PT  - JOURNAL ARTICLE
AU  - Ying Ruan
AU  - Hong Kan
AU  - Kafait U. Malik
TI  - <em>Beta</em> Adrenergic Receptor Stimulated Prostacyclin Synthesis in Rabbit Coronary Endothelial Cells Is Mediated by Selective Activation of Phospholipase D: Inhibition by Adenosine  3′5′-Cyclic Monophosphate
DP  - 1997 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1038--1046
VI  - 281
IP  - 3
4099  - http://jpet.aspetjournals.org/content/281/3/1038.short
4100  - http://jpet.aspetjournals.org/content/281/3/1038.full
SO  - J Pharmacol Exp Ther1997 Jun 01; 281
AB  - Activation of beta adrenergic receptors in the isolated rabbit heart by catecholamines stimulates prostacyclin (PGI2) synthesis, which is inhibited by adenosine 3′5′-cyclic monophosphate (cAMP). The purpose of this study was to determine if activation of beta adrenergic receptors in cultured coronary endothelial cells (CEC) of rabbit heart with isoproterenol (ISOP) stimulates PGI2 synthesis and if cAMP inhibits the synthesis of this prostanoid and to investigate the underlying mechanism. Incubation of CEC with ISOP increased production of cAMP and PGI2, measured as immunoreactive cAMP and 6-keto-prostaglandin F1α, (6-keto-PGF1α), respectively. Forskolin, an activator of adenylyl cyclase, increased cAMP accumulation and inhibited ISOP-stimulated 6-keto-PGF1α synthesis. 8-(4-chlorophenylthio) cAMP also inhibited ISOP-induced 6-keto-PGF1α production. However, miconazole, an inhibitor of adenylyl cyclase, reduced cAMP accumulation and enhanced ISOP-stimulated 6-keto-PGF1α synthesis in CEC. ISOP-induced 6-keto-PGF1α synthesis was attenuated by C2-ceramide, an inhibitor of phospholipase D (PLD) by propranolol, a beta-AR antagonist that also inhibits phosphatidate phosphohydrolase and by the diacylglycerol lipase inhibitor 1,6-bis-(cyclohexyloximinocarbonylamino)-hexane (RHC 80267). Acetylcholine (ACh) induced 6-keto-PGF1α synthesis was also inhibited by these agents. Both ISOP and ACh increased PLD activity, which was inhibited by C2-ceramide but not by RHC 80267 or propranolol. ACh but not ISOP increased phospholipase A2 activity in CEC. ISOP- but not ACh-induced increase in PLD activity was attenuated by forskolin and 8-(4-chlorophenyl-thio)-adenosine 3′-5′-cyclic monophosphate and augmented by miconazole. These data suggest thatbeta adrenergic receptors activation promotes PGI2 synthesis in the CEC by selective activation of PLD and that cAMP decreases PGI2 synthesis by decreasing PLD activity. Moreover, beta adrenergic receptors activated PLD appears to be distinct from that stimulated by ACh. The American Society for Pharmacology and Experimental Therapeutics