This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wright, H. M. Articles by Malik, K. U. Search for Related Content PubMed PubMed Citation Articles by Wright, H. M. Articles by Malik, K. U.

(Circulation Research. 1996;79:271-276.)
© 1996 American Heart Association, Inc.

Articles

Prostacyclin Formation Elicited by Endothelin-1 in Rat Aorta Is Mediated via Phospholipase D Activation and Not Phospholipase C or A₂

Harold M. Wright, Kafait U. Malik

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

Correspondence to Dr K.U. Malik, Department of Pharmacology, College of Medicine, The University of Tennessee, 874 Union Ave, Memphis, TN 38163. E-mail kmalik@utmem1.utmem.edu.

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that also stimulates production of prostacyclin (PGI₂) from arachidonic acid. The purpose of this study was to determine the contribution of phospholipases (PLs) A₂, C, and/or D in ET-1–induced PGI₂ formation in the rat aorta, measured as immunoreactive 6-ketoprostaglandin (PG) F₁. ET-1 increased 6-keto-PGF₁ formation, which was not affected by a PLA₂ inhibitor, 7,7-dimethyl eicosadienoic acid (DEDA). Furthermore, ET-1 failed to stimulate PLA₂ activity measured in the cytosol (cPLA₂), using phosphatidylcholine, L-a-1-palmitoyl-2-arachidonyl[¹⁴C] as a substrate. However, the adrenergic agonist norepinephrine increased 6-keto-PGF₁ formation, which was attenuated by DEDA, and enhanced PLA₂ 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-PGF₁ production was not altered by U-73122. An inhibitor of PLD activation, C₂-ceramide, attenuated ET-1–induced PLD activity, as indicated by the production of phosphatidylethanol. Furthermore, ET-1–induced 6-keto-PGF₁ formation was inhibited by C₂-ceramide as well as by ethanol treatment. Moreover, inhibitors of phosphatidate phosphohydrolase (propranolol) and diacylglycerol lipase (RHC-80267), attenuated ET-1–induced 6-keto-PGF₁ 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 PGI₂ formation in the rat aorta involving activation of PLD but not cPLA₂ and independent of PLC or PKC activation.

Key Words: endothelin • phospholipases • aorta • prostaglandins

This article has been cited by other articles:

				H. Wilkens, M. Bauer, N. Forestier, J. Konig, A. Eichler, S. Schneider, H.J. Schafers, and G.W. Sybrecht Influence of Inhaled Iloprost on Transpulmonary Gradient of Big Endothelin in Patients With Pulmonary Hypertension Circulation, March 25, 2003; 107(11): 1509 - 1513. [Abstract] [Full Text] [PDF]

				M. M. Muthalif, I. F. Benter, Z. Khandekar, L. Gaber, A. Estes, S. Malik, J.-H. Parmentier, V. Manne, and K. U. Malik Contribution of Ras GTPase/MAP Kinase and Cytochrome P450 Metabolites to Deoxycorticosterone-Salt-Induced Hypertension Hypertension, January 1, 2000; 35(1): 457 - 463. [Abstract] [Full Text] [PDF]

				G. Liu, L. Kleine, R. Nasrallah, and R. L. Hebert Bradykinin inhibits ceramide production and activates phospholipase D in rabbit cortical collecting duct cells Am J Physiol Renal Physiol, April 1, 1999; 276(4): F589 - F598. [Abstract] [Full Text] [PDF]

				E. F. LaBelle and E. Polyak Norepinephrine stimulates arachidonic acid release from vascular smooth muscle via activation of cPLA2 Am J Physiol Cell Physiol, April 1, 1998; 274(4): C1129 - C1137. [Abstract] [Full Text] [PDF]