Nonanticoagulant heparin reduces myocyte Na⁺and Ca²⁺loading during simulated ischemia and decreases reperfusion injury

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 balloon left anterior descending coronary artery occlusion (75-min) and reperfusion (3-h). ODSH effects on [Na(+)](i) (Na Green) and [Ca(2+)](i) (Fluo-3) were measured by flow cytometry in rabbit ventricular myocytes after 45-min of simulated ischemia [metabolic inhibition with 2 mM cyanide, 0 glucose, 37 degrees C, pacing at 0.5 Hz; i.e., pacing-metabolic inhibition (PMI)]. 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 microg/ml) reduced [Na(+)](i) and [Ca(2+)](i) during PMI. The NCX inhibitor KB-R7943 (10 microM) or the late Na(+) current (I(Na-L)) inhibitor ranolazine (10 microM) reduced [Ca(2+)](i) during PMI 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, a selective activator of I(Na-L). ODSH directly stimulated NCX and reduced I(Na-L). These results suggest that in the intact heart ODSH reduces Na(+) influx during early reperfusion, when I(Na-L) is activated by a burst of reactive oxygen production. This reduces Na(+) overload and thus Ca(2+) influx via NCX. Stimulation of Ca(2+) extrusion via NCX later after reperfusion may also reduce myocyte Ca(2+) loading and decrease infarct size.

The Revised Cardiac Risk Index in the new millennium: a single-centre prospective cohort re-evaluation of the original variables in 9,519 consecutive elective surgical patients

“…19 Focused attempts to include modified terms related to diabetes mellitus or preoperative blood sugar levels could not significantly improve the ability to predict the risk of MCCs or improve the accuracy or the discrimination of the index. Glycosylated hemoglobin has been advocated as an important risk factor in diabetic outcomes and may be a factor that could potentially improve the index; [20][21][22] however, the data in our database were insufficient to assess this variable. In our view, it would be important to drop the diabetes terminology from the RCRI; inclusion has the potential to create patient safety issues.…”

“…As a result, troponin was measured more frequently in patients with elevated RCRI scores, and we have previously documented and shown that this clinically based measurement can deliver up to a threefold underestimation of the rate of myocardial damage. 20 In conclusion, the four validated terms from the original RCRI (i.e., high-risk type of surgery, history of ischemic heart disease, history of congestive heart failure, and history of cerebrovascular disease) should continue to be used to estimate risk and allocate resources in elective surgical patients. The elimination of diabetes from the index would have little effect on the performance of the ''index'' except to move more patients to a lower risk category.…”

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

“…Adult mouse ventricular myocytes were isolated as previously described on laminin-coated chambers (4,51). After superfusion in a normoxic solution (pO 2 ϭ 580 Ϯ 2.0 mmHg), cells were bathed in an ischemic solution (pO2 ϭ 20.5 Ϯ 3.5 mmHg) for 5 min (8).…”

Ranolazine Attenuates the Enhanced Reverse Na+-Ca2+ Exchange Current via Inhibiting Hypoxia-Increased Late Sodium Current in Ventricular Myocytes

“…In recent years, many studies show that RAN inhibits I Na.L under pathological conditions and thus alleviates Ca 2+ overload and cell damage (37, 41 -45). In addition, RAN remarkably attenuates ischemia-induced myocardial diastolic Ca 2+ overload, improves left ventricular function during isch- emia/reperfusion, and protects cardiac cells from necrosis (12,17,18,22,27,34,40,46). However, to our knowledge, the effect of RAN on hypoxia-increased I Na.L has not been studied to date.…”