This study investigated whether cross-talk between insulin and the bradykinin receptor exists to modulate bradykinin-induced increase in inositol 1,4,5-triphosphate (IP3) in neonatal rat cardiomyocytes. Treatment of the cultures with 1, 2, and 20 nM of insulin for 90 min before adding bradykinin increased the IP3 response to the same bradykinin dose to 372.0 +/- 17.8, 413.7 +/- 17.7, and 457.3 +/- 18.2 pmol/mg protein, respectively. Tyrphostine A23 and genistein (tyrosine kinase inhibitors) decreased the bradykinin (10 nM)-induced IP3 production potentiated by 2 nM insulin from 400.7 +/- 19.4 pmol/mg protein to 297.3 +/- 42.4 and 314.3 +/- 37.5 pmol/mg protein, respectively. Administration of 100 nM N-(6-aminohexyl)-5-chloro-naphthalenesulfonamide (W7, a calmodulin antagonist) significantly increased the bradykinin (10 nM)-induced IP3 production from 311.7 +/- 13.0 pmol/mg protein in the absence of insulin to 457.8 +/- 19.9, 578.2 +/- 25.9, and 665.2 +/- 16.0 pmol/mg protein in the presence of 1, 2, and 20 nM insulin, respectively. These results demonstrate that cross-talk between the insulin receptor and the bradykinin signaling system may exist in neonatal rat cardiomyocytes. Tyrosine kinase appears to play an important role in the cross-talking. Calmodulin controls the IP3 response to bradykinin by a negative feedback mechanism.
SUMMARYWe investigated whether alteration of extracellular and intracellular Ca 2+ concentrations, protein kinase C, and calmodulin modulate norepinephrine(NE)-induced inositol 1,4,5-trisphosphate (IP 3 ) formation in neonatal rat atrial myocytes. NE-induced IP 3 production in atrial myocytes was stimulated by elevation of extracellular Ca 2+ in a dosedependent manner. However, TMB-8 (an intracellular calcium antagonist) and A23187 (an intracellular calcium agonist) did not significantly affect NE-induced IP 3 production. PMA (a protein kinase C agonist) significantly decreased and staurosporine (a protein kinase C antagonist) significantly stimulated NE-induced IP 3 production. W7 (a calmodulin antagonist) significantly increased the NE-induced IP 3 . In conclusion, elevation of extracellular Ca 2+ concentrations affects NE-induced IP 3 formation in atrial myocytes. Protein kinase C and calmodulin may control the IP 3 response to NE by a negative feedback mechanism. ( 2) The signal transduction of NE occurs through activation of phospholipase C (PLC), which leads to release of IP 3 . On the other hand, release of IP 3 by NE in atrial cells is also associated with the development of arrhythmias.3) Thus, NE-stimulated IP 3 plays an important role in atrial cells, however, intracellular regulation of NE-stimulated IP 3 formation in atrial myocytes remains unclear.
Ketamine inhibits norepinephrine-induced inositol 1,4,5-triphosphate formation in a dose-dependent manner via pathways that involve protein kinase C and a decrease in intracellular Ca(2+) concentrations.
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