Alterations of phosphatidylethanolamine N-methylation in rat heart by quinidine.
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.
Panagia
V
V
Division of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Canada.
Ganguly
P K
PK
Gupta
M P
MP
Taira
Y
Y
Dhalla
N S
NS
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
D010743:Phospholipids; D012436:S-Adenosylmethionine; D010625:Phenylethanolamine N-Methyltransferase; D011802:Quinidine; D011342:Procainamide