Peripheral type benzodiazepine receptors and response to adenosine on the guinea-pig isolated trachea.
It has been reported that dipyridamole, an adenosine uptake inhibitor, and some benzodiazepines potentiate the responses to adenosine in peripheral organs and in particular, on guinea-pig isolated atria. In this paper, we have examined the potentiation of responses to adenosine produced by dipyridamole, diazepam and four compounds with selective agonistic activity towards the central (clonazepam) or peripheral (Ro5-4864) type benzodiazepine receptors or antagonistic activity towards the central (flumazenil) or peripheral (PK 11195) benzodiazepine receptors in guinea-pig trachea in vitro. In preparations under basal tone and in the absence of adenosine, dipyridamole (10(-5) M) and benzodiazepines (10(-4) M) with the exception of flumazenil induced a relaxation of the airway smooth muscle. In addition, diazepam (10(-4) M) attenuated the phasic response to histamine (10(-5) M). Dipyridamole, and the benzodiazepine agonists diazepam, Ro5-4864 and clonazepam (10(-5) to 10(-4) M) produced potentiation of the tracheal response to adenosine, the rank order of potency being dipyridamole (pKi = 7.77 +/- 0.12, n = 8) greater than Ro5-4864 (pKi = 5.43 +/- 0.18, n = 6) greater than or equal to diazepam greater than clonazepam (pKi = 4.84 +/- 0.11, n = 6). The two benzodiazepine receptor antagonists, flumazenil and PK 11195, gave a significant but small potentiation to adenosine only at 10(-4) M. In the presence of dipyridamole (10(-5) M), diazepam (10(-4) M) did not cause any further potentiation to adenosine. Additionally, the potentiation produced by diazepam was not antagonised by flumazenil, whereas it was potently antagonised by PK 11195. Similarly, PK 11195 potently inhibited the adenosine potentiation produced by Ro5-4864.(ABSTRACT TRUNCATED AT 250 WORDS)
Advenier
C
C
Department of Pharmacology, Faculty of Medicine, Paris, France.
Devillier
P
P
Blanc
M
M
Gnassounou
J P
JP
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D002998:Clonazepam / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology*; D004176:Dipyridamole / Q000494:pharmacology; D004357:Drug Synergism; D058787:GABA-A Receptor Antagonists; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000187:drug effects*; D013806:Theophylline / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D002998:Clonazepam; D004176:Dipyridamole; D006632:Histamine; D013806:Theophylline; D000241:Adenosine; D003975:Diazepam