Related Experiment Videos
Diabetes and hyperglycemia impair activation of mitochondrial K(ATP) channels
J R Kersten1, M W Montgomery, T Ghassemi
1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. jkerstan@mcw.edu
Abstract:
Hyperglycemia is an important predictor of cardiovascular mortality in patients with diabetes. We investigated the hypothesis that diabetes or acute hyperglycemia attenuates the reduction of myocardial infarct size produced by activation of mitochondrial ATP-regulated potassium (K(ATP)) channels. Acutely instrumented barbiturate-anesthetized dogs were subjected to a 60-min period of coronary artery occlusion and 3 h of reperfusion. Myocardial infarct size (triphenyltetrazolium chloride staining) was 25 +/- 1, 28 +/- 3, and 25 +/- 1% of the area at risk (AAR) for infarction in control, diabetic (3 wk after streptozotocin-alloxan), and hyperglycemic (15% intravenous dextrose) dogs, respectively. Diazoxide (2.5 mg/kg iv) significantly decreased infarct size (10 +/- 1% of AAR, P < 0.05) but did not produce protection in the presence of diabetes (28 +/- 5%) or moderate hyperglycemia (blood glucose 310 +/- 10 mg/dl; 23 +/- 2%). The dose of diazoxide and the degree of hyperglycemia were interactive. Profound (blood glucose 574 +/- 23 mg/dl) but not moderate hyperglycemia blocked the effects of high-dose (5.0 mg/kg) diazoxide [26 +/- 3, 15 +/- 3 (P < 0.05), and 11 +/- 2% (P < 0.05), respectively]. There were no differences in systemic hemodynamics, AAR, or coronary collateral blood flow (by radioactive microspheres) between groups. The results indicate that diabetes or hyperglycemia impairs activation of mitochondrial K(ATP) channels.
Insights
Diabetes and hyperglycemia impair the protective effects of mitochondrial ATP-regulated potassium (K(ATP)) channel activation, increasing the risk of cardiovascular mortality. This study shows that K(ATP) channel openers are less effective in diabetic or hyperglycemic conditions.
Area of Science:
- Cardiovascular Science
- Metabolic Disease Research
- Pharmacology
Background:
- Hyperglycemia is a significant risk factor for cardiovascular mortality in diabetic patients.
- Mitochondrial ATP-regulated potassium (K(ATP)) channels play a role in protecting the heart during ischemia.
- The impact of diabetes and hyperglycemia on K(ATP) channel-mediated cardioprotection is not fully understood.
Purpose of the Study:
- To investigate whether diabetes or acute hyperglycemia attenuates the infarct size reduction by activating mitochondrial K(ATP) channels.
- To determine the interactive effects of diazoxide dose and hyperglycemia severity on cardioprotection.
Main Methods:
- A canine model was used, inducing myocardial infarction via coronary artery occlusion and reperfusion.
- Infarct size was assessed using triphenyltetrazolium chloride staining.
- The effects of diazoxide, a K(ATP) channel activator, were evaluated in control, diabetic, and hyperglycemic dogs.
Main Results:
- Diazoxide significantly reduced infarct size in control dogs.
- The cardioprotective effect of diazoxide was abolished in diabetic dogs and dogs with moderate hyperglycemia.
- Profound hyperglycemia blocked the protective effects of even high-dose diazoxide, while moderate hyperglycemia did not.
- No significant differences in hemodynamics, area at risk, or collateral blood flow were observed between groups.
Conclusions:
- Diabetes and hyperglycemia impair the activation of mitochondrial K(ATP) channels.
- This impairment likely contributes to the increased cardiovascular mortality observed in diabetic patients.
- Targeting K(ATP) channels may be less effective for cardioprotection in hyperglycemic states.