Protective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation.
BACKGROUND
JTV519 is know to protect cardiomyocytes from calcium overloading-induced damage. The aim of this study was to investigate the potential protective effect of JTV519 on myocardium subjected to prolonged ischemia and the underlying mechanism of such protection. The effect of JTV519 was also compared with that of diltiazem, a 1,5-benzothiazepine derivative.


METHODS
Isolated rat hearts were randomly divided into three groups. Control hearts were arrested with histidine-tryptophan-ketoglutarat (HTK) cardioplegic solution alone. In the JTV519 group of hearts, cardiac arrest was achieved with JTV519 (10(-3) mmol/L) in the HTK solution. Hearts in the diltiazem group were arrested with diltiazem (0.5 mmol/L) in the HTK solution. All the hearts were then subjected to 6-hour storage in HTK solution at 4 degrees C.


RESULTS
After a 30-minute reperfusion, the left ventricular developed pressure in the JTV519 and diltiazem groups were improved significantly compared with the control group. There was a significantly lower left ventricular end-diastolic pressure level and higher recovery of coronary flow in the JTV519 group than in the control group. The postischemic intracellular calcium concentration was attenuated by adding JTV519 or diltiazem to HTK cardioplegia.


CONCLUSIONS
As an adjunct to cardioplegia, JTV519 showed a significant protective effect on myocardium undergoing 6 hours of ischemia. The beneficial protective effects of JTV519 are correlated with its ability to inhibit the postischemic rise in intracellular calcium.
Hachida
M
M
Department of Cardiovascular Surgery, The Heart Institute of Japan, Tokyo Women's Medical College, Shinjuku. shachida@hij.twmc.ac.jp
Kihara
S
S
Nonoyama
M
M
Koyanagi
H
H
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D002314:Cardioplegic Solutions; D004110:Diltiazem / Q000494:pharmacology; D005069:Evaluation Studies as Topic; D005947:Glucose; D066298:In Vitro Techniques; D008353:Mannitol; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D019188:Organ Preservation Solutions / Q000494:pharmacology; D011189:Potassium Chloride; D011343:Procaine; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013841:Thiazepines / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
C039984:Bretschneider cardioplegic solution; D002121:Calcium Channel Blockers; D002314:Cardioplegic Solutions; D019188:Organ Preservation Solutions; D013841:Thiazepines; C109183:K201 compound; D008353:Mannitol; D011343:Procaine; D011189:Potassium Chloride; D004110:Diltiazem; D005947:Glucose