Indirect inhibition by bradykinin of cyclic AMP generation in isolated rat glomeruli and mesangial cells.
The present study was designed to evaluate the effect of the activation of bradykinin (BK) receptors on intracellular cAMP levels in isolated glomeruli as well as in cultured rat mesangial cells. BK affected basal cAMP content only in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Furthermore, BK inhibited forskolin-, prostaglandin E2-, and isoproterenol-stimulated cAMP accumulation, both in the presence and in the absence of isobutylmethylxanthine. The inhibitory effect of BK was independent of stimulation of cAMP degradation by phosphodiesterase. No direct inhibition of the in vitro adenylyl cyclase activity was observed, suggesting a requirement for cytoplasmic constituents. Use of the phospholipase A2 inhibitor mepacrine and treatment with pertussis toxin did not modify the inhibitory effect of BK, indicating that neither the phospholipase A2 pathway nor the inhibitory G protein is involved. The effect of BK was completely prevented by two selective protein kinase C (PKC) inhibitors, staurosporine and bisindolylmaleimide. Furthermore, use of the diacylglycerol analog 1-oleoyl-2-acetyl-rac-glycerol and direct activation of PKC with phorbol-12-myristate-13-acetate mimicked the effect of BK, whereas the biologically inactive phorbol ester 4 alpha-phorbol-12, 13-didecanoate was without effect. Furthermore, down-regulation of PKC by long term pretreatment with phorbol-12-myristate-13-acetate abolished the inhibitory effect of BK on stimulated cAMP levels. These results demonstrate that BK inhibits forskolin-, prostaglandin E2-, and isoproterenol-stimulated cAMP formation through activation of the phospholipase C pathway. The subsequent production of diacylglycerol associated with stimulation of PKC in turn inhibits stimulated cAMP accumulation.
Bascands
J L
JL
Institute National de la Santé et de la Recherche Medicale (CJF 92.05), Institut Louis Bugnard, School of Medicine Rangueil, Toulouse, France.
Pecher
C
C
Girolami
J P
JP
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002478:Cells, Cultured; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D004075:Diglycerides / Q000096:biosynthesis / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions; D004789:Enzyme Activation; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D037342:Pertussis Toxin; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018002:Receptors, Bradykinin / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D004075:Diglycerides; D018002:Receptors, Bradykinin; D010566:Virulence Factors, Bordetella; D005576:Colforsin; C038237:1-oleoyl-2-acetylglycerol; D000242:Cyclic AMP; D037342:Pertussis Toxin; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D011796:Quinacrine; D015232:Dinoprostone; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate; D001920:Bradykinin; D015056:1-Methyl-3-isobutylxanthine