Prostacyclin Formation Elicited by Endothelin-1 in Rat Aorta Is Mediated via Phospholipase D Activation and Not Phospholipase C or A 2

Author:

Wright Harold M.1,Malik Kafait U.1

Affiliation:

1. the Department of Pharmacology, College of Medicine, The University of Tennessee, Memphis.

Abstract

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that also stimulates production of prostacyclin (PGI 2 ) from arachidonic acid. The purpose of this study was to determine the contribution of phospholipases (PLs) A 2 , C, and/or D in ET-1–induced PGI 2 formation in the rat aorta, measured as immunoreactive 6-ketoprostaglandin (PG) F . ET-1 increased 6-keto-PGF formation, which was not affected by a PLA 2 inhibitor, 7,7-dimethyl eicosadienoic acid (DEDA). Furthermore, ET-1 failed to stimulate PLA 2 activity measured in the cytosol (cPLA 2 ), using phosphatidylcholine, l -a-1-palmitoyl-2-arachidonyl[ 14 C] as a substrate. However, the adrenergic agonist norepinephrine increased 6-keto-PGF formation, which was attenuated by DEDA, and enhanced PLA 2 activity. ET-1 enhanced PLC activity, as indicated by increased inositol phosphate production, which was prevented by a PLC inhibitor, U-73122. However, ET-1–induced 6-keto-PGF production was not altered by U-73122. An inhibitor of PLD activation, C 2 -ceramide, attenuated ET-1–induced PLD activity, as indicated by the production of phosphatidylethanol. Furthermore, ET-1–induced 6-keto-PGF formation was inhibited by C 2 -ceramide as well as by ethanol treatment. Moreover, inhibitors of phosphatidate phosphohydrolase (propranolol) and diacylglycerol lipase (RHC-80267), attenuated ET-1–induced 6-keto-PGF formation. Finally, ET-1–induced activation of PLD was not attenuated by a selective PKC inhibitor, bisindolylmaleimide I. These data suggest a novel pathway for ET-1–induced PGI 2 formation in the rat aorta involving activation of PLD but not cPLA 2 and independent of PLC or PKC activation.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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