Biochemical mechanisms of quinidine cardiotoxicity

"Quinidine-like action" and the synonym "membrane-stabilizing activity" are often encountered descriptions for adverse cardiac effects of drugs. Quinidine, 50 mg/kg/day, 5 days/week for 4 weeks, was found to cause disturbance of intracardiac conduction in rats. It was the purpose of this study to investigate the effect of the same dose of quinidine on biochemical activities involved in the energy metabolism of the heart. Electron transfer activities in heart mitochondria were progressively slowed down. At the same time, uncoupling of oxidative phosphorylation was observed and mitochondrial creatinephosphate kinase activity decreased. Concomitantly, mitochondria showed a progressive loss in semipermeability, manifested by an increasing creatine content. Total adenine nucleotides (especially ATP) content declined to 65% of control values to return to normal levels at the end of the 4 week treatment period. Calcium-binding activity and various ATPases (Na/K, Mg, Ca) of myocyte membranes (sarcolemma + sarcoplasmatic reticulum fraction) were also impaired by quinidine. Protein synthesis in total heart tissue and heart mitochondria, an energy-requiring process, was also moderately inhibited by quinidine. Maximal quinidine concentration in heart tissue was 0.123 microgram/g fresh weight 24 h after the last of 19 medications.