Modulation of calcium transport improves myocardial contractility and enzyme profiles after prolonged ischemia-reperfusion.
BACKGROUND
Ischemia-reperfusion (IR) injury causes myocardial dysfunction in part through intracellular calcium overload. A recently described pharmacologic compound, MCC-135 (5-methyl-2-[1-piperazinyl] benzenesulfonic acid monohydrate, Mitsubishi Pharma Corporation), alters intracellular calcium levels. This project tested the hypothesis that MCC-135 would influence regional myocardial contractility when administered at reperfusion and after a prolonged period of ischemia.


METHODS
A circumflex snare and sonomicrometry crystals within remote and area-at-risk regions were placed in pigs (n = 18, 32 kg). Coronary occlusion was instituted for 120 minutes followed by 180 minutes of reperfusion. At 105 minutes of ischemia pigs were randomly assigned to IR only (n = 11) or MCC-135 (IR-MCC [300 microg. kg(-1). h(-1), n = 7]) administered intravenously. Regional myocardial contractility was determined by calculation of the regional end-systolic pressure-dimension relation (RESPDR [mm Hg/cm]). Myocardial injury was determined by measurement of plasma levels of myocyte-specific enzymes.


RESULTS
At 90 minutes ischemia, mean troponin-I was 35 +/- 8 ng/mL with no significant difference between groups. At 180 minutes reperfusion, heart rate was increased by 18% +/- 5% in the IR only group (p < 0.05) and was reduced by 11% +/- 4% with IR-MCC (p < 0.05). At 90 minutes ischemia RESPDR was reduced from baseline by 51% +/- 6% (p < 0.05). By 30 minutes reperfusion, reductions in RESPDR were attenuated with IR-MCC compared with IR only values. The CK-MB levels were increased at 180 minutes reperfusion in the IR only group (52 +/- 9 ng/mL) compared with baseline (6 +/- 1 ng/mL, p < 0.05) but were attenuated with IR-MCC (24 +/- 4 ng/mL, p < 0.05) compared with IR only values.


CONCLUSIONS
Despite similar degrees of injury at 90 minutes ischemia MCC-135 improved regional contractility and reduced the egress of CK-MB. Moreover MCC-135 was associated with decreased heart rate, a determinant of myocardial oxygen demand. Pharmacologic modulation of calcium transport ameliorates myocardial dysfunction in the acute IR period.
Yarbrough
William M
WM
Division of Cardiothoracic Surgery, Medical University of South Carolina, and the Ralph H. Johnson Veteran's Association Medical Center, Charleston, South Carolina, USA.
Mukherjee
Rupak
R
Escobar
G Patricia
GP
Hendrick
Jennifer W
JW
Sample
Jeffrey A
JA
Dowdy
Kathryn B
KB
McLean
Julie E
JE
Mingoia
Joseph T
JT
Crawford
Fred A
FA
Spinale
Francis G
FG
D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D003402:Creatine Kinase / Q000097:blood*; D052279:Creatine Kinase, MB Form; D006339:Heart Rate / Q000187:drug effects; D007527:Isoenzymes / Q000097:blood*; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D010879:Piperazines / Q000494:pharmacology; D013552:Swine; D019210:Troponin I / Q000097:blood
D001557:Benzenesulfonates; D007527:Isoenzymes; C434457:MCC 135; D010879:Piperazines; D019210:Troponin I; D003402:Creatine Kinase; D052279:Creatine Kinase, MB Form; D002118:Calcium