from both kallidin and bradykinin. Thus, these data demonstrate that the vasculature has the enzymatic capacity to form B1 kinins, and that stimulation of B1 receptors in resistance vessels can be associated with peripheral vasodilation.