Objective To investigate the effects of pre-treatment of α-ketoglutarate （α-KG） on cyanide-induced lethality and changes in various physiological parameters in rodents. Methods The LD50 of potassium cyanide （KCN...Objective To investigate the effects of pre-treatment of α-ketoglutarate （α-KG） on cyanide-induced lethality and changes in various physiological parameters in rodents. Methods The LD50 of potassium cyanide （KCN） given orally （po）, intraperitoneally （ip）, subcutaneously （sc） or intravenously （iv） was determined in male mice, in the presence or absence α-KG given po, ip or iv. α-KG was administered 10, 20 or 40 min prior to KCN at 0.50, 1.0 or 2.0 g/kg by po or ip route, and at 0.10, 0.20 or 0.40 g/kg by iv route. Protection index （PI） was calculated as the ratio of LD50 of KCN in the presence of α-KG （protected animals） and LD50 of KCN in the absence of α-KG （unprotected animals）. In a separate experiment, several physiological variables viz. mean arterial pressure （MAP）, heart rate （HR）, respiratory rate （RR）, neuromuscular transmission （NMT） and rectal temperature （RT） were measured in anesthetized female rats pre-treated （-10 rain） with po （2.0 g/kg） or iv （0.125 g/kg） α-KG and then administered sub-lethal （0.75 LD50） or lethal （2.0, 4.0 or 8.0 LD50） doses of KCN （po）. Results PI of 4.52, 6.40 and 7.60 at -10 min, 3.20, 5.40 and 6.40 at -20 min, and 1.40, 3.20 and 5.40 at -40 min of po administration with α-KG was observed for 0.50, 1.0 and 2.0 g/kg doses, respectively, against KCN given by po route. When KCN was given ip, a PI of 3.38, 4.79 and 5.70 was observed for 0.50, 1.0 and 2.0 g/kg α-KG given ip （-10 min）, respectively. A lower PI of 3.37, 2.83 and 2.38 was observed when KCN given sc was challenged by 2.0 g/kg α-KG given ip at -10, -20 or -40 min, respectively. Similarly, a PI of 3.37, 2.83 and 2.0 was noted when KCN given sc was antagonized by 2.0 g/kg α-KG given po at -10, -20 or -40 rain, respectively. No appreciable protection was observed when lower doses of α-KG （ip or po） challenged KCN given by sc route. Pre-treatment of iv or po administration of α-KG did not afford any protection against KCN given po or iv route. Oral treatment of 0.75 LD50 KCN caused significant decrease in MAP and HR after 15 min, RR after 30 min and NMT after 60 min. There was no effect on RT. No reduction in MAP, HR, RR and RT was observed when rats received 2.0 or 4.0 LD50 KCN after pre-treatment of α-KG （po; 2.0 g/kg）. However, no protection was observed on NMT. Protective efficacy of α-KG was not observed on MAP, HR, RR, and NMT decreased by 8.0 LD50 KCN. Decrease in MAP and NMT caused by 2.0 LD50 KCN （po） was resolved by iv administration of α-KG Conclusions Cyanide antagonism by α-KG is best exhibited when both α-KG and KCN are given by po route. The protective effect of α-KG on cyanide-induced changes in several physiological parameters also indicates a promising role of α-KG as an alternative cyanide antidote.展开更多
文摘Objective To investigate the effects of pre-treatment of α-ketoglutarate （α-KG） on cyanide-induced lethality and changes in various physiological parameters in rodents. Methods The LD50 of potassium cyanide （KCN） given orally （po）, intraperitoneally （ip）, subcutaneously （sc） or intravenously （iv） was determined in male mice, in the presence or absence α-KG given po, ip or iv. α-KG was administered 10, 20 or 40 min prior to KCN at 0.50, 1.0 or 2.0 g/kg by po or ip route, and at 0.10, 0.20 or 0.40 g/kg by iv route. Protection index （PI） was calculated as the ratio of LD50 of KCN in the presence of α-KG （protected animals） and LD50 of KCN in the absence of α-KG （unprotected animals）. In a separate experiment, several physiological variables viz. mean arterial pressure （MAP）, heart rate （HR）, respiratory rate （RR）, neuromuscular transmission （NMT） and rectal temperature （RT） were measured in anesthetized female rats pre-treated （-10 rain） with po （2.0 g/kg） or iv （0.125 g/kg） α-KG and then administered sub-lethal （0.75 LD50） or lethal （2.0, 4.0 or 8.0 LD50） doses of KCN （po）. Results PI of 4.52, 6.40 and 7.60 at -10 min, 3.20, 5.40 and 6.40 at -20 min, and 1.40, 3.20 and 5.40 at -40 min of po administration with α-KG was observed for 0.50, 1.0 and 2.0 g/kg doses, respectively, against KCN given by po route. When KCN was given ip, a PI of 3.38, 4.79 and 5.70 was observed for 0.50, 1.0 and 2.0 g/kg α-KG given ip （-10 min）, respectively. A lower PI of 3.37, 2.83 and 2.38 was observed when KCN given sc was challenged by 2.0 g/kg α-KG given ip at -10, -20 or -40 min, respectively. Similarly, a PI of 3.37, 2.83 and 2.0 was noted when KCN given sc was antagonized by 2.0 g/kg α-KG given po at -10, -20 or -40 rain, respectively. No appreciable protection was observed when lower doses of α-KG （ip or po） challenged KCN given by sc route. Pre-treatment of iv or po administration of α-KG did not afford any protection against KCN given po or iv route. Oral treatment of 0.75 LD50 KCN caused significant decrease in MAP and HR after 15 min, RR after 30 min and NMT after 60 min. There was no effect on RT. No reduction in MAP, HR, RR and RT was observed when rats received 2.0 or 4.0 LD50 KCN after pre-treatment of α-KG （po; 2.0 g/kg）. However, no protection was observed on NMT. Protective efficacy of α-KG was not observed on MAP, HR, RR, and NMT decreased by 8.0 LD50 KCN. Decrease in MAP and NMT caused by 2.0 LD50 KCN （po） was resolved by iv administration of α-KG Conclusions Cyanide antagonism by α-KG is best exhibited when both α-KG and KCN are given by po route. The protective effect of α-KG on cyanide-induced changes in several physiological parameters also indicates a promising role of α-KG as an alternative cyanide antidote.
