STIMULATION OF ENDOTHELIAL ADENOSINE A(1) RECEPTORS ENHANCES ADHESIONOF NEUTROPHILS IN THE INTACT GUINEA-PIG CORONARY SYSTEM

Objective: The primary aim was to determine the action of pathophysiol ogically relevant adenosine concentrations (0.1-1 mu M) on adhesion of neutrophils to coronary endothelium. Further aims were to evaluate th e nature and localisation of the adenosine receptor involved, and to a ssess the effect of endogenous adenosine. Methods: Adhesion was studie d in isolated perfused guinea pig hearts by determining the number of cells emerging in the coronary effluent after intracoronary bolus inje ctions of 600 000 neutrophils prepared from guinea pig or human blood. The system was characterised by the use of the proadhesive stimulus t hrombin. Results: A 5 min infusion of adenosine (0.1-0.3 mu M) or the A(1) receptor agonist N-6-cyclopentyladenosine (CPA, 0.01 mu M) signif icantly increased adhesion from about 20% (control) to 30%. This effec t was prevented by the A(1) receptor antagonist dipropyl-8-cyclopentyl xanthine (DPCPX, 0.1 mu M). It was not diminished by cessation of aden osine infusion 90 s prior to neutrophil injection. At a higher concent ration of adenosine (1 mu M), adhesion did not seem to be enhanced. Ho wever, coinfusion of the A(2) receptor antagonist 3,7-dimethyl-1-propa rgy/xanthine (DMPX, 0.1 mu M) with 1 mu M adenosine unmasked the A(1) action, adhesion rising to 39%. Adenosine had a quantitatively identic al effect on adhesion of human neutrophils. Total ischaemia of 15 min duration raised adhesion of subsequently applied neutrophils to 35%. T his effect was completely blocked by DPCPX, as well as by ischaemic pr econditioning (3 X 3 min). Preconditioning raised initial postischaemi c coronary effluent adenosine from about 0.8 mu M to 1.5 mu M. Conclus ions: The findings suggest a bimodal participation of adenosine in the development of postischaemic dysfunction by an endothelium dependent modulation of neutrophil adhesion. Stimulation occurs via endothelial A(1) receptors at submicromolar adenosine levels, whereas cardioprotec tion by adenosine may in part relate to the use of pharmacologically h igh concentrations of adenosine or enhanced endogenous production afte r preconditioning.