A protein kinase C inhibitor attenuates cyanide toxicity in vivo.
We have examined the effect of pretreatment with a potent protein kinase C (PKC) inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine (H-7), against metabolic alterations induced by sodium cyanide (NaCN), 4.2 mg/kg, in brain of anesthetized male micropigs (6-10 kg). Brain high energy phosphates were analyzed using a 31P nuclear magnetic resonance (NMR) spectroscopic surface coil in a 4.7 Telsa horizontal bore magnet. H-7, 1 mg/kg, was given intravenously (i.v.) 30 min before NaCN challenge (H-7 + CN-). Prior to NaCN, H-7, or H-7 + CN- administration, baseline 31P resonance spectra of 1-min duration were acquired for 5-10 min, and continued for an additional 60 min following i.v. NaCN injection, each animal serving as its own control. Peaks were identified as phosphomonoester (PME), inorganic phosphate (Pi), phosphodiester (PDE), phosphocreatine (PCr) and adenosine triphosphate (ATP), based on their respective chemical shifts. Without H-7 pretreatment, NaCN effects were marked by a rising Pi and a declining PCr peak 2 min after injection, with only 2/5 of the animals surviving the 60 min experiment. Through a pretreatment period of 30 min, H-7 did not affect baseline cell energy profile as reflected by the 31P-NMR spectra, but in its presence, those changes (i.e. diminishing PCr and rising Pi peaks) elicited by NaCN were markedly blunted; 4/5 of the animals in this group survived the NaCN challenge. It is proposed that H-7, a pharmacologic inhibitor of PKC, may be useful in CN- antagonism, underscoring the role of PKC in cyanide intoxication.
Maduh
E U
EU
Pharmacology Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA.
Nealley
E W
EW
Song
H
H
Wang
P C
PC
Baskin
S I
SI
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000139:chemically induced / Q000188:drug therapy; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010710:Phosphates / Q000008:administration & dosage / Q000378:metabolism; D010759:Phosphorus Isotopes; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D012966:Sodium Cyanide / Q000008:administration & dosage / Q000633:toxicity*; D013552:Swine; D013556:Swine, Miniature
D007546:Isoquinolines; D010710:Phosphates; D010759:Phosphorus Isotopes; D010879:Piperazines; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D012966:Sodium Cyanide