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Vol. 294, Issue 1, 248-254, July 2000

Angiotensin-Converting Enzyme-Independent Angiotensin Formation in a Human Model of Myocardial Ischemia: Modulation of Norepinephrine Release by Angiotensin Type 1 and Angiotensin Type 2 Receptors1

Ryushi Maruyama, Eiichiro Hatta, Keishu Yasuda, Neil C. E. Smith and Roberto Levi

Department of Pharmacology, Cornell University, Weill Medical College, New York, New York (R.M., N.C.E.S., R.L.); and Department of Cardiovascular Surgery, Hokkaido University School of Medicine, Sapporo, Japan (E.H., K.Y.).

Angiotensin II (Ang II) promotes norepinephrine (NE) release from cardiac sympathetic nerve endings. We assessed in a human model in vitro whether locally formed Ang II contributes to NE release in myocardial ischemia. Surgical specimens of human right atrium were incubated in anoxic conditions. After 70 min of anoxia, NE release (carrier-mediated; caused by NE transporter reversal) was 8-fold greater than normoxic release. Angiotensin-converting enzyme inhibition with enalaprilat failed to reduce anoxic NE release. In contrast, prevention of chymase-dependent Ang II formation with chymostatin, Bowman-Birk inhibitor, or alpha 1-antitrypsin significantly inhibited anoxic, but not exocytotic, NE release. Two mast-cell stabilizers, cromolyn and lodoxamide, markedly reduced NE release, implicating cardiac mast cells as a major source of chymase. Angiotensin type 1 receptor (AT1R) blockade with EXP3174 inhibited NE release, whereas angiotensin type 2 receptor (AT2R) blockade with PD123319 did not. Interestingly, PD123319 reversed the inhibitory effect of EXP3174. Furthermore, synergisms were uncovered between EXP3174 and an AT2R agonist, and between EXP3174 and a Na+/H+ exchanger inhibitor. Thus, angiotensin-converting enzyme-independent Ang II formation via chymase is important for carrier-mediated ischemic NE release in the human heart. Locally generated Ang II promotes NE release by acting predominantly at AT1Rs, which are likely coupled to the Na+/H+ exchanger. Effects of Ang II at AT2Rs, seemingly opposite to those resulting from AT1R activation, are uncovered when AT1Rs are blocked. Because NE release is associated with coronary vasoconstriction and arrhythmias, and mast-cell density and chymase content increase in the ischemic heart, the notion that chymase-generated Ang II plays a major role in carrier-mediated NE release may have important clinical implications.

1 This work was supported by National Institutes of Health Grants HL34215 and HL46403. A preliminary version of these findings was presented at Experimental Biology `99, April 1999 (Washington, DC) and was published in abstract form in FASEB J (1999) 13:A761.

0022-3565/00/2941-0248$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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