title: Mechanisms of reduced digitalis tolerance with advancing age in the guinea pig.
abstract: In the present study, arrhythmogenic toxicity of cardiac glycoside ouabain was investigated in guinea pigs after intravenous infusion (5 micrograms/kg/min). Guinea pigs of 18-24 months of age required significantly (P less than 0.05) lower doses of ouabain that 3-month-old animals (72 +/- 3 vs 100 +/- 3 micrograms/kg) for the initiation of cardiac arrhythmias. Investigation of Na(+)-Ca2+ exchange in the isolated sarcolemmal vesicles revealed a marked reduction in the Na(+)-dependent Ca2+ uptake. Kinetic analysis of these data has demonstrated a 70% reduction in Vmax and reduced affinity for Ca2+ in vesicles from 18-month-old as compared to 3-month-old guinea pigs. The rate of Na(+)-dependent Ca2+ efflux was also markedly lower in the vesicles of older animals, and the vesicles retained more Ca2+ after 3 min of Na(+)-dependent Ca2+ extrusion than did those from 3-month-old animals. The results suggest that the sensitivity to cardiac glycocide increases with age and may be associated with altered sarcolemmal Na(+)-Ca2+ exchange activity.
authors.affiliation: Department of Medicine, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: J C
authors.initials: JC
authors.lastname: Khatter
authors.forename: S
authors.initials: S
authors.lastname: Navaratnam
authors.forename: M
authors.initials: M
authors.lastname: Agbanyo
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004361:Drug Tolerance; D004562:Electrocardiography; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D007474:Ion Exchange; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010042:Ouabain / Q000633:toxicity*; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000139:chemically induced
chemical_list: D010042:Ouabain; D012964:Sodium; D002118:Calcium