EFFECTS OF NOVEL ANTIARRHYTHMIC AGENTS, BRB-I-28 AND ITS DERIVATIVES,ON THE HEART MITOCHONDRIAL RESPIRATORY-CHAIN AND SARCOPLASMIC-RETICULUM CA2-ATPASE()

The effects of BRB-I-28 and its derivatives (GLG-V-13, SAZ-VII-22 and SAZ-VII-23), a novel group of antiarrhythmic agents, were investigated on the rat heart mitochondrial respiratory chain. The results indicat e that BRB-I-28 and its derivatives have concentration-dependent inhib itory effects on NADH oxidase and NADH-CoQ reductase (complex I), but they have no significant effects on succinate oxidase, succinate dehyd rogenase (complex II), CoQ-cytochrome c reductase (complex III), cytoc hrome c oxidase (complex IV), and NADH-K3Fe(CN)(6) reductase. The site of inhibition of BRB-I-28 and its derivatives on the respiratory chai n was localized between flavoprotein n (FPn) and CoQ, which is similar to the effect of rotenone and several other antiarrhythmic drugs such as amiodarone, propranolol, etc. BRB-I-28 and its derivatives also ha ve significant inhibitory effects on mitochondrial ATPase activity as reported from other antiarrhythmic drugs such as amiodarone, propranol ol, quinidine, and lidocaine. However, BRB-I-28 and its derivatives ha ve no direct effects on sarcoplasmic reticulum Ca2+-ATPase activity. T he inhibitory effects of BRB-I-28 and its derivatives on mitochondrial oxidative phosphorylation may result in the depletion of ATP. This ef fect, in combination with their effects on Na+,K+(-)ATPase, could poss ibly produce an increase in Ca2+ concentration in cytosol. This may be another mechanism by which these DHBCN derivatives produce an increas e in systemic arterial blood pressure and contractile force of isolate d cardiac muscle. On the other hand, inhibition on mitochondrial respi ration may account for some of the potential toxic effects of these di heterabicyclo[3.3.1]nonane derivatives.