Abstract

The concentration-related sensitization of guinea-pig left atria to adenosine produced by six benzodiazepines and dipyridamole was analyzed with a quantitative procedure which theoretically yields the pKI (-log equilibrium dissociation constant) of an uptake inhibitor for the site of uptake. Four benzodiazepines produced sensitization of atria to adenosine and no alteration of responses to 2-chloroadenosine (a purine agonist which is not a substrate for adenosine uptake or degradation), the rank order of potency being diazepam (pKI = 5.6) much greater than oxazepam (pKI = 4.6) greater than clonazepam (pKI = 4.3) = lorazepam (pKI = 4.2). Chlordiazepoxide and prazepam produced little sensitization to adenosine, but a concentration-related antagonism of responses to 2-chloroadenosine. Prior inhibition of adenosine uptake with dipyridamole unmasked antagonism of responses to adenosine by these two benzodiazepines as well, indicating a dual self-cancelling effect (for inhibition of adenosine uptake; chlordiazepoxide, pKI = 5.0; prazepam, pKI = 4.8). Although benzodiazepines have been shown to inhibit uptake of adenosine in the central nervous system, the potency of these drugs and dipyridamole is more in accord with inhibition of a myocardial uptake process distinct from the synaptosomal transport of adenosine.