Combined Effects of Ephedrine-Containing Dietary Supplements, Caffeine, and Nicotine on Morphology and Ultrastructure of Rat Hearts

Abstract

Cigarette smokers have an increased risk for coronary artery disease. Nicotine present in cigarettes can adversely affect the cardiovascular system via stimulation of both sympathetic and parasympathetic neurons. Caffeine, another cardiovascular and central nervous system (CNS) stimulant, is commonly found in Ephedra and Ephedra-free dietary supplements. These caffeine-containing supplements also have been linked to cardiovascular toxicities. Although no longer on the U.S market, Ephedra-containing supplements are another source of cardiovascular and CNS stimulants, namely the ephedrine alkaloids. Together caffeine, nicotine, and ephedrine can individually stress the cardiovascular system, and an overlap of these agents is predicted in smokers and dieters. To understand the collective effects of these stimulants on the heart morphology and ultrastructure, rats were exposed to synthetic combinations of nicotine (0.2 mg/kg/day), ephedrine (0-30 mg/kg/day), and/or caffeine (0-24 mg/kg/day) as well as an extract from a caffeine-containing Ephedra supplement (Metabolife 356). After exposure for 3 days, the hearts were removed and examined for hypersensitivity myocarditis and myocardial necrosis. None of the drugs tested alone affected heart tissue morphology, nor were atypical cardiac cells observed. However, in combination, significant interactions were found between caffeine and ephedrine; the interventricular septum was most susceptible, with a significant increase in atypical cardiac cells observed. Nicotine pretreatment caused greater susceptibility to cardiotoxicity associated with combinations of caffeine + ephedrine or Metabolife, particularly in the left ventricle wall. These results indicate that sympathomimetic combinations present in Ephedra supplements may have produced cardiotoxicity reported in consumers of these products. Moreover, the presence of nicotine exacerbates these toxic effects.

Effect of nicotine-caffeine interaction on rat’s coronaries and cardiac muscle

“…Our findings suggest that nicotine leads to marked vascular congestion nearby muscles looked darker and degenerated while caffeine showed no apparent changes in cardiac fibers and sudden deaths were not recorded [13] while Nyska et al [15] demonstrated acute hemorrhagic myocardial necrosis and sudden death of rats exposed to a combination of ephedrine and caffeine.…”

“…or did not alter its structure, but it resulted in dilation of cardiac interfibrillar capillaries with no apparent histopathological changes [15,16]. Caffeine consumption when combined with nicotine is considered stimulants.…”

Safety assessment of the dietary supplement OxyELITE™ Pro (New Formula) in inbred and outbred mouse strains

“…For example, caffeine, a major constituent of OEP-NF, is recognized for its ability to augment the toxicity of other stimulants and sympathomimetics (Brown et al, 1991; Derlet et al, 1992; Haller et al, 2004; McNamara et al, 2006). Combinations of caffeine and ephedrine alkaloids can produce a host of cardiovascular and central nervous system pathologies that are more remarkable than those observed after administration of each individual component (Brown et al, 2012; Dunnick et al, 2007). Such findings reinforced the FDA’s decision to remove of Ephedra -containing dietary supplements from the U.S. market in 2004 (Anonymous, 2004).…”

Impact of obesity on the toxicity of a multi-ingredient dietary supplement, OxyELITE Pro™ (New Formula), using the novel NZO/HILtJ obese mouse model: Physiological and mechanistic assessments

“…Moreover, when combined, these alkaloids may exacerbate each other’s pharmacodynamic effects (Calvert et al, 2015; Kimura et al, 1989). Such additive or synergistic effects may produce unexpected cardiovascular toxicities, as was demonstrated for caffeine and ephedrine (Brown et al, 2012; Dunnick et al, 2007), and caffeine and 1,3-dimethylamylamine (DMAA) (Farney et al, 2012). Studies in small cohorts of human subjects have shown that short-term administration of caffeine, higenamine and yohimbine to healthy subjects elevate heart rate and systolic blood pressure (Bloomer et al, 2015; Lee et al, 2013).…”