| Title | Non-Anticoagulant Heparin Reduces Myocyte Na+ and Ca2+ Loading During Simulated Ischemia and Decreases Reperfusion Injury. | | Author(s) | Barry WH, Zhang XQ, Halkos ME, Vinten-Johansen J, Saegusa N, Spitzer KW, Matsuoka N, Sheets MF, Rao NV, Kennedy TP | | Institution | University of Utah. | | Source | Am J Physiol Heart Circ Physiol 2009 Oct 23. | | Abstract | Heparin desulfated at the 2-O and 3-O positions (ODSH) decreases canine myocardial reperfusion injury. We hypothesized that this occurs from effects on ion channels rather than solely from anti-inflammatory activities, as previously proposed. We studied closed chest pigs with 75 min balloon left anterior descending coronary occlusion and 3 h reperfusion. ODSH effects on [Na(+)]i (NaGreen) and [Ca(2+)]I (Fluo-3) were measured by flow cytometry in rabbit ventricular myocytes after 45 min simulated ischemia (metabolic inhibition with 2 mM cyanide, 0 glucose, 37 degrees C, pacing at 0.5 Hz, P-MI). Na(+)/Ca(2+) exchange (NCX) activity and Na(+) channel function were assessed by voltage clamping. ODSH (15 mg/kg) 5 min before reperfusion significantly decreased myocardial necrosis, but neutrophil influx into reperfused myocardium was not consistently reduced. ODSH (100 mug/ml) reduced [Na(+)]i and [Ca(2+)]i during P-MI. The NCX inhibitor KB-R7943 (10muM), or the late Na(+) current (INa-L) inhibitor ranolazine (10muM) reduced [Ca(2+)]i during P-MI and prevented effects of ODSH on Ca(2+) loading. ODSH also reduced the increase in Na(+) loading in paced myocytes caused by 10 nM sea anemone toxin II (ATXII), a selective activator of the late Na current, INa-L. ODSH directly stimulated NCX and reduced INa-L. These results suggest that in the intact heart ODSH reduces Na(+) influx during early reperfusion, when INa-L is activated by a burst of reactive oxygen production. This reduces Na(+) overload and thus Ca(2+) influx via Na(+)/Ca(2+) exchange. Stimulation of Ca(2+) extrusion via NCX later after reperfusion may also reduce myocyte Ca(2+) loading and decrease infarct size. Key words: myocardial reperfusion, postischemic conditioning, sodium-calcium exchange, late sodium current. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19855066 |
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