(Hypertension. 1995;26:696-704.)
© 1995 American Heart Association, Inc.
Articles |
Regulation of Vascular Smooth Muscle Soluble Guanylate Cyclase Activity, mRNA, and Protein Levels by cAMP-Elevating Agents
From the Vascular Biology Center (A.P., J.D.C.), Department of Pharmacology and Toxicology (A.P., N.M., A.M., J.D.C.), and Department of Physiology and Endocrinology (G.M.), Medical College of Georgia, Augusta, and Molecular Geriatrics Corp, Lake Bluff, Ill (F.M.).
Abstract Although the biochemical properties of soluble
guanylate cyclase (sGC) have been extensively studied,
little is known about the regulation of gene expression of sGC subunits
by second messengers. cAMP analogues and elevating agents have been
previously shown to alter gene expression in vascular cells. The aim of
the present study was to investigate the effects of cAMP-elevating
agents on sodium nitroprusside–stimulated sGC activity and to
correlate activity changes with mRNA and protein levels in cultured rat
aortic smooth muscle cells. Pretreatment of cells with 50 to 1000
µmol/L isobutylmethylxanthine or 0.01 to 10 µmol/L forskolin
led to a time- and concentration-dependent decrease in sodium
nitroprusside–induced cGMP accumulation, first evident after 3 hours
of pretreatment with forskolin and 6 hours of pretreatment with
isobutylmethylxanthine. Incubation of cells with a protein kinase
A–selective inhibitor (H89 or KT 5720) partially or fully
prevented the downregulation in sodium nitroprusside–induced cGMP
accumulation caused by cAMP-elevating agents. Quantification of reverse
transcriptase–polymerase chain reaction products by
high-performance liquid chromatography
revealed that mRNA for both 
1- and
ß1-subunits of sGC were decreased in cells pretreated
with isobutylmethylxanthine and forskolin but not with dideoxyforskolin
(inactive analogue). Moreover, protein levels for the sGC
1-subunit of cells pretreated with
isobutylmethylxanthine and forskolin but not with dideoxyforskolin were
decreased as indicated by Western blot analysis. These data
indicate that cAMP-elevating agents decrease sGC activity, possibly by
decreasing mRNA or protein levels or both.
Key Words: guanylate cyclase • cyclic AMP • cyclic GMP • nitroprusside
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