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Characterization of Cardioprotection Mediated by AT2 Receptor Antagonism After Ischemia-Reperfusion in Isolated Working Rat Hearts

Cardiology Division of the Department of Medicine, University of Alberta

Alexander S. Clanachan

Department of Pharmacology, University of Alberta. Edmonton, Alberta, Canada

Bodh I. Jugdutt

Cardiology Division of the Department of Medicine, University of Alberta

Background: Whether cardioprotection induced by the angiotensin II (AngII) type 2 receptor (AT ₂R) antagonist PD123,319 (PD) after ischemia-reperfusion (IR) is influenced by the concentration of PD, presence of AngII, timing of exposure, or inhibition of proton produc tion from glucose metabolism is not known.

Methods and Results: We examined these factors in isolated working rat hearts subjected to IR injury, no treatment (control), or treatment with N6-cyclohexyl adenosine (CHA, 0.5 µmol/L), an adenosine A₁ receptor agonist that induces cardioprotection by decreasing pro tons ("positive" control). Compared with control, 1 µmol/L PD present throughout IR im proved recovery of left ventricular work (73 ± 5 vs. 40 ± 8%) to the level with CHA (82 ± 5%), but 0.1 µmol/L PD did not (58 ± 6 vs. 40 ± 8%). AngII (1 nmol/L) did not effect postischemic recovery associated with 1 µmol/L PD (73 ± 7%) but improved that associated with 0.1 µmol/L PD (86 ± 3%). PD (1 µmol/L), present solely during reperfusion, enhanced postischemic left ventricular recovery to 72 ± 5%. Also, PD (1 µmol/L) did not affect glycolytic rates or proton production in nonischemic or IR hearts.

Conclusion: PD-induced cardioprotection is 1) PD concentration-dependent, 2) AngII- sensitive, 3) mediated during reperfusion, and 4) independent of proton production, suggest ing that reduction in IR injury and indirect AT ₁R stimulation might be involved.

Key Words: angiotensin • receptor • ischemia-reperfusion • myocardium.

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 5, No. 3, 211-221 (2000)
DOI: 10.1054/JCPT.2000.7451


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