Enhancement by benzodiazepines of the inhibitory effect of adenosine on skeletal neuromuscular transmission.

1. Interactions of benzodiazepines with adenosine on the neuromuscular transmission were studied in mouse diaphragm preparations. 2. In tubocurarine (0.6-0.8 microM)-partially paralyzed preparations, diazepam (35 microM) and Ro 5-4864 (3-30 microM), a peripheral type benzodiazepine receptor agonist, potentiated the inhibitory effect of adenosine on indirect twitch responses. 3. The central type receptor agonist, clonazepam did not affect the inhibitory effect of adenosine. 4. The peripheral benzodiazepine receptor antagonist, PK11195 (1-10 microM) attenuated the adenosine inhibition and antagonized the potentiation by Ro 5-4864. 5. Ro 5-4864 failed to enhance further the inhibitory effect of adenosine in the presence of dipyridamole, an adenosine uptake inhibitor that also potentiated adenosine inhibition. 6. Neither Ro 5-4864 nor PK 11195 affected the inhibition produced by a stable adenosine analogue, 2-chloroadenosine, which is not a substrate for the adenosine uptake system. 7. Ro 5-4864 did not affect endplate potentials (e.p.ps) in the absence of adenosine, but reduced the amplitude of e.p.ps in the presence of adenosine without affecting miniature e.p.ps. 8. It is suggested that benzodiazepines potentiate the adenosine-effected presynaptic inhibition of neuromuscular transmission by an inhibition of adenosine uptake through activation of peripheral type benzodiazepine receptors.