Differential regulation of natriuretic peptide receptor activity in vascular cells.
We studied the regulation of the individual natriuretic peptide receptor subtypes by 12-O-tetradecanoylphorbol 13-acetate (TPA) and forskolin in cultured bovine aortic endothelial and smooth muscle cells. In cultured endothelial cells, 10(-8) mol/L TPA caused a reduction in atrial natriuretic peptide (ANP) receptor binding activity that was seen as early as 2 hours after the treatment and reached a maximum (88 +/- 3% of control) after 24 hours, whereas the inhibition of ANP-stimulated cyclic GMP (cGMP) accumulation peaked at 2 hours (62 +/- 13% of control) and returned to control levels after 12 hours. After 24 hours of forskolin (10(-4) mol/L) treatment, ANP binding activity fell to 47 +/- 6%, and cGMP accumulation was 52 +/- 11% of control. Northern blot analysis revealed that 10(-8) mol/L TPA suppressed natriuretic peptide C receptor transcript levels, and forskolin increased levels modestly after 24 hours of treatment. Natriuretic peptide A receptor transcript levels remained unchanged by either treatment. In cultured smooth muscle cells, 10(-8) mol/L TPA suppressed ANP binding activity and ANP-stimulated cGMP formation in a fashion similar to that seen in endothelial cells. TPA treatment also resulted in an inhibition of C-type natriuretic peptide-stimulated cGMP production (59 +/- 7% of control); however, this response persisted for as long as 24 hours after addition of the agonist. Treatment with 10(-4) mol/L forskolin produced a time-dependent inhibition of ANP binding activity and did not inhibit cGMP production stimulated by either ANP or C-type natriuretic peptide. In contrast to the effects seen with endothelial cells, TPA caused a dose-dependent stimulation of natriuretic peptide C receptor mRNA, whereas forskolin was inhibitory in smooth muscle cells. These results indicate that the effects of the kinase activators are a function of the individual receptor subtype as well as the cell in which it is expressed and imply a considerable degree of flexibility in the response to regulatory stimuli.
Cao
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Metabolic Research Unit, University of California at San Francisco 94143.
Zlock
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Gardner
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D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D012333:RNA, Messenger; D005576:Colforsin; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP; D013755:Tetradecanoylphorbol Acetate