Am. J. Respir. Cell Mol. Biol., Volume 21, Number 1, July, 1999 30-36

Mechanisms of the Potentiation by Adenosine of Adenosine Triphosphate-Induced Calcium Release in Tracheal Smooth-Muscle Cells

Marie Claire Michoud, Florence C. Tao, Amynah A. Pradhan, and James G. Martin

Meakins-Christie Laboratories and the Heisler Laboratory of the Montreal Chest Institute Research Centre, McGill University, Montreal, Quebec, Canada

The effects of concomitant P₁-receptor stimulation on peak intracellular Ca²⁺ release by extracellular adenosine 5'-triphosphate (ATP) and 5-hydroxytryptamine (5-HT) were investigated in cultured airway smooth-muscle (ASM) cells. The results show that peak Ca²⁺ release to ATP is enhanced by preincubation with adenosine (ADO) and with the specific A₃ receptor agonist 1-Deoxy-1-(6-{[(3-iodophenyl)methyl] amino}-9H-purin-9-yl)-N-methyl--D-ribofuranuronamide (1B-MECA). The response to 5-HT, a smooth-muscle contractile agonist, was also enhanced after preincubation with ADO. Further measurements showed that this enhancement of the response to ATP was dependent on extracellular calcium because it was abolished by the removal of Ca²⁺ from the extracellular fluid and by incubation with the calcium channel blocker nifedipine. In addition, there was no difference between the levels of total inositol phosphates measured in the presence of ATP alone or of ADO + ATP. AACOCF3, a specific blocker of phospholipase A₂, decreased the peak Ca²⁺ response to ATP and abolished the enhanced response to ATP and 5-HT produced by ADO. We conclude that stimulation of P₁ and P₂ receptors in ASM cells activates not only phospholipase C but also phospholipase A₂. The enhancement of ATP-induced and 5-HT-induced Ca²⁺ release is due to Ca²⁺ influx from the extracellular fluid through a Ca²⁺ channel presumably modulated by arachidonic acid. These data show that endogenous ADO may modulate airway hyperresponsiveness by enhancing the ASM response to contractile agonists.

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