Antiarrhythmic properties of specific inhibitors of sarcoplasmic reticulum calcium ATPase in the isolated perfused rat heart after coronary artery ligation.
OBJECTIVE
The hypothesis tested was that sequestration of calcium by the sarcoplasmic reticulum and internal calcium oscillations may play a role in the genesis of ischemic and reperfusion ventricular arrhythmias.


BACKGROUND
Previous data suggest that inhibition of the release of intracellular calcium from the sarcoplasmic reticulum by ryanodine may prevent ventricular fibrillation.


METHODS
The isolated Langendorff perfused rat heart was treated with two specific inhibitors of the calcium ATPase pump of the sarcoplasmic reticulum (thapsigargin [10(-6) mol/liter] or cyclopiazonic acid [10(-7) mol/liter]) for 5 min before left anterior descending coronary artery ligation was performed. One group of hearts was subject to 30 min of coronary artery ligation, and ischemic arrhythmias were monitored. In a second group, the incidence of reperfusion arrhythmias was measured after 10, 15, 20, 25 and 30 min of coronary artery ligation.


RESULTS
Thapsigargin treatment during ischemia and reperfusion decreased the incidence of reperfusion ventricular fibrillation after 10 min of coronary artery ligation from 67% (n = 6) to 0% (n = 6) (p < 0.05), after 15 min from 81% (n = 16) to 25% (n = 20) (p < 0.002) and after 20 min of ischemia from 90% (n = 10) to 46% (n = 13) (p < 0.05). Thapsigargin treatment also decreased the incidence of ischemic ventricular fibrillation from 83% (n = 12) to 0% (n = 12) (p < 0.002). Cyclopiazonic acid treatment during ischemia and reperfusion likewise decreased the incidence of ischemic and reperfusion arrhythmias.


CONCLUSIONS
The highly specific inhibitors of the calcium uptake pump of the sarcoplasmic reticulum--thapsigargin and cyclopiazonic acid--have antifibrillatory properties in the isolated perfused rat heart. They appear to act by restriction of calcium oscillations between the sarcoplasmic reticulum and the cytosol.
du Toit
E F
EF
Ischaemic Heart Disease Research Unit, University of Cape Town, South Africa.
Opie
L H
LH
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000209:etiology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D003331:Coronary Vessels / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007211:Indoles / Q000627:therapeutic use*; D008026:Ligation; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000209:etiology; D009206:Myocardium / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D013729:Terpenes / Q000627:therapeutic use*; D019284:Thapsigargin; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D007211:Indoles; D013729:Terpenes; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; C000543:cyclopiazonic acid