Modulation of calcium transport improves myocardial contractility and enzyme profiles after prolonged ischemia-reperfusion.

Abstract

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.

• Authors: William M Yarbrough, Rupak Mukherjee, G Patricia Escobar, Jennifer W Hendrick, Jeffrey A Sample, Kathryn B Dowdy, Julie E McLean, Joseph T Mingoia, Fred A Crawford Jr, Francis G Spinale
• Journal: The Annals of thoracic surgery (Ann Thorac Surg) Vol. 76 Issue 6 Pg. 2054-61; discussion 2061 (Dec 2003) ISSN: 0003-4975 [Print] Netherlands
• PMID: 14667641 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzenesulfonates
• Isoenzymes
• MCC 135
• Piperazines
• Troponin I
• Creatine Kinase
• Creatine Kinase, MB Form
• Calcium

Topics

• Animals
• Benzenesulfonates (pharmacology)
• Biological Transport (drug effects)
• Calcium (metabolism)
• Creatine Kinase (blood)
• Creatine Kinase, MB Form
• Heart Rate (drug effects)
• Isoenzymes (blood)
• Myocardial Contraction (drug effects)
• Myocardial Reperfusion Injury (metabolism, physiopathology)
• Piperazines (pharmacology)
• Swine
• Troponin I (blood)