The influence of diazepam and midazolam on adenosine-induced forearm vasodilation in humans

Adenosine is an endogenous purine with vasodilating and cardioprotective properties. Animal experiments have shown that some benzodiazepine-induced effects can be explained by potentiation of adenosine effects, via inhibition of the nucleoside transport system. The objective of this study was to determine whether the frequently used benzodiazepines diazepam and midazolam increase adenosine-induced vasodilation in the human forearm vascular bed, measured by venous occlusion plethysmography. Adenosine (0.6, 6, 20, and 60 nmol/min/dl ForeArm Volume) was infused into the brachial artery with and without concomitant separate infusion of diazepam (21 nmol/min/dl, n = 9) and midazolam (23 nmol/min/dl, n = 8). Plasma concentrations of diazepam resp. midazolam at the end of the infusion protocol averaged 0.5 +/- 0.2 microg/ml plasma (1.6 microM) for diazepam versus 1.2 +/- 0.4 microg/ml plasma (3 microM) for midazolam. Intra-arterial infusion of the benzodiazepines did not alter baseline vascular tone, and had no significant influence on the forearm vasodilator response to adenosine. The adenosine-induced relative change in Forearm Vascular Resistance (FVR) was -3 +/- 7, -48 +/- 8, -75 +/- 6, and -85 +/- 3% in the absence and 3.5 +/- 11, -54 +/- 5, -74 +/- 5, and -82 +/- 3% resp. in the presence of diazepam (P > 0.1, repeated measures ANOVA, n = 9). Likewise, in the absence resp. presence of midazolam, FVR fell by 1 +/- 6, 55 +/- 5, 74 +/- 3, and 84 +/- 2% resp. 11 +/- 11, 59 +/- 2, 80 +/- 3, and 87 +/- 2% (P > 0.1, n = 7). Intra-brachial infusion of diazepam and midazolam resulting in forearm concentrations in the high therapeutic range does not augment adenosine-induced forearm vasodilation. A possible interaction at supra-therapeutic levels of the benzodiazepines can not be excluded from the present study, but lacks clinical significance.