Abstract
In this study, the pharmacological activity of HCT-3012 [(S)-6-methoxy-α-methyl-2-naphtaleneacetic acid 4-(nitrooxy)butyl ester], a nitric oxide (NO)-releasing derivative of naproxen, was compared with that of naproxen in a model of acute ischemia (40 min) and reperfusion (20 min) of the rabbit heart. HTC-3012 (3–100 μM), in spite of inhibition of 6-keto-prostaglandin F1α generation by the cardiac tissues, brought about a dose-dependent normalization of coronary perfusion pressure, associated with a reduction of ventricular contracture during ischemia with remarkable improvement of left ventricular developed pressure at reperfusion. These beneficial effects were accompanied by a substantial release of nitrite/nitrate in the heart perfusates, indicating that NO has been released by HCT-3012 and donated to the cardiac tissue. These events were paralleled by a significant reduction of creatine kinase activity in heart perfusates during reperfusion. Naproxen (10–100 μM) aggravated the myocardial damage in ischemic reperfused hearts, severely depressing the postischemic ventricular dysfunction. Perfusion of the heart with NG-monomethyl-l-arginine (10 μM) caused a marked aggravation of myocardial damage of the reperfused hearts, and this effect was dose dependently prevented by HCT-3012 but not by naproxen. The results of the present experiments clearly indicate that HCT-3012, by donating NO, displays a noticeable anti-ischemic effect in reperfused ischemic rabbit hearts. The safer gastrointestinal profile of HCT-3012 and its ability to control experimental hypertension, suggest that this compound may have therapeutical potential in cardiovascular disease, namely in the prevention of myocardial ischemic events, and may represent a better alternative to conventional nonsteroidal anti-inflammatory drugs.
Footnotes
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DOI: 10.1124/jpet.104.067397.
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ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; NO, nitric oxide; HCT-3012, (S)-6-methoxy-α-methyl-2-naphtaleneacetic acid 4-(nitrooxy)butyl ester; KHS, Krebs-Henseleit solution; CPP, coronary perfusion pressure; LVP, left ventricular pressure; LVSP, left ventricular systolic pressure; LVEDP, left ventricular end-diastolic pressure; LVDevP, left ventricular developed pressure; CK, creatine kinase; PGI2, prostacyclin; NOx, nitrite/nitrate; 6-keto-PGF1α, 6-keto-prostaglandin F1α; l-NMMA, NG-monomethyl-l-arginine; NCX 4016, 2-acetoxy-benzoate 2-(1-nitroxy-methyl)-phenyl ester; AUC, area under the curve.
- Received February 23, 2004.
- Accepted April 12, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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