Exacerbation of acidosis during ischemia and reperfusion arrhythmia in hearts from type 2 Diabetic Otsuka Long-Evans Tokushima Fatty rats

Abstract Background Sensitivity to ischemia and its underlying mechanisms in type 2 diabetic hearts are still largely unknown. Especially, correlation between reperfusion induced ventricular arrhythmia and changes in intracellular pH has not been elucidated. Methods and results Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats at 16 and 32 weeks of age were used along with age-matched nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. Hearts from rats in these 4 groups were perfused in the working heart mode, thus inducing whole heart ischemia. At 16 weeks of age, no differences in blood glucose levels or incidence and duration of reperfusion arrhythmia were found between the strains. At 32 weeks of age, both impaired glucose tolerance and obesity were observed in the OLETF rats. Further, the duration of reperfusion-induced ventricular fibrillation (VF) was significantly longer in the OLETF rats, while the pH level was significantly lower and proton contents were significantly higher in coronary effluent during ischemia in those rats. Following treatment with troglitazone, improvements in pH and proton level in coronary effluent during ischemia were observed, as was the duration of reperfusion-induced VF in OLETF rats at 32 weeks of age. Conclusion The hearts of spontaneously diabetic OLETF rats were found to be more susceptible to ischemic insult. Troglitazone treatment improved ischemic tolerance by improving glucose metabolism in the myocardium of those rats.</p

Incidence (A) and duration (B) of ventricular fibrillation after reperfusion

<p><b>Copyright information:</b></p><p>Taken from "Exacerbation of acidosis during ischemia and reperfusion arrhythmia in hearts from type 2 Diabetic Otsuka Long-Evans Tokushima Fatty rats"</p><p>http://www.cardiab.com/content/6/1/17</p><p>Cardiovascular Diabetology 2007;6():17-17.</p><p>Published online 5 Jun 2007</p><p>PMCID:PMC1896150.</p><p></p> * p < 0.05 vs. OLETF rats at 32 weeks of age, † p < 0.05 vs. LETO rats at 32 weeks of age

Changes in proton content in coronary effluent from LETO and OLETF rats at 16 weeks of age (A) and 32 weeks of age (B)

<p><b>Copyright information:</b></p><p>Taken from "Exacerbation of acidosis during ischemia and reperfusion arrhythmia in hearts from type 2 Diabetic Otsuka Long-Evans Tokushima Fatty rats"</p><p>http://www.cardiab.com/content/6/1/17</p><p>Cardiovascular Diabetology 2007;6():17-17.</p><p>Published online 5 Jun 2007</p><p>PMCID:PMC1896150.</p><p></p> Closed circles show LETO rats, open circles show OLETF rats. * p < 0.05 vs. LETO rats

Changes in pH of coronary effluent in troglitazone-treated and non-treated LETO rats (A), and in troglitazone-treated and non-treated OLETF rats (B) at 32 weeks of age

<p><b>Copyright information:</b></p><p>Taken from "Exacerbation of acidosis during ischemia and reperfusion arrhythmia in hearts from type 2 Diabetic Otsuka Long-Evans Tokushima Fatty rats"</p><p>http://www.cardiab.com/content/6/1/17</p><p>Cardiovascular Diabetology 2007;6():17-17.</p><p>Published online 5 Jun 2007</p><p>PMCID:PMC1896150.</p><p></p> Closed circles show non-treated LETO rats, gray circles show troglitazone-treated LETO rats, open circles show non-treated OLETF rats, bias circles show troglitazone-treated OLETF rats. * p < 0.05 vs. OLETF rats

Changes in pH of coronary effluent in LETO and OLETF rats at 16 weeks of age (A) and 32 weeks of age (B)

<p><b>Copyright information:</b></p><p>Taken from "Exacerbation of acidosis during ischemia and reperfusion arrhythmia in hearts from type 2 Diabetic Otsuka Long-Evans Tokushima Fatty rats"</p><p>http://www.cardiab.com/content/6/1/17</p><p>Cardiovascular Diabetology 2007;6():17-17.</p><p>Published online 5 Jun 2007</p><p>PMCID:PMC1896150.</p><p></p> Closed circles show LETO rats, open circles show OLETF rats. * p < 0.05 vs. LETO rats

Changes in proton content in coronary effluent from troglitazone-treated and non-treated LETO rats (A), and from troglitazone-treated and non-treated OLETF rats (B) at 32 weeks of age

<p><b>Copyright information:</b></p><p>Taken from "Exacerbation of acidosis during ischemia and reperfusion arrhythmia in hearts from type 2 Diabetic Otsuka Long-Evans Tokushima Fatty rats"</p><p>http://www.cardiab.com/content/6/1/17</p><p>Cardiovascular Diabetology 2007;6():17-17.</p><p>Published online 5 Jun 2007</p><p>PMCID:PMC1896150.</p><p></p> Closed circles show non-treated LETO rats, gray circles show troglitazone-treated LETO rats, open circles show non-treated OLETF rats, bias circles show troglitazone-treated OLETF rats. * p < 0.05 vs. OLETF rats

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice.

Sodium-glucose cotransporter 1 (SGLT1) is thought to be expressed in the heart as the dominant isoform of cardiac SGLT, although more information is required to delineate the subtypes of SGLTs in human hearts. Moreover, the functional role of SGLTs in the heart remains to be fully elucidated. We herein investigated whether SGLT1 is expressed in human hearts and whether SGLTs significantly contribute to cardiac energy metabolism during ischemia-reperfusion injury (IRI) via enhanced glucose utilization in mice.We determined that SGLT1 was highly expressed in both human autopsied hearts and murine perfused hearts, as assessed by immunostaining and immunoblotting with membrane fractionation. To test the functional significance of the substantial expression of SGLTs in the heart, we studied the effects of a non-selective SGLT inhibitor, phlorizin, on the baseline cardiac function and its response to ischemia-reperfusion using the murine Langendorff model. Although phlorizin perfusion did not affect baseline cardiac function, its administration during IRI significantly impaired the recovery in left ventricular contractions and rate pressure product, associated with an increased infarct size, as demonstrated by triphenyltetrazolium chloride staining and creatine phosphokinase activity released into the perfusate. The onset of ischemic contracture, which indicates the initiation of ATP depletion in myocardium, was earlier with phlorizin. Consistent with this finding, there was a significant decrease in the tissue ATP content associated with reductions in glucose uptake, as well as lactate output (indicating glycolytic flux), during ischemia-reperfusion in the phlorizin-perfused hearts.Cardiac SGLTs, possibly SGLT1 in particular, appear to provide an important protective mechanism against IRI by replenishing ATP stores in ischemic cardiac tissues via enhancing availability of glucose. The present findings provide new insight into the significant role of SGLTs in optimizing cardiac energy metabolism, at least during the acute phase of IRI

Phlorizin increased myocardial injury after ischemia-reperfusion.

<p>(A) CPK profiles in the effluent collected during the reperfusion period. (B) Area under the curve (AUC) was calculated from the CPK profile shown in (A). (phlorizin-perfused hearts, n = 11; control hearts, n = 10). (C) Micrograph showing representative TTC staining of cardiac sections obtained from the control (top row) and phlorizin-perfused hearts (bottom row). (D) Effects on quantitated cumulative infarct area size in the phlorizin-perfused hearts (n = 9) compared with that observed in the control group (n = 8). %MI, myocardial infarct area/ventricular area. *P<0.05 and **P<0.01 versus control.</p