Relationship between myocardial cation content and injury in reperfused rat hearts treated with cation channel blockers.
A role for K+ and Ca2+ channel blockers in cardiac contractile dysfunction and myocardial ionic imbalance was examined in isolated rat hearts with 35-min ischemia and 60-min reperfusion. The K+ channel blockers glibenclamide (1-30 microM) and sematilide (1-30 microM), Ca2+ channel blockers diltiazem (0.1-3 microM) and nicardipine (0.03-1 microM) and fast Na+ channel blocker tetrodotoxin (0.01-0.3 microM) were delivered for the last 3-min pre-ischemia. Ischemia-induced increase in Na+ content was attenuated by diltiazem and tetrodotoxin at all concentrations employed and by nicardipine at 0.3 microM, whereas the ischemia-induced loss of K+ was suppressed partially by glibenclamide and sematilide and almost completely by the two drugs in combination. Left ventricular developed pressure of untreated hearts did not recover upon reperfusion, which was associated with increases in myocardial Na+ and Ca2+ contents and decreases in K+ and Mg2+ contents. Glibenclamide and sematilide neither enhanced the post-ischemic recovery of left ventricular developed pressure nor affected cation changes during reperfusion. Diltiazem enhanced the recovery of left ventricular developed pressure and attenuated imbalance of the myocardial Na+ during ischemia and of all myocardial cations examined during reperfusion. The effects of nicardipine on these parameters were small. Tetrodotoxin enhanced the recovery of left ventricular developed pressure and reversed the imbalance of all myocardial cations examined during reperfusion in a concentration-dependent manner. The results suggest that blockade of transmembrane flux of K+ during ischemia plays a minor role in the improvement of post-ischemic contractile recovery, rather blockade of transmembrane flux of Na+ attenuates the ischemia and reperfusion injury.
Tanonaka
K
K
Department of Pharmacology, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
Kajiwara
H
H
Kameda
H
H
Takasaki
A
A
Takeo
S
S
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002412:Cations / Q000378:metabolism*; D003402:Creatine Kinase / Q000187:drug effects / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D009529:Nicardipine / Q000494:pharmacology; D011342:Procainamide / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D002412:Cations; D007004:Hypoglycemic Agents; C062818:sematilide; D013779:Tetrodotoxin; D009529:Nicardipine; D003402:Creatine Kinase; D004110:Diltiazem; D011342:Procainamide; D005905:Glyburide