The relaxant effect of diazepam on rat tracheal strips

The effect of diazepam was studied on the rat isolated trachea precontracted with acetylcholine 10-3M. Diazepam induced a dose dependent relaxant effect EC50 values 2.02 +/- 0.28.10(-4)M in controls (n = 38). The effect of diazepam was not modified by flumazenil (10-(6) to 10-(4) M) or RP 52028 (10-(6) to 10-(4)M) which are antagonists of central and peripheral benzodiazepines receptors respectively. No antagonism was observed between diazepam and nucleotides or endogenous ligands (adenosine 10(-6) to 10(-4)M, UTP 10(-6) to 10(-4)M, hématoporphyrin 10(-5) and 10(-4)M or nicotinamide 10(-5) and 10(-4)M). These results excluded an endogenous ligand-mediated interaction between nucleotides and diazepam. Propranolol (10(-7)M) did not modify the diazepam-induced relaxation, which excluded an involvement of beta receptors in diazepam relaxation. Theophylline (10(-7) and 10(-6)M), IBMX (10(-5) and 10(-4)M) rolipram (10(-5) and 10(-4)M) and siguazodan (10(-6) to 10(-4)M) displayed to the left the concentration-response curves to diazepam. The adenylcyclase activator forskolin (10(-7) to 10(-5)M, the beta adrenor stimulant isoprenaline (3.10(-5)M) and the direct acting G stimulant NaF (10(-3)M) also produced a leftward shift in the diazepam concentration-response curve. The relaxant concentration-effect curves to isoprenaline and to sodium nitroprusside were shifted to the left in a concentration-related manner by diazepam. Diazepam was more potent on the isoprenaline than on nitroprusside-induced relaxation. These results suggest that the diazepam-induced relaxation in the rat isolated trachea is mediated by an inhibition of cyclic nucleotide phosphodiesterases.