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Ca 2+ ‐dependent and ‐independent mechanism of cyclic‐AMP reduction: mediation by bradykinin B 2 receptors
Author(s) -
Sipma Henk,
Hertog Adriaan,
Nelemans Adriaan
Publication year - 1995
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/j.1476-5381.1995.tb15901.x
Subject(s) - bradykinin , forskolin , ionomycin , medicine , isoprenaline , endocrinology , bradykinin receptor , chemistry , receptor , biology , stimulation
1 Bradykinin caused a transient reduction of about 25% in the cyclic AMP level in forskolin prestimulated DDT 1 MF‐2 smooth muscle cells (IC 50 : 36.4 ±4.9 nM) and a pronounced, sustained inhibition (40%) of the isoprenaline‐stimulated cyclic AMP level (IC 50 : 37.5 ±1.1 nM). 2 The Ca 2+ ionophore, ionomycin, mimicked both the bradykinin‐induced transient reduction in the forskolin‐stimulated cyclic AMP level and the sustained reduction in the isoprenaline‐stimulated cyclic AMP level. 3 The Ca 2+ ‐dependent effect on cyclic AMP induced by bradykinin was mediated solely by Ca 2+ release from internal stores, since inhibition of Ca 2+ entry with LaCl 3 did not reduce the response to bradykinin. 4 The involvement of calmodulin‐dependent enzyme activities, protein kinase C or an inhibitory GTP binding protein in the bradykinin‐induced responses was excluded since a calmodulin inhibitor, calmidazolium, a PKC inhibitor, staurosporine and pertussis toxin, respectively did not affect the decline in the cyclic AMP level. 5 Bradykinin enhanced the rate of cyclic AMP breakdown in intact cells, which effect was not mimicked by ionomycin. This suggested a Ca 2+ ‐independent activation of phosphodiesterase activity by bradykinin in DDT 1 MF‐2 cells. 6 The bradykinin B 1 receptor agonist, desArg 9 –bradykinin, did not affect cyclic AMP formation in isoprenaline prestimulated cells, while the bradykinin B 2 receptor antagonists, Hoe 140 (D‐Arg[Hyp 3 , Thi 5 , D‐Tic 7 , Oic 8 ]‐BK) and D‐Arg[Hyp 3 , Thi 5–8 , D‐Phe 7 ]‐BK completely abolished the bradykinin response in both forskolin and isoprenaline prestimulated cells. 7 Bradykinin caused an increase in intracellular Ca 2+ , which was antagonized by the bradykinin B 2 receptor antagonists, Hoe 140 and D‐Arg[Hyp 3 , Thi 5,8 , D‐Phe 7 ]‐BK. The bradykinin B 2 receptor agonist, desArg 9 –bradykinin, did not evoke a rise in cytoplasmic Ca 2+ . 8 It is concluded, that stimulation of bradykinin B 2 receptors causes a reduction in cellular cyclic AMP in DDT 1 MF‐2 cells. This decline in cyclic AMP is partly mediated by a Ca 2+ /calmodulin independent activation of phosphodiesterase activity. The increase in [Ca 2+ ] i mediated by bradykinin B 2 receptors inhibited forskolin‐ and isoprenaline‐activated adenylyl cyclase differently, most likely by interfering with different components of the adenylyl cyclase signalling pathway.