title: The influence of age on bupivacaine cardiotoxicity.
abstract: BACKGROUND
  The susceptibility of children and newborns to cardiotoxicity from racemic bupivacaine, RS(±)-bupivacaine, is controversial. Some studies indicate that newborns can sustain higher bupivacaine plasma levels than adults, without severe toxicity. In this study, we compared the influence of age on cardiotoxicity from RS(±)-bupivacaine and S(-)-bupivacaine in rats. The effects of these local anesthetics (LAs) on the regulation of intracellular Ca(2+) concentrations in cardiac fibers were also investigated.
  
  
  METHODS
  The lethal dose was determined in ventilated male Wistar rats at 2, 4, 8, and 16 weeks of age by monitoring when cardiac electrical activity stopped after infusion of RS(±)-bupivacaine and S(-)-bupivacaine (4 mg · kg(-1) · min(-1)). The effects on cardiac muscle contraction were investigated by in vitro measurement of papillary muscle twitches in the presence and absence of RS(±)-bupivacaine or S(-)-bupivacaine. Skinned ventricular fibers were used to investigate the intracellular effects on Ca(2+) regulation induced by both LAs.
  
  
  RESULTS
  The lethal dose for RS(±)-bupivacaine and S(-)-bupivacaine in 2-week-old animals (46.0 ± 5.2 and 91.3 ± 4.9 mg · kg(-1), respectively) was higher than in 16-week-old animals (22.7 ± 1.3 and 22.0 ± 2.7 mg · kg(-1), respectively). Papillary muscle twitches were reduced in a dose-dependent manner, with significant difference between young and adult hearts. In adults, the muscle twitches were reduced to 8.6% ± 0.8% of control by RS(±)-bupivacaine, and to 18.1% ± 2.7% of control by S(-)-bupivacaine (100 μM). S(-)-bupivacaine had a positive inotropic effect at <10 μM, but only in 2-week-old animals. In chemically skinned ventricular fibers, RS(±)-bupivacaine and S(-)-bupivacaine induced similar increases in Ca(2+) release from the sarcoplasmic reticulum (SR) preactivated with caffeine (1 mM), and this effect was greater in younger rats than adults. In 16-week-old rats, caffeine-induced tension was 53.9% ± 1.7% of the maximal fiber response with RS(±)-bupivacaine, and 54.1% ± 3.2% with S(-)-bupivacaine. The caffeine response in 2-week-old rats was 81.1% ± 3.7% of the maximal response with RS(±)-bupivacaine, and 78.1% ± 4.5% with S(-)-bupivacaine. The Ca(2+) sensitivity of contractile proteins was equally increased at both ages tested, with RS(±)-bupivacaine or S(-)-bupivacaine. Ca(2+) uptake from the SR was not altered by the LA or by age.
  
  
  CONCLUSIONS
  Differences in the mechanisms for regulating intracellular SR Ca(2+) may contribute to the decreased susceptibility of young animals to cardiodepression induced by RS(±)-bupivacaine and S(-)-bupivacaine.
authors.affiliation: Programa de Desenvolvimento de Farmacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rua Republica do Peru 114/802 Rio de Janeiro, Brazil 22021-040.
authors.forename: Marcio G
authors.initials: MG
authors.lastname: Kiuchi
authors.forename: Gisele
authors.initials: G
authors.lastname: Zapata-Sudo
authors.forename: Margarete M
authors.initials: MM
authors.lastname: Trachez
authors.forename: Douglas
authors.initials: D
authors.lastname: Ririe
authors.forename: Roberto T
authors.initials: RT
authors.lastname: Sudo
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002045:Bupivacaine / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D054715:Cardiotoxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D054715:Cardiotoxins; D002118:Calcium; D002045:Bupivacaine