title: Alterations of phosphatidylethanolamine N-methylation in rat heart by quinidine.
abstract: To elucidate the molecular mechanism underlying the adverse depression of myocardial contractility observed during antiarrhythmic therapy of quinidine, we investigated its action on the phosphatidylethanolamine N-methyltransferase (EC 2.1.1.17) activities of cardiac subcellular membranes. Rat heart sarcolemma, mitochondria, and microsomes (sarcoplasmic reticular fragments) were isolated, and the three catalytic sites for N-methylation activities were examined with 0.055 (site I), 10 (site II), and 150 (site III) microM concentrations of S-adenosyl-L-[methyl-3H]methionine as a methyl donor. Total methyl group incorporation into sarcolemmal phosphatidylethanolamine was depressed by 10(-6)-10(-3) M quinidine at sites II and III. The activity of site I was stimulated at low (10(-9) M) concentrations and inhibited at high concentrations of the drug. A similar behaviour was observed with procainamide, although the inhibitory effect was less pronounced and was not additive with quinidine. Quinidine-induced inhibition was associated with a depression of Vmax, while the apparent affinity for S-adenosyl-L-methionine was unaltered. Analysis of individual methylated phospholipids confirmed inhibition by quinidine at sites II and III in sarcolemma. Microsomal phosphatidylethanolamine N-methylation was affected by 10(-6) M quinidine only at site II, whereas no changes were noted in mitochondria. Quinidine also inhibited both the positive inotropic response and concomitant increase in tissue N-methylated phospholipids observed upon L-methionine perfusion of rat heart. These results suggest that quinidine alters the intramembranal level of N-methylated phospholipids, and this may serve as a biochemical mechanism contributing to its negative inotropic effect.
authors: Division of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Canada.
authors: V
authors: V
authors: Panagia
authors: P K
authors: PK
authors: Ganguly
authors: M P
authors: MP
authors: Gupta
authors: Y
authors: Y
authors: Taira
authors: N S
authors: NS
authors: Dhalla
mesh_terms: D000818:Animals; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D010625:Phenylethanolamine N-Methyltransferase / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D011342:Procainamide / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012436:S-Adenosylmethionine / Q000378:metabolism; D012508:Sarcolemma / Q000201:enzymology; D013347:Subcellular Fractions / Q000201:enzymology
chemical_list: D010743:Phospholipids; D012436:S-Adenosylmethionine; D010625:Phenylethanolamine N-Methyltransferase; D011802:Quinidine; D011342:Procainamide