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Abstract
BackgroundA higher increase in intracellular Na+ via Na+/H+ exchanger (NHE) during ischemia has been reported in type 2 diabetic mouse hearts. We investigated the role of NHE in inducing changes in cytoplasmic Ca2+ concentration ([Ca2+]i) and alterations in ventricular function during ischemia-reperfusion in type 2 diabetic mouse hearts.MethodsHearts from male type 2 diabetic db/db (12-15 weeks old) and age-matched control db/+ mice were subjected to Langendorff perfusion and loaded with 4μM of the Ca2+ indicator fura-2. The hearts were exposed to no-flow ischemia for 15 minutes and then reperfused. [Ca2+]i was measured by monitoring fura-2 fluorescence at 500 nm (excitation wavelengths of 340 and 380 nm), while left ventricular (LV) pressure was simultaneously measured.Resultsdb/db hearts exhibited a lower recovery of LV developed pressure than db/+ hearts during reperfusion following ischemia. Diastolic [Ca2+]i was increased to a greater level in diabetic hearts than in the control hearts during ischemia and reperfusion. Such an increase in cytoplasmic Ca2+ overload during ischemia-reperfusion in diabetic hearts was markedly reduced in the presence of the NHE inhibitor cariporide. This was accompanied by a significantly improved recovery of ventricular function on reperfusion, as shown by a lower increase in diastolic pressure and increased recovery of developed pressure.ConclusionNHE plays a key role in enhancing cytoplasmic Ca2+ overload during ischemia-reperfusion and severely impairing post-ischemic cardiac function in hearts from type 2 diabetic db/db mice.
Highlights
A higher increase in intracellular Na+ via Na+/H+ exchanger (NHE) during ischemia has been reported in type 2 diabetic mouse hearts
Pilot experiments In pilot experiments without the ischemia-reperfusion protocol, a decrease of left ventricular developed pressure (LVDP) by 12% was observed after fura-2 loading and the washing out process
When the initial left ventricular end diastolic pressure (LVEDP) was adjusted to 10 mmHg, LVDP tended to decrease after 50 minutes of perfusion in both db/db and db/+ hearts
Summary
A higher increase in intracellular Na+ via Na+/H+ exchanger (NHE) during ischemia has been reported in type 2 diabetic mouse hearts. We investigated the role of NHE in inducing changes in cytoplasmic Ca2+ concentration ([Ca2+]i) and alterations in ventricular function during ischemia-reperfusion in type 2 diabetic mouse hearts. It is recognized that cytoplasmic Ca2+ overload is an important mechanism in myocardial ischemic injury [7,8,9,10]. The purpose of the present study was to determine changes in diastolic [Ca2+]i and Ca2+ transient amplitude during ischemia and reperfusion in isolated type 2 diabetic db/db mouse hearts loaded with fura-2, a fluorescent dye [8,14]. The correlation between [Ca2+]i and cardiac function was investigated, as well as the importance and role of NHE in [Ca2+]i changes
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