The interaction of sildenafil with the anticonvulsant effect of diazepam.
In order to assess the role of nitric oxide/cyclicGMP signaling pathway in the anticonvulsant effect of benzodiazepines, we studied the potential interaction of a phosphodiesterase type 5 inhibitor, sildenafil with the effect of diazepam on a mouse model of clonic seizures induced by intravenous infusion of GABA antagonist, pentylenetetrazole (PTZ). Administration of sildenafil (10 mg/kg; per se effective on seizure threshold) could abolish the anticonvulsive effect of diazepam, and a subeffective dose (5 mg/kg), when added to NO precursor L-arginine (50 mg/kg) could cause the same effect. Conversely, subeffective doses of diazepam (0.02 mg/kg) and NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 5 mg/kg), administered together, reversed the proconvulsive effect of sildenafil. Our findings indicate that the enhancement of NO/cGMP signaling pathway by sildenafil attenuates the anticonvulsant effect of the benzodiazepine prototype, diazepam. This suggests that the effects of facilitating GABA(A)-mediated inhibition and modulating NO pathways are additive and there might be a role for NO pathway in benzodiazepine effect against PTZ-induced seizures in mice.
Gholipour
Taha
T
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Rasouli
Aylar
A
Jabbarzadeh
Atieh
A
Nezami
Behtash Ghazi
BG
Riazi
Kiarash
K
Sharifzadeh
Mohammad
M
Dehpour
Ahmad Reza
AR
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006152:Cyclic GMP / Q000378:metabolism; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010433:Pentylenetetrazole; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013379:Substrate Specificity; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D006152:Cyclic GMP; D003975:Diazepam; D010433:Pentylenetetrazole