Effect of diazepam and clonazepam on the function of isolated rat platelet and neutrophil.
BACKGROUND
Benzodiazepine binding sites distinct from the GABA-receptor-chloride-complex in the central nervous system have been recognized in many peripheral tissues, but their physiological role remains unexplained. Our study was undertaken to examine the effects of diazepam, clonazepam, and PK 11195, a peripheral benzodiazepine receptor antagonist, on the functional and biochemical responses of platelets and neutrophils stimulated by different physiological agonists.


METHODS
The experiments were conducted on isolated washed rat platelets activated by arachidonic acid (AA), adenosine 5'-diphosphate (ADP), or thrombin and on isolated rat neutrophils activated by a chemotactic peptide, formyl methionyl leucyl phenylalanine (fMLP).


RESULTS
The results showed that neither diazepam nor clonazepam nor PK 11195 alone augmented the response of resting platelets or modified neutrophil response, but diazepam and clonazepam in a concentration-dependent manner inhibited thrombin, ADP or AA-stimulated platelet aggregation and the thrombin-induced increase in free intracellular Ca2+. Both drugs also exerted an inhibitory effect on reactive oxygen species (ROS) produced by fMLP-stimulated neutrophils. However, diazepam was about 10 times more effective than clonazepam. PK11195 did not influence platelet and neutrophil function stimulated by agonists, but reversed the inhibitory action of both benzodiazepines on platelet activation and ROS production.


CONCLUSIONS
The results indicated that in vitro diazepam, and in a much smaller degree clonazepam, may down-regulate platelet activation and release of some proinflammatory mediators by stimulated neutrophils. These effects are probably exerted by a specific benzodiazepine binding sites.
Rajtar
Grazyna
G
Department of Pharmacology and Toxicology, Lublin Medical University, Lublin, Poland.
Zółkowska
Dorota
D
Kleinrok
Zdzisław
Z
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects; D002998:Clonazepam / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004347:Drug Interactions; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000097:blood; D011963:Receptors, GABA-A / Q000187:drug effects*; D016897:Respiratory Burst / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology
D007546:Isoquinolines; D010975:Platelet Aggregation Inhibitors; D017382:Reactive Oxygen Species; D011963:Receptors, GABA-A; D016718:Arachidonic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002998:Clonazepam; D000244:Adenosine Diphosphate; D013917:Thrombin; D000527:Alprostadil; D003975:Diazepam; C037850:PK 11195