Y. Ruan et al., MODULATION BY CYCLIC-AMP OF BETA-ADRENERGIC RECEPTOR-STIMULATED PROSTACYCLIN SYNTHESIS IN RABBIT VENTRICULAR MYOCYTES, The Journal of pharmacology and experimental therapeutics, 278(2), 1996, pp. 482-489
The purpose of the present study was to determine the possible interac
tion of cyclic AMP (cAMP) and the synthesis of prostacyclin [measured
as immunoreactive 6-keto-prostaglandin (PG)F-1 alpha] elicited by the
beta adrenergic receptor agonist isoproterenol (ISOP), in freshly diss
ociated rabbit ventricular myocytes. ISOP (10(-13) to 10(-11) M) incre
ased 6-keto-PGF(1 alpha) synthesis without altering the level of cAMP.
Increasing the concentration of ISOP from 10(-10) to 10(-7) M enhance
d accumulation of cAMP, which was associated with a decline in 6-keto-
PGF(1 alpha) synthesis. Forskolin (10(-6) M), an activator of adenylyl
cyclase, and 3-isobutyl-1-methylxanthine (10(-5) M), an inhibitor of
cAMP phosphodiesterase, increased cAMP accumulation and inhibited ISOP
-induced 8-keto-PGF(1 alpha) synthesis. 8-(4-chlorophenylthio) (cpt)-c
AMP (10(-7) M) also inhibited ISOP-induced 6-keto-PGF(1 alpha) product
ion. On the other hand, miconazole (10(-4) M), an inhibitor of adenyly
l cyclase, reduced cAMP accumulation and enhanced ISOP-induced 6-keto-
PGF(1 alpha) synthesis in myocyies. Miconazole also attenuated ISOP-,
forskolin- and cpt-cAMP-induced increases in protein kinase A activity
. The protein kinase A inhibitor H-89 omocinnamylamino)ethyl]-5-isoqui
nolinesulfonamide} attenuated the ISOP (10(-7) M)-induced increase in
the activity of this enzyme and minimized the decline in 6-keto-PGF(1
alpha) synthesis produced by 10(-7) M ISOP and the inhibitory effect o
f cpt-cAMP and forskolin on 6-keto-PGF(1 alpha) production. 3-Isobutyl
-1-methylxanthine, forskolin and cpt-cAMP did not alter the conversion
of exogenous arachidonic acid to 6-keto-PGF(1 alpha). These data indi
cate that beta adrenergic receptor activation promotes prostacyclin sy
nthesis in rabbit ventricular myocytes and that GAMP acts as an inhibi
tory modulator. This action is mediated via activation of protein kina
se A, probably by decreasing the activity of the lipase,involved in be
ta adrenergic receptor induced arachidonic acid release.