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Cardioprotection with a novel adenosine regulating agent mediated by intravascular adenosine
M A Kurz1, D A Bullough, C J Buggé
1Department of Cardiovascular Pharmacology, Gensia, Inc., San Diego, CA 92121, USA.
Insights
Novel agent GP531 enhances adenosine's cardioprotective effects by increasing intravascular adenosine levels during ischemia, improving recovery from myocardial stunning.
Area of Science:
- Cardiology
- Pharmacology
- Physiology
Background:
- Adenosine demonstrates cardioprotective properties in myocardial stunning and infarction models.
- The specific cardiac compartment where adenosine exerts its protective effects remains unclear.
Purpose of the Study:
- To evaluate the impact of a novel adenosine-regulating agent, GP531, on post-ischemic myocardial function.
- To determine the role of endogenous adenosine within intravascular and interstitial spaces in mediating cardioprotection.
Main Methods:
- Utilized a pig model to assess myocardial segment shortening and measure adenosine concentrations in coronary venous blood and myocardial interstitial fluid.
- Induced myocardial dysfunction through coronary occlusions and monitored functional recovery over 2 hours.
- Administered GP531 and employed adenosine receptor blockade (8-sulfophenyltheophylline) to investigate mechanisms.
Main Results:
- GP531 significantly improved functional recovery (55% vs. 24% of baseline) after ischemia-reperfusion injury.
- GP531-mediated cardioprotection was abolished by adenosine receptor blockade.
- GP531 increased intravascular adenosine concentrations during ischemia but did not significantly alter interstitial adenosine levels.
Conclusions:
- GP531 enhances recovery of myocardial function through an adenosine receptor-dependent pathway.
- The cardioprotective effects of GP531 are linked to increased intravascular adenosine during ischemia.
- Cardioprotection mediated by GP531-enhanced adenosine relies on an intravascular site of action.
Abstract:
Adenosine is cardioprotective in models of myocardial stunning and infarction, but the precise compartment within the heart in which adenosine elicits its cardioprotective effects has not been determined. The goals of the present study were to (i) investigate the effects of a novel adenosine regulating agent, GP531 (5-amino-1-beta-n-(5-benzylamino-5-deoxyribofuranosyl) imidazole-4-carboxamide), on post-ischemic myocardial function, and (ii) examine the contribution of endogenous adenosine in the intravascular and interstitial compartments in mediating the beneficial effects. Pigs were instrumented for measurement of myocardial segment shortening, and for sampling of coronary venous blood and myocardial interstitial fluid for determination of adenosine concentration. Myocardial dysfunction was induced by 4 x 8 min coronary occlusions, and recovery of regional function was monitored for 2 h. In control pigs, function recovered to 24 +/- 2% of baseline after 2 h. Treatment with GP531 improved functional recovery to 55 +/- 3%. GP531-mediated cardioprotection was prevented by adenosine receptor blockade with 8-sulfophenyltheophylline (23 +/- 2%). GP531 did not affect basal adenosine levels, but caused a 2-fold greater increase in vascular adenosine concentration with ischemia (54.6 +/- 10.6 vs. 28.1 +/- 8.0 microM in controls. P < 0.05). In contrast, the interstitial adenosine concentration was not significantly different in treated vs. untreated control pigs (9.4 +/- 3.9 vs. 15.0 +/- 1.8 microM in controls). These data indicate that (1) GP531 improves recovery of myocardial function following ischemia reperfusion injury via an adenosine receptor-dependent mechanism, and (2) the cardioprotection is associated with increased intravascular, but not interstitial, adenosine concentration during ischemia. Therefore, we conclude that cardioprotection elicited by GP531-enhanced endogenous adenosine is dependent on an intravascular site of action.