This Article Full Text Full Text (PDF) 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 Woodcock, E. A. Articles by Du, X.-J. Search for Related Content PubMed PubMed Citation Articles by Woodcock, E. A. Articles by Du, X.-J. Related Collections Biochemistry and metabolism Arrythmias-basic studies Other Vascular biology

(Circulation. 1999;99:823-828.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Inhibition of Inositol(1,4,5)Trisphosphate Generation by Endothelin-1 During Postischemic Reperfusion

A Novel Antiarrhythmic Mechanism

Elizabeth A. Woodcock, PhD; Nancy Reyes, Dipl Biol Sci; Alexander N. Jacobsen, MBBS; Xiao-Jun Du, MB, PhD

From the Cellular Biochemistry Laboratory and the Experimental Cardiology Laboratory (X.-J.D.), Baker Medical Research Institute, Prahran, Victoria, Australia.

Correspondence to Dr E.A. Woodcock, Baker Medical Research Institute, PO Box 6492, Melbourne 8008, Victoria, Australia. E-mail liz.woodcock{at}baker.edu.au

Background—Reperfusion of ischemic rat hearts in the presence of thrombin or norepinephrine but not endothelin-1 causes the generation of inositol 1,4,5-trisphosphate (Ins 1,4,5P₃) and arrhythmias. The present study investigates the effect of endothelin-1 on these responses.

Methods and Results—Ins 1,4,5P₃ generation was quantified by use of [³H] labeling and high-performance liquid chromatography as well as by mass analysis. Twenty minutes of global ischemia followed by 2 minutes of reperfusion increased [³H]Ins 1,4,5P₃ from 2828±265 to 5033±650 cpm/g tissue in the presence of thrombin 2.5 IU/mL and to 4561±286 cpm/g tissue in response to release of norepinephrine (n=4, P<0.01) in both cases. Reperfusion in the presence of endothelin-1 alone caused no change in Ins 1,4,5P₃ (2762±240 cpm/g tissue), but when added together with thrombin or norepinephrine, endothelin-1 reduced the Ins 1,4,5P₃ responses to 2313±197 and 1764±168 cpm/g tissue, respectively (n=4, P<0.01 in both cases). Similar inhibitory interactions between endothelin-1 10 nmol/L and thrombin 2.5 IU/mL were observed under normoxic conditions in nonperfused ventricle, eliminating the possibility that excessive vasoconstriction was responsible. In parallel studies, endothelin-1 suppressed the development of reperfusion arrhythmias initiated by either thrombin (ventricular fibrillation, 75% to 39%, n=16 to 18) or norepinephrine (83% to 8%, n=12 to 22) (P<0.01 in both cases).

Conclusions—Inhibition of Ins 1,4,5P₃ generation during myocardial reperfusion by endothelin-1 represents a novel antiarrhythmic mechanism.

Key Words: inositol trisphosphate • arrhythmias • endothelin • thrombin • receptors, adrenergic, alpha

This article has been cited by other articles:

				D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]

				A. T. Goodwin, R. T. Smolenski, C. C. Gray, J. Jayakumar, M. Amrani, and M. H. Yacoub Role of endogenous endothelin on coronary reflow after cardioplegic arrest J. Thorac. Cardiovasc. Surg., December 1, 2001; 122(6): 1167 - 1173. [Abstract] [Full Text] [PDF]

				G. Vassort Adenosine 5'-Triphosphate: a P2-Purinergic Agonist in the Myocardium Physiol Rev, April 1, 2001; 81(2): 767 - 806. [Abstract] [Full Text] [PDF]

				F. Duru, M. Barton, T. F. Luscher, and R. Candinas Endothelin and cardiac arrhythmias: do endothelin antagonists have a therapeutic potential as antiarrhythmic drugs? Cardiovasc Res, February 1, 2001; 49(2): 272 - 280. [Abstract] [Full Text] [PDF]

				S. J. Matkovich and E. A. Woodcock Ca2+-activated but Not G Protein-mediated Inositol Phosphate Responses in Rat Neonatal Cardiomyocytes Involve Inositol 1,4,5-Trisphosphate Generation J. Biol. Chem., April 6, 2000; 275(15): 10845 - 10850. [Abstract] [Full Text] [PDF]