Adenosine receptor antagonism accounts for the seizure-prolonging effects of aminophylline.
The mechanism of action of aminophylline in prolonging seizures was tested in amygdala-kindled rats. Aminophylline prolonged the afterdischarge duration of kindled seizures. This seizure-prolonging action of aminophylline was strongly antagonized by the adenosine A1 agonist cyclohexyladenosine and partially antagonized by the benzodiazepine partial agonist RO 15-1788. However, the specific benzodiazepine antagonist CGS 8216 did not affect the seizure-prolonging action of aminophylline. Also, the potent anticonvulsant effect of diazepam on kindled seizures, which was completely antagonized by CGS 8216, was unaffected by aminophylline. Furthermore, a range of benzodiazepine inverse agonists, GABA antagonists, phosphodiesterase inhibitors and xanthines did not prolong afterdischarge durations. These results demonstrate that the seizure-prolonging action of aminophylline is due to block of A1 adenosine receptors since it is prevented by adenosine A1 agonists.
Dragunow
M
M
Department of Pharmacology, School of Medicine, University of Auckland, New Zealand.
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000628:Aminophylline / Q000633:toxicity*; D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001921:Brain / Q000033:anatomy & histology; D002243:Carbolines / Q000494:pharmacology; D003975:Diazepam / Q000037:antagonists & inhibitors; D005442:Flumazenil / Q000494:pharmacology; D007696:Kindling, Neurologic; D008297:Male; D010852:Picrotoxin / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000187:drug effects*; D020889:Rolipram; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D000241:Adenosine; D000628:Aminophylline; D002243:Carbolines; D003975:Diazepam; D005442:Flumazenil; D010852:Picrotoxin; D011720:Pyrazoles; D011760:Pyrrolidinones; D011983:Receptors, Purinergic; D020889:Rolipram; D013806:Theophylline; D014970:Xanthines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; C027513:N(6)-cyclohexyladenosine; C035874:FG 7142; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one; C034347:enprofylline; C028322:8-phenyltheophylline