Contribution of bradykinin and nitric oxide to AT2 receptor-mediated differentiation in PC12 W cells.
We investigated the effect of angiotensin II on intracellular cyclic GMP content and neurite outgrowth as an indicator of cell differentiation in PC12 W cells. Neurite outgrowth was examined by phase-contrast microscopy. Outgrown neurites were classified as small, medium and large, and were expressed as neurites per 100 cells. Angiotensin II (10-7 m) increased the outgrowth of medium and large neurites by mean +/- SEM 20.2 +/- 2.3 and 6.6 +/- 1.4 compared with 1.66 +/- 0.5 and 0.1 +/- 0.06 neurites per 100 cells in control. Cellular cyclic GMP content increased by 50-250% with angiotensin II at concentrations of 10-6-10-4 m. Both blockade of AT2 receptors and of nitric oxide synthase markedly reduced angiotensin II-induced neurite outgrowth and cyclic GMP production. In contrast, B2 receptor blockade had no effect or even increased these angiotensin II effects. Sodium nitroprusside and 8-bromo-cyclic GMP both mimicked the effects of angiotensin II on cell differentiation. The protein kinase G inhibitor KT-5823 inhibited the neurite outgrowth induced by both angiotensin II and 8-bromo-cyclic GMP. Our results demonstrate that angiotensin II can stimulate cell differentiation in PC12 W cells by nitric oxide-related and cyclic GMP-dependent mechanisms. The effects of angiotensin II on cell differentiation and cyclic GMP production were mediated via the AT2 receptor and further enhanced by bradykinin B2 receptor blockade.
Zhao
Yi
Y
Institute of Pharmacology, Christian-Albrechts University of Kiel, Kiel, Germany.
Biermann
Torsten
T
Luther
Claudia
C
Unger
Thomas
T
Culman
Juraj
J
Gohlke
Peter
P
D000470:Alkaloids / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001920:Bradykinin / Q000378:metabolism* / Q000494:pharmacology; D002227:Carbazoles; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles; D016501:Neurites / Q000145:classification / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000819:agonists / Q000378:metabolism*
D000470:Alkaloids; D057911:Angiotensin Receptor Antagonists; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D020030:Nitric Oxide Donors; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C073601:KT 5823; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D001920:Bradykinin