Mehmet Ensari Guneli

Comparison of the effects of dexmedetomidine administered at two different times on renal ischemia/reperfusion injury in rats

BACKGROUND AND OBJECTIVES We investigated the effect of dexmedetomidine on ischemic renal failure in rats. METHODS In the present study, 26 male adult Wistar albino rats weighting 230-300 g were randomly separated into four groups: sham-operated (n=5), ischemia reperfusion (IR) (IR group, n=7), IR/reperfusion treatment with dexmedetomidine (Dex. R group, n=7) and IR/pre-ischemic treatment with dexmedetomidine (Dex. I group, n=7). In the first group, sham operation was achieved and renal clamps were not applied. For the IR group, renal ischemia was induced by occlusion of the bilateral renal arteries and veins for 60 min followed by reperfusion for 24h. For the Dex. R and Dex. I groups, the same surgical procedure as in the IR group was performed, and dexmedetomidine (100 mcg/kg intraperitoneal) was administrated at the 5th min after reperfusion and before ischemia. At the end of reperfusion, blood samples were drawn, the rats were sacrificed, and the left kidney was processed for histopathology. RESULTS The blood urea nitrogen (BUN) levels in groups Dex. R and Dex. I were significantly lower than in the IR group (p=0.015, p=0.043), although urine flow was significantly higher in group Dex. R (p=0.003). The renal histopathological score in the IR group was significantly higher than in the other groups. There was no significant difference between the Dex. R and Dex. I groups. CONCLUSIONS The results were shown that administration of dexmedetomidine reduced the renal IR injury histomorphologically. Administration of dexmedetomidine in the reperfusion period was considered as more effective due to increase in urinary output and decrease in BUN levels.

Evaluation of the effectiveness of sugammadex for verapamil intoxication.

Previous studies have shown that medications from the cyclodextrin family bind to verapamil. The aim of our study was to determine whether sugammadex could bind to verapamil and prevent the cardiovascular toxicity of that drug. Twenty‐eight sedated Wistar rats were infused with verapamil at 37.5 mg/kg/h. Five minutes after the start of infusion, the animals were treated with a bolus of either 16 mg/kg, 100 mg/kg or 1000 mg/kg sugammadex. The control group was treated with an infusion without sugammadex. The heart rate and respiratory rate were monitored, and an electrocardiogram was recorded. The primary end‐point was the time to asystole. The verapamil infusion continued until the animals arrested. The asystole time for the S16 group was significantly longer compared to those for the control and S1000 groups (p < 0.05). The asystole time for the S1000 group was significantly shorter than those for all of the other groups (p < 0.05). Reflecting these data, there was a near doubling of the mean lethal dose of verapamil from 13.57 mg/kg (S.D. ±8.1) in the saline‐treated rats to 22.42 mg/kg (S.D. ±9.9) in the sugammadex 16 group (p < 0.05). However, for the sugammadex 1000 group, the mean lethal dose was found to be 6.28 ± 1.11 mg/kg. This dose is significantly lower than those for all of the other groups (p < 0.05). We found that treatment with 16 mg/kg sugammadex delayed verapamil cardiotoxicity in rats. However, 1000 mg/kg sugammadex accelerated verapamil cardiotoxicity in rats. Further studies must be conducted to investigate the interaction between verapamil and sugammadex.

Efeitos de dexmedetomidina em conjunto com o pré-condicionamento isquêmico remoto em lesão de isquemia-reperfusão renal em ratos

BACKGROUND AND OBJECTIVES The aim of this study was to evaluate the effects of remote ischemic preconditioning by brief ischemia of unilateral hind limb when combined with dexmedetomidine on renal ischemia-reperfusion injury by histopathology and active caspase-3 immunoreactivity in rats. METHODS 28 Wistar albino male rats were divided into 4 groups. Group I (Sham, n=7): Laparotomy and renal pedicle dissection were performed at 65th minute of anesthesia and the rats were observed under anesthesia for 130min. Group II (ischemia-reperfusion, n=7): At 65th minute of anesthesia bilateral renal pedicles were clamped. After 60min ischemia 24h of reperfusion was performed. Group III (ischemia-reperfusion+dexmedetomidine, n=7): At the fifth minute of reperfusion (100μg/kg intra-peritoneal) dexmedetomidine was administered with ischemia-reperfusion group. Reperfusion lasted 24h. Group IV (ischemia-reperfusion+remote ischemic preconditioning+dexmedetomidine, n=7): After laparotomy, three cycles of ischemic preconditioning (10min ischemia and 10min reperfusion) were applied to the left hind limb and after 5min with group III. RESULTS Histopathological injury scores and active caspase-3 immunoreactivity were significantly lower in the Sham group compared to the other groups. Histopathological injury scores in groups III and IV were significantly lower than group II (p=0.03 and p=0.05). Active caspase-3 immunoreactivity was significantly lower in the group IV than group II (p=0.01) and there was no significant difference between group II and group III (p=0.06). CONCLUSIONS Pharmacologic conditioning with dexmedetomidine and remote ischemic preconditioning when combined with dexmedetomidine significantly decreases renal ischemia-reperfusion injury histomorphologically. Combined use of two methods prevents apoptosis via active caspase-3.

Renal Ischemia/Reperfusion Injury in Diabetic Rats: The Role of Local Ischemic Preconditioning

Background. The aim of this study was to evaluate the effects of local ischemic preconditioning using biochemical markers and histopathologically in the diabetic rat renal IR injury model. Methods. DM was induced using streptozotocin. Rats were divided into four groups: Group I, nondiabetic sham group (n = 7), Group II, diabetic sham group (n = 6), Group III, diabetic IR group (diabetic IR group, n = 6), and Group IV, diabetic IR + local ischemic preconditioning group (diabetic IR + LIPC group, n = 6). Ischemic renal injury was induced by clamping the bilateral renal artery for 45 min. 4 h following ischemia, clearance protocols were applied to assess biochemical markers and histopathologically in rat kidneys. Results. The histomorphologic total cell injury scores of the nondiabetic sham group were significantly lower than diabetic sham, diabetic IR, and diabetic IR + LIPC groups. Diabetic IR group scores were not significantly different than the diabetic sham group. But diabetic IR + LIPC group scores were significantly higher than the diabetic sham and diabetic IR groups. Conclusion. Local ischemic preconditioning does not reduce the risk of renal injury induced by ischemia/reperfusion in diabetic rat model.

The Effect of Insulin Treatment on Rac1 Expression in Diabetic Kidney

This study was designed to evaluate the renoprotective effect of insulin on diabetic nephropathy through Rac1 inhibition. Twenty Wistar rats were divided into three groups: control (C), diabetic (D), and insulin-treated diabetic (D + I). Diabetes was induced by a single streptozotocin (STZ) injection (45 mg/kg i.p.) in adult male rats. Diabetic animals were treated subcutaneously with insulin (6 U/kg), or saline once a day for 8 weeks. Age-matched control rats received only saline. The kidney tissue samples were analyzed by immunohistochemical staining for Rac1 and cleaved caspase-3 expressions and using the TUNEL method for determining apoptotic cells. Diabetes increased the number of TUNEL (+) cells and cleaved caspase-3 and Rac1 expression levels in kidney. Administration of insulin for 8 weeks reduced Rac1 expression and ameliorated histopathological changes in kidney of STZ-induced diabetes model. These results may suggest that the renoprotective effect of insulin at least partly results from inhibition of Rac1 overexpression.