Cardiotoxicity of Ma Huang/caffeine or ephedrine/caffeine in a rodent model system

Abstract

Ma Huang (equivalent to 0, 12.5, 25, or 50 mg/kg ephedrine) or ephedrine (0, 6.25, 12.5, 25 mg/kg) were administered as one bolus oral dose to male F344 rats with and without caffeine. The herbal medicine Ma Huang (ephedra) in combination with caffeine caused rapid clinical signs of toxicity including salivation, hyperactivity, ataxia, and eventually lethargy, and failure to respond to stimuli. When this syndrome of clinical signs emerged, animals were moribund sacrificed, and a histological analysis for heart lesions performed. Cardiotoxicity included hemorrhage, necrosis, and degeneration in the ventricles or interventricular septum within 2-4 hours after treatment with Ma Huang (ephedra)/caffeine or ephedrine (the principal active component in Ma Huang)/caffeine. There was a steep dose response curve for cardiotoxicity with minimal toxicity seen at levels of Ma Huang (equivalent to 12.5 mg/kg ephedrine) with caffeine. However, cardiotoxic lesions occurred in 28% of animals with Ma Huang dosages equivalent to 25 mg/kg ephedrine with 15 or 30 mg/kg caffeine, and in 90% of animals at Ma Huang exposures equivalent to 50 mg/kg ephedrine with 15 or 30 mg/kg caffeine. Cardiotoxic lesions occurred in 47% of animals in the 25 mg/kg ephedrine groups with caffeine at 7.25, 15, or 30 mg/kg. There was no statistical difference in the occurrence of cardiotoxic lesions when 15 or 30 mg/kg caffeine was combined with Ma Huang equivalent to 25 or 50 mg/kg ephedrine; likewise there was no statistical difference in the occurrence of cardiotoxic lesions when 7.25, 15, or 30 mg/kg caffeine was combined with 25 mg/kg ephedrine. These results show that the cardiotoxic effects of the herbal medicine, Ma Huang, are similar to that of ephedrine, the principal active ingredient in the herbal medicine. The combination of Ma Huang or ephedrine with caffeine enhanced the cardiotoxicity over that with the herbal medicine or the active ingredient alone.

Figure 1

Chemical structure of ephedrine and caffeine.

Figure 2

Clinical signs of toxicity from ephedrine or Ma Huang administered alone and in combination with caffeine.

Figure 3

Treatment-related cardiotoxic lesions. (A) Cardiomyopathy, minimal (25 mg/kg ephedrine and 7.25 mg/kg caffeine). This change is considered to be an incidental background change. Note a single small focus of mononuclear cell (lymphocytes and histiocytes) infiltration, associated with variable myofiber degeneration, necrosis and loss. H&E, 20×. (B) Degeneration, minimal (12.5 mg/kg ephedrine and 15 mg/kg caffeine), 20×. Note a focus of myocardial fibers with clear, vacuolated cytoplasm. These vacuoles varied from large vacuoles, which distended the myofiber. H&E, 20×. (C) Hemorrhage, minimal (25 mg/kg). Note small foci in which free red blood cells filling the spaces between adjacent myocardial fibers. H&E, 20×. (D) Necrosis, minimal (25 mg/kg ephedrine and 30 mg/kg caffeine), 40×. Note the presence of numerous minute clusters of deeply basophilic fragments of nuclear debris, mixed with some macrophages. H&E, 40×.

Figure 4

Proposed mechanism of ephedrine cardiotoxicity (cardiotoxicity at 25 mg/kg ephedrine and 30 mg/kg caffeine is depicted in figure).