TOXIC DOSES OF RAC-PROPRANOLOL, (-)-(S)-PROPRANOLOL AND (-(R)-PROPRANOLOL IN RATS AND RABBITS())

The contribution of the individual enantiomers ([+]-[R]- and [-]-[S]-p ropranolol) to rac-propranolol intoxication was studied in anaesthetiz ed, spontaneously breathing (SE) rats and artificially ventilated (AV) rats and rabbits. In the SE rat, propranolol (30 mg.kg(-1).h(-1) i.v. ) decreased heart rate and mean arterial blood pressure and caused hyp oventilation, serious hypoxaemia, respiratory acidosis, and death by r espiratory arrest. Survival time (ST) in the (+)-(R)-propranolol group (ST 91 +/- 5 min) was significantly longer than in the rac-propranolo l group (ST 68 +/- 6 min). In AV rats and rabbits toxic doses of rac-, (-)-(S)- and (+)-(R)-propranolol, 30 mg.kg(-1).h(-1) and 15 mg.kg(-1) .h(-1) i.v., respectively, induced comparable effects on haemodynamic variables as in the SE rat. Artificial ventilation lengthened ST by a factor of three to four in rats. In the AV rat, ST's were not signific antly different between the rac-, (-)-(S)- and (+)-(R)-propranolol gro ups. In the rabbit, as in the SE rat, ST in the (+)-(R)-propranolol gr oup was significantly longer than ST's in the rac- and (-)-(S)-propran olol groups. The acute respiratory acidosis in SE rats and the prolong ed ST in AV rats suggest that respiratory failure is the primary and c ardiovascular failure the secondary cause of death in propranolol into xication. The potentiation of the toxic effect of the enantiomers obse rved after dosing the racemate instead of the pure enantiomers could n ot be explained by a stereoselective difference in plasma propanolol c oncentration. (C) 1996 Wiley-Liss, Inc.