Adenosine and adenosine uptake inhibitors potentiate the neuromuscular blocking action of rocuronium mediated by adenosine A(1) receptors in isolated rat diaphragms.
BACKGROUND
Adenosine, which pre-junctionally modulates neuromuscular transmission, and adenosine uptake inhibitors, which increase extracellular adenosine, have been used clinically. We investigated the effects of adenosine, dipyridamole and midazolam on the neuromuscular blocking action of rocuronium.


METHODS
Isometric twitch tensions of rat nerve-hemidiaphragm preparations elicited by indirect (phrenic nerve) supra-maximal stimulation at 0.1 Hz were evaluated (n=6 in all data).


RESULTS
Pre-treatments with adenosine (0.1 and 1 microM) and CCPA (1 microM, adenosine A(1) receptor agonist), but not that with CGS21680 (0.5 microM, A(2) receptor agonist), shifted the rocuronium concentration-twitch tension curves to the left and decreased the rocuronium concentration for 50% twitch depression (IC(50)) compared with the control (P<0.01). The leftward shift induced by 1 microM adenosine was inhibited by pre-treatments with theophylline (50 microM, non-selective adenosine receptor antagonist) and DPCPX (0.2 microM, A(1) receptor antagonist) but not by that with DPMA (5 microM, A(2) receptor antagonist). Pre-treatments with dipyridamole and midazolam, adenosine uptake inhibitors, shifted the curve to the left and decreased IC(50) at supra-therapeutic concentrations (10 and 2.5 microM, respectively) but not at clinical concentrations (2 and 0.5 microM, respectively), and the leftward shifts were inhibited by pre-treatment with DPCPX (0.2 microM).


CONCLUSIONS
The results indicate that adenosine potentiates the neuromuscular blocking action of rocuronium mediated by adenosine A(1) receptors and that supra-therapeutic concentrations of dipyridamole and midazolam also potentiate the action of rocuronium by increasing endogenous adenosine concentration.
Narimatsu
E
E
Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan. enarimat@sapmed.ac.jp
Niiya
T
T
Kawamata
M
M
Namiki
A
A
D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D058907:Adenosine A1 Receptor Agonists; D000732:Androstanols / Q000494:pharmacology*; D000818:Animals; D003964:Diaphragm / Q000187:drug effects*; D004176:Dipyridamole / Q000494:pharmacology; D004357:Drug Synergism; D004558:Electric Stimulation; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D023421:Models, Animal; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D000077123:Rocuronium; D014970:Xanthines / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D000732:Androstanols; D009466:Neuromuscular Blocking Agents; D010627:Phenethylamines; D043682:Receptor, Adenosine A1; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C058394:2-chloro-N(6)cyclopentyladenosine; D004176:Dipyridamole; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D008874:Midazolam; D000077123:Rocuronium