title: Cardiac sarcolemma as a possible site of action of caffeine in rat heart.
abstract: Caffeine (0.1-10 mM) produced a biphasic effect on Na(+)-K+ ATPase activity in the rat heart sarcolemmal preparations. The Na(+)-K+ ATPase activity was stimulated by about 25% at low concentrations (0.1-1 mM), whereas the enzyme was inhibited by about 25% at higher concentrations (10 mM) of caffeine. The stimulatory effect of 1 mM caffeine was associated with about 30% increase in the Vmax value for Na(+)-K+ ATPase, whereas the depressant action of 10 mM caffeine was associated with an increase of the Km value from 1.4 to 2.1 mM ATP. The Na(+)-induced Ca++ release from the sarcolemmal vesicles was stimulated with caffeine in a concentration-dependent manner; about 80% increase in the activity was observed at 0.1 mM caffeine. The apparent Ka (millimolar Na+) values for the Na(+)-induced Ca++ release were about 17 and 6 in the absence and presence of 1 mM caffeine, respectively. However, the sarcolemmal Na(+)-dependent Ca++ uptake and ATP-independent Ca++ binding were not affected, whereas the ATP-dependent Ca++ accumulation and Ca+(+)-stimulated ATPase activities were depressed by 1 to 10 mM caffeine. This agent at concentrations of 0.1 to 10 mM produced a biphasic effect on the contractile activity of the isolated perfused rat heart. The initial transient positive inotropic (30-60%) effect was followed by a sustained negative inotropic (50-80%) response of the drug; the delayed decrease in contractile force was associated with a significant increase (35-50%) in the resting tension. The initial positive inotropic effect of caffeine was dependent on the concentration of Ca++ (0.2-3 mM) in the perfusion medium; however, this response was attenuated either by lowering the concentration of Na+ from 140 to 35 mM or by different concentrations (0.5-1 mM) of amiloride in the medium.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Division of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Manitoba, Canada.
authors.forename: M P
authors.initials: MP
authors.lastname: Gupta
authors.forename: N
authors.initials: N
authors.lastname: Makino
authors.forename: S
authors.initials: S
authors.lastname: Takeo
authors.forename: M
authors.initials: M
authors.lastname: Kaneko
authors.forename: N S
authors.initials: NS
authors.lastname: Dhalla
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012508:Sarcolemma / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D002110:Caffeine; D000255:Adenosine Triphosphate; D012964:Sodium; D014700:Verapamil; D000251:Adenosine Triphosphatases; D017301:Ca(2+) Mg(2+)-ATPase; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium