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JA Smith, C Webb, J Holford and GM Burgess
Sandoz Institute for Medical Research, London, UK.
Bovine pulmonary artery endothelial (CPAE) cells respond to bradykinin, and it has been suggested that the receptors on these cells do not fall into the normal B1/B2 classification of bradykinin receptors [J. Pharmacol. Exp. Ther. 244:646-649 (1988)]. The present study describes a detailed characterization of the subtypes of bradykinin receptors on CPAE cells. The B1-selective agonist des-Arg9-bradykinin and the B2- selective agonist bradykinin both activated polyphosphoinositide phospholipase C (PLC), caused an elevation in cytosolic Ca2+ concentration ([Ca2+]i), and increased the rate of 45Ca2+ efflux in CPAE cells. The pharmacology of these responses was consistent with interactions with B1 and B2 receptors. The effects of maximal concentrations of bradykinin and des-Arg9-bradykinin on the activity of PLC in populations of cells were not additive, suggesting that the two subtypes were expressed on the same cells. Indeed, des-Arg9-bradykinin and bradykinin both evoked increases in [Ca2+]i in 85% of single cells tested. The Ca2+ entry blocker NiCl2 inhibited bradykinin-induced increases in [Ca2+]i and 45Ca2+ efflux. In contrast, NiCl2 did not inhibit the increase in 45Ca2+ efflux evoked by des-Arg9-bradykinin and induced oscillatory increases in [Ca2+]i in response to the B1 agonist. NiCl2 had no effect on [3H]inositol trisphosphate generation by either agonist, indicating that its inhibitory effects on bradykinin-mediated Ca2+ responses were distal to B2 receptor-induced activation of PLC. LaCl3 did not differentiate between the 45Ca2+ efflux responses evoked by bradykinin and des-Arg9-bradykinin, attenuating both to a similar degree. Bradykinin-induced [3H]inositol trisphosphate formation was desensitized after pretreatment with bradykinin, but the response to des-Arg9-bradykinin was unchanged. Pretreatment with the B1 agonist did not inhibit responses evoked by subsequent challenges with either des- Arg9-bradykinin or bradykinin. These results provide pharmacological evidence for the existence of two distinct bradykinin receptor subtypes (B1 and B2) on CPAE cells, with no evidence for heterologous desensitization. Although both subtypes operated similar signal transduction pathways, the Ca2+ responses evoked by the two receptors could be differentiated by NiCl2.
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