title: Inhibition of myocardial Na(+)-K(+)-ATPase activity by bretylium: role of potassium.
abstract: The effects of bretylium on the Mg(2+)-dependent ATP-hydrolytic action of myocardial Na(+)-K(+)-ATPase (EC 3.6.1.3) were studied in guinea-pig heart preparations in media containing various K+ concentrations. Under "standard" conditions (5 mM K+), bretylium inhibited the Na(+)-K(+)-ATPase activity in a concentration-dependent fashion in the range of 0.001-80 mM, with an IC20 value of 0.19 +/- 0.05 mM and an IC50 value of 1.38 +/- 0.11 mM. Reducing the K+ concentration from 5 to 2.5 mM enhanced the inhibitory action, shifting the effective (5-95% inhibition) concentration range to 0.0003-9.6 mM, with IC20 and IC50 values of 0.036 +/- 0.004 mM and 0.92 +/- 0.30 mM, respectively. On the other hand, increasing the K+ concentration to 10 mM shifted the range to 10-90 mM. The corresponding IC20 value was 0.48 +/- 0.02 mM and the IC50 was 2.24 +/- 0.36 mM. The results show that K+ plays an important role in the inhibition of myocardial Na(+)-K(+)-ATPase activity by bretylium. This is probably pertinent to the mode by which the drug may interfere with the electrogenic Na+/K+ pump activity of the enzyme, and, consequently, cause or aggravate cardiac arrhythmias.
authors.affiliation: Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: N
authors.initials: N
authors.lastname: Dzimiri
authors.forename: A A
authors.initials: AA
authors.lastname: Almotrefi
mesh_terms: D000818:Animals; D001949:Bretylium Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D011188:Potassium / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
chemical_list: D001949:Bretylium Compounds; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium