Myocardial ischaemic and diazoxide preconditioning both increase PGC-1alpha and reduce mitochondrial damage.

OBJECTIVES: Pretreatment with diazoxide, a mitochondrial ATP-sensitive potassium channel (mito KATP) opener, was found to protect the rat heart against ischaemia-reperfusion (I/R) injury by mimicking ischaemic preconditioning (IPC). However, the protection mechanisms have not been fully clarified yet.We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective programme. We explored the involvement of peroxisome proliferator-activated receptor gamma coactivator-1-1alpha (PGC-1alpha) in the effect of IPC and diazoxide preconditioning (DPC) with regard to its role in protection against I/R injury. METHODS: 30 Wistar rats were used to establish the Langendorff isolated perfused heart model. Rats were randomly divided into 5 groups, 6 in each group: (1) the I/R group: after 30 min of equilibration perfusion, the heart was subjected to 30 min of ischaemia and 1 h of reperfusion; (2) the IPC group: after 10 min of equilibration perfusion, the heart was subjected to two times 5 min ischaemia and 5 min of reperfusion, followed by 30 min of ischaemia and 1 h of reperfusion; (3) the DPC group: after 10 min of equilibration perfusion, the heart was given two times a K-H perfusion solution containing diazoxide (100 micromol/l) for 5 min then a non-diazoxide K-H perfusion solution for 5 min, followed by 30 min of ischaemia and 1 h of reperfusion; (4) a blank control group: an equal amount of saline was used instead of diazoxide. The perfusion procedure was the same as in the DPC group; (5) the dimethyl sulfoxide (DMSO) group: DMSO was applied instead of diazoxide, and the perfusion procedure was the same as in the DPC group. Cardiac apex muscle was cut for frozen section. Immunohistochemistry staining of PGC-1alpha was performed and average absorbance was calculated. An electron microscope was used for Flameng scoring of the myocardial mitochondria. RESULTS: The average absorbance values of PGC-1alpha were: I/R group (3.88 +/- 1.72), IPC group (10.94 +/- 5.23), DPC group (8.40 +/- 3.64), blank control group (3.55 +/- 1.56) and DMSO group (4.16 +/- 0.52), respectively. The expression of PGC- 1alpha was significantly increased in the IPC and DPC groups and the differences were statistically significant compared to the I/R, blank control and DMSO groups, i.e., P < 0.01 for IPC group and P < 0.05 for DPC group. However, there was no significant difference between the IPC and DPC groups (P > 0.05). Flameng score: IPC group (0.44 +/- 0.13), DPC group (0.47 +/- 0.10), I/R group (1.78 +/- 0.14), blank control group (1.70 +/- 0.03) and DMSO group (1.68 +/- 0.06). The Flameng score of the IPC and DPC groups was statistically significantly different as compared to the I/R group, blank control group and DMSO group (P < 0.01), but no significant difference was detected between the IPC and DPC groups (P > 0.05). CONCLUSION: IPC and DPC have a protective effect on myocardial mitochondria, and their mechanism of action may be related to activation and over-expression of PGC-1alpha.

[Diabetes counteracts the protective effect of the diazoxide preconditioning on ischemic reperfused rat heart].

OBJECTIVE: To explore the impact of diabetic condition on the protective effect of diazoxide preconditioning (DPC) on ischemic-reperfused (I/R) myocardium in rats. METHODS: Thirty normal male Sprague-Dawley rats were divided into 3 groups, including non-diabetic control group, non-diabetic I/R group, and non-diabetic I/R DPC group. Thirty diabetic male rats were also divided into the same 3 groups. The Langendorff isolated heart perfusion models were established. The control groups had a 90 min perfusion without any intervention. The I/R groups had a 30 min equilibration period, a 30 min ischemia, and a 30 min reperfusion. The I/R DPC groups had a 10 min equilibration, two cycles of 100 micromol/L diazoxide perfusion, 5 min each, followed by a 5 min diazoxide-free period before the 30 min ischemia and a 30 min reperfusion. The recovery rate of the left ventricular function, including cardiac output, left ventricular developed pressure (LVDP), and the maximum change rate of left ventricular pressure rise and fall (+/- dp/dt(max)) were recorded. The activity of creatine kinase in coronary outflow and activities of malonyldialdehyde, and superoxide dismutase in myocardium were detected. Myocardial water content was also assessed. RESULTS: In non-diabetic rats, the content of creatine kinase, malonyldialdehyde and water content were significantly decreased in I/R DPC group compared with those in I/R group. Furthermore, in I/R DPC group, the activity of superoxide dismutase and the recovery rate of the left ventricular function, including cardiac output, LVDP and +/- dp/dt(max), were significantly increased compared with those in I/R group (P < 0.05). By contrast, there were no significant changes between I/R DPC group and I/R group in diabetic rats (P > 0.05). CONCLUSION: Diabetes counteracts the protective effect of the diazoxide preconditioning on ischemic reperfused rat heart, which may be related with acute insulin resistance in cardiomyocytes.

[Protective effect of ischemia and diazoxide preconditioning on postischemic reperfused myocardium and possible mechanism thereof].

OBJECTIVE: To study the protective mechanism of ischemic preconditioning (IPC) and diazoxide preconditioning (DPC) against myocardium ischemia-reperfusion (I/R) injury. METHODS: The hearts were taken out from 30 male Wistar rats and were divided randomly into 3 equal groups: I/R group undergoing 30-min equilibration perfusion and 30-min ischemia and then 60-min reperfusion, IPC group undergoing 10-min equilibration perfusion and then two cycles of 5 min ischemia interspersed with 5 min reperfusion prior to 30 min ischemia and a 60-min reperfusion, and DPC group undergoing 10-min equilibration perfusion and 2 cycles of 5 min of 100 microM diazoxide perfusion followed by 5-min drug-free period before the 30 min ischemia and 60-min reperfusion. Frozen sections of myocardium at the cardiac apex were made and immunohistochemical staining was used to detect the expression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha). Ultrathin sections 70 nm thick were made and transmission electron microscopy was used to detect the structure of the mitochondria with the Flameng scoring system. RESULTS: The PGC-1alpha expression of the IPC and DPC groups were significantly higher than that of the I/R group (P<0.01 and P<0.05), however, there was no significant difference in PGC-1alpha is expression between the IPC and DPC groups (P >0.05). The Flameng scores of the IPC and DPC groups were 0.44 +/- 0.13 and 0.47 +/- 0.10 respectively, both significantly higher than that of the I/R group (1.78 +/- 0.14, both P <0.01), however, there was no significant difference between IPC and DPC groups (P>0.05). CONCLUSION: IPC and DPC can protect myocyte mitochondria from the injury of ischemia/ reperfusion. The cardioprotective effects of IPC and DPC may be concerned with the activation and high expression of PGC-1alpha.

[Clinical analysis for 232 cases of primary heart neoplasms].

OBJECTIVE: To summarize the clinical characterizations and outcome of surgical treatment of primary heart neoplasms. METHODS: The clinical data of cardiac neoplasms were analyzed retrospectively in 232 patients. There were 14 malignant tumors (6.0%) and 218 benign tumors (94.0%), of which 200 were left atrial myxomas (86.2%). Palpitation and dyspnea on exertion added up to 87.1% (202/232) of all clinical symptoms. Two hundred and twenty-three out of 230 patients underwent complete removal of the tumors, remaining 2 patients had partial removal. Five patients received biopsy only. Other procedures had done in the same stage including 5 cases with mitral valve replacement, 1 case with pulmonary arterial valve replacement, 5 cases with thrombectomy through the Fogarty catheter. RESULTS: Two cases died preoperatively operation. Three cases died intraoperative operation. One hundred and eighty-five cases were followed up for 6 months to 24 years, of which 10 malignant tumors died in 1 year and 1 malignant case recurred after 4 months. Of 174 benign neoplasms, 1 case recurred and 10 cases were dead, remaining were cured. CONCLUSIONS: Left atrial myxomas are most commonly seen in patients with primary heart neoplasms. Palpitation and dyspnea on exertion are the most frequent symptoms. It is suggested that the patients should accept surgical treatment as soon as possible once the diagnosis is confirmed. Surgical treatment is effective for the benign cardiac tumors. Prognosis is poor in patients with malignant cardiac tumors.