Effects of novel antiarrhythmic agents, BRB-I-28 and its derivatives, on the heart mitochondrial respiratory chain and sarcoplasmic reticulum Ca(2+)-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 indicate that BRB-I-28 and its derivatives have concentration-dependent inhibitory effects on NADH oxidase and NADH-CoQ reductase (complex I), but they have no significant effects on succinate oxidase, succinate dehydrogenase (complex II), CoQ-cytochrome c reductase (complex III), cytochrome c oxidase (complex IV), and NADH-K3Fe(CN)6 reductase. The site of inhibition of BRB-I-28 and its derivatives on the respiratory chain 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 have significant inhibitory effects on mitochondrial ATPase activity as reported for other antiarrhythmic drugs such as amiodarone, propranolol, quinidine, and lidocaine. However, BRB-I-28 and its derivatives have no direct effects on sarcoplasmic reticulum Ca(2+)-ATPase activity. The inhibitory effects of BRB-I-28 and its derivatives on mitochondrial oxidative phosphorylation may result in the depletion of ATP. This effect, in combination with their effects on Na+,K(+)-ATPase, could possibly produce an increase in Ca2+ concentration in cytosol. This may be another mechanism by which these DHBCN derivatives produce an increase in systemic arterial blood pressure and contractile force of isolated cardiac muscle. On the other hand, inhibition on mitochondrial respiration may account for some of the potential toxic effects of these diheterabicyclo[3.3.1]nonane derivatives.
Chen
C L
CL
Department of Physiological Sciences, Oklahoma State University, Stillwater 74078.
Sangiah
S
S
Yu
C A
CA
Chen
H
H
Berlin
K D
KD
Garrison
G L
GL
Scherlag
B J
BJ
Lazzara
R
R
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D002352:Carrier Proteins; D004579:Electron Transport / Q000187:drug effects*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D013367:Submitochondrial Particles / Q000201:enzymology
D000889:Anti-Arrhythmia Agents; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002352:Carrier Proteins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; C041492:7-benzyl 3-thia-7-azabicyclo(3.3.1)nonane; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D016660:NAD(P)H Dehydrogenase (Quinone); D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; C020439:oligomycin sensitivity-conferring protein; D000252:Calcium-Transporting ATPases