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Adenosine A2-receptor activation inhibits neutrophil-mediated injury to coronary endothelium
Z Q Zhao1, H Sato, M W Williams
1Department of Cardiothoracic Surgery, Bowman Gray School of Medicine, of Wake Forest University, Winston-Salem, North Carolina 27157, USA.
Abstract:
Adenosine (ADO) attenuates polymorphonuclear neutrophil (PMN)-mediated damage, partly by inhibiting superoxide anion (O2-.) generation and PMN adherence to the coronary artery endothelium. This study tests the hypothesis that the antineutrophil effects of ADO are mediated by A2-receptor activation. Isolated canine PMN were activated by 100 nM platelet-activating factor (PAF). Compared with untreated activated PMN (100%), ADO attenuated O2-. production (46 +/- 9% of activated PMN), which was mimicked by the A2 agonist CGS-21680 (50 +/- 6% of activated PMN), unaltered by A1-selective antagonism with KW-3902 in the presence of ADO (40 +/- 7%), but blocked by combined A1-A2 blockade with 8-p-sulfophenyl theophylline (8-SPT, 94 +/- 14%). ADO reduced adherence of fluorescent PMN to endothelial surfaces of isolated canine coronary artery segments from 174 +/- 12 to 29 +/- 9/mm2 (P < 0.01), which was unaltered by A1 antagonism (35 +/- 7/mm2) but was reversed by 8-SPT (150 +/- 11/mm2). CGS-21680 inhibited adherence (48 +/- 8/mm2), comparable to that of ADO. Canine coronary artery rings were incubated with activated PMN to induce injury to the endothelium. The concentration of drug required to elicit 50% of maximal relaxation (-log M) derived from dose-relaxation responses to acetylcholine in PMN-damaged rings was significantly (P < 0.05) less in ADO-treated (6.88 +/- 0.08) and CGS-21680-treated (7.12 +/- 0.09) rings than untreated rings (6.54 +/- 0.10). This protection with ADO was reversed by inclusion of 8-SPT (6.49 +/- 0.12) but not KW-3902 (6.96 +/- 0.07). We conclude that ADO reduces PMN-induced coronary endothelial injury by A2-receptor-mediated inhibition of O2-. generation and adherence.
Insights
Adenosine (ADO) protects against neutrophil-induced damage by activating A2 receptors, reducing superoxide generation and adherence to coronary arteries. This mechanism preserves endothelial function, highlighting ADO
Area of Science:
- Cardiovascular Research
- Immunology
- Pharmacology
Background:
- Polymorphonuclear neutrophils (PMNs) contribute to cardiovascular injury.
- Adenosine (ADO) is known to attenuate PMN-mediated damage.
- The specific receptor subtypes mediating ADO's anti-PMN effects require elucidation.
Purpose of the Study:
- To test the hypothesis that adenosine's anti-neutrophil effects are mediated by A2-receptor activation.
- To investigate the role of A2 receptors in adenosine's protective effects on coronary endothelium against PMN-induced injury.
Main Methods:
- Isolated canine neutrophils were activated with platelet-activating factor (PAF).
- Superoxide anion (O2-.) generation and PMN adherence to coronary artery endothelium were measured.
- Effects of ADO, A2 agonist (CGS-21680), and receptor antagonists (KW-3902, 8-SPT) were assessed.
- Coronary artery ring function was evaluated after PMN-induced injury.
Main Results:
- ADO significantly attenuated O2-. production and PMN adherence, effects mimicked by the A2 agonist CGS-21680.
- A1-selective antagonism did not alter ADO's effects, while combined A1-A2 blockade reversed them.
- ADO and CGS-21680 protected coronary artery rings from PMN-induced endothelial dysfunction, an effect blocked by 8-SPT.
Conclusions:
- Adenosine reduces PMN-induced coronary endothelial injury.
- These protective effects are mediated primarily through A2-receptor activation.
- A2-receptor activation inhibits PMN superoxide generation and adherence, preserving endothelial function.