The effects of EDRF/NO releasers or calcium ionophore A23187 on cyanide toxicity in mice.
Cyanide (CN) is a well-recognized poison whose complete actions are unclear. It has been shown that a vasoactive role may be partially responsible for the toxic effects of CN. Sodium nitrite, a known methemoglobin former and vasodilator, has been used to treat CN toxicity. It is rapidly transformed to nitric oxide (NO) which is thought to be endothelium-derived relaxing factor (EDRF). Since the literature suggests that NO can influence the biological effects of CN, studies were undertaken to determine if compounds known to release EDRF/NO will modify CN toxicity. Mice were administered a series of compounds which act through EDRF/NO release. These substances included, platelet-activating factor (PAF), hydralazine, bradykinin, histamine, calcium ionophore A23187, carbachol, or substance P at 0.060, 98.7, 50.0, 125, 1.0, 2.26, and 1.0 mg/kg, respectively. As a control, NG-monomethyl-L-arginine (NMA) 70 mg/kg, which inhibits NO synthesis, was administered to mice iv (tail vein) in combination with each test compound. All test compounds and NMA were administered prior to NaCN: NMA, 5 min; carbachol, 0.5 min; hydralazine, 0.5 min; bradykinin, 1 min; histamine, 1 min; substance P, 4 min; PAF, 5 min; and A23187, 5 min. Dose-response relationships were analyzed by probit dose-response methods and protective ratios for each compound were computed. Results suggest (i) that a portion of the action of CN is affected by a particular EDRF/NO-releasing compound, suggesting that each drug specifically affects regional EDRF/NO receptor sites, and (ii) that NO can play a role as a component in CN intoxication. It is suggested that CN does not act uniformly on all EDRF/NO receptor sites to produce toxicity and site-specific EDRF/NO agents may be useful for treating CN.
Baskin
S I
SI
Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, Maryland 21010, USA.
Nealley
E W
EW
Lempka
J C
JC
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D003486:Cyanides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006830:Hydralazine / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000494:pharmacology* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010972:Platelet Activating Factor / Q000494:pharmacology; D012640:Seizures / Q000517:prevention & control; D013373:Substance P / Q000494:pharmacology; D015996:Survival Rate; D019323:omega-N-Methylarginine / Q000494:pharmacology
D003486:Cyanides; D007476:Ionophores; D010972:Platelet Activating Factor; D006830:Hydralazine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D013373:Substance P; D000001:Calcimycin; D002217:Carbachol; D019001:Nitric Oxide Synthase; D001920:Bradykinin