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Brett T Reece - One of the best experts on this subject based on the ideXlab platform.

  • optimizing Nicorandil for spinal cord protection in a murine model of complex aortic intervention
    Seminars in Thoracic and Cardiovascular Surgery, 2021
    Co-Authors: Yuki Ikeno, Christian V Ghincea, Gavriel F Roda, Linling Cheng, Xianzhong Meng, Micheal J Weyant, Joseph C Cleveland, David A Fullerton, Muhammad Aftab, Brett T Reece
    Abstract:

    There are currently no clinically utilized pharmacological agents for the induction of metabolic tolerance to spinal cord ischemia-reperfusion injury in the setting of complex aortic intervention. Nicorandil, a nitric oxide donor and ATP-sensitive potassium (KATP) channel opener, has shown promise in neuroprotection. However, the optimized clinical application of the drug and its mechanism of neuroprotection remains unclear. We hypothesized that 3-days pretreatment would confer the most effective neuroprotection, mediated by mitochondrial KATP channel activation. Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Time course: mice received 0.1 mg/kg Nicorandil for 10 min, 4 hours, and 3 consecutive days prior to ischemia compared with control. Dose challenge: mice received 3-days Nicorandil pretreatment comparing 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, and saline administration. Mitochondrial KATP channel blocker 5-hydroxy-decanoate (5HD) was co-administered to elucidate mechanism. Limb motor function was evaluated, and viable anterior horn neurons quantified. Nicorandil pretreatment at 4 hours and 3 days before ischemia demonstrated significant motor function preservation; administration 10 min before ischemia showed no neuroprotection. All Nicorandil doses showed significant motor function preservation. Three days administration of Nicorandil 1.0 mg/kg was most potent. Neuroprotection was completely abolished by 5HD co-administration. Histological analysis showed significant neuron preservation with Nicorandil pretreatment, which was attenuated by 5HD co-administration. Three days administration of Nicorandil 1.0 mg/kg showed near-total motor function preservation in a murine spinal cord ischemia-reperfusion model, mediated by the mitochondrial KATP channel.

  • reactive oxygen species mediate Nicorandil induced metabolic tolerance to spinal cord injury
    The Annals of Thoracic Surgery, 2020
    Co-Authors: Yuki Ikeno, Christian V Ghincea, Gavriel F Roda, Linling Cheng, Xianzhong Meng, Micheal J Weyant, Joseph C Cleveland, David A Fullerton, Muhammad Aftab, Brett T Reece
    Abstract:

    Abstract Background Spinal cord injury remains a devastating complication of thoracoabdominal aortic surgery. We previously demonstrated that pretreatment with Nicorandil preserved motor function in a murine SCI model via mitochondrial ATP-sensitive potassium (KATP) channel activation. We hypothesized that the neuroprotective effect of Nicorandil is mediated by downstream generation of reactive oxygen species. Methods SCI was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Five groups were evaluated: ischemic control (n=19), Nicorandil 1.0 mg/kg (n=17), Nicorandil 1.0 mg/kg + N acetyl L-cysteine 150 mg/kg (NAC: reactive oxygen species scavenger, n=18), NAC 150 mg/kg (n=13), and sham (n=10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated. Results Mice in the sham group showed no functional deficits following surgery. Compared to ischemic control, motor function was significantly preserved in the Nicorandil pretreatment group at every time point after ischemia. In the Nicorandil+NAC group, the motor preserving effect of Nicorandil was completely abolished (p Conclusions Reactive oxygen species generation plays a key role in the Nicorandil induced metabolic tolerance to spinal cord injury. Manipulation of mitochondrial KATP channels may lead to improvement in preventing spinal cord injury after thoracoabdominal aortic interventions.

Yuki Ikeno - One of the best experts on this subject based on the ideXlab platform.

  • optimizing Nicorandil for spinal cord protection in a murine model of complex aortic intervention
    Seminars in Thoracic and Cardiovascular Surgery, 2021
    Co-Authors: Yuki Ikeno, Christian V Ghincea, Gavriel F Roda, Linling Cheng, Xianzhong Meng, Micheal J Weyant, Joseph C Cleveland, David A Fullerton, Muhammad Aftab, Brett T Reece
    Abstract:

    There are currently no clinically utilized pharmacological agents for the induction of metabolic tolerance to spinal cord ischemia-reperfusion injury in the setting of complex aortic intervention. Nicorandil, a nitric oxide donor and ATP-sensitive potassium (KATP) channel opener, has shown promise in neuroprotection. However, the optimized clinical application of the drug and its mechanism of neuroprotection remains unclear. We hypothesized that 3-days pretreatment would confer the most effective neuroprotection, mediated by mitochondrial KATP channel activation. Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Time course: mice received 0.1 mg/kg Nicorandil for 10 min, 4 hours, and 3 consecutive days prior to ischemia compared with control. Dose challenge: mice received 3-days Nicorandil pretreatment comparing 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, and saline administration. Mitochondrial KATP channel blocker 5-hydroxy-decanoate (5HD) was co-administered to elucidate mechanism. Limb motor function was evaluated, and viable anterior horn neurons quantified. Nicorandil pretreatment at 4 hours and 3 days before ischemia demonstrated significant motor function preservation; administration 10 min before ischemia showed no neuroprotection. All Nicorandil doses showed significant motor function preservation. Three days administration of Nicorandil 1.0 mg/kg was most potent. Neuroprotection was completely abolished by 5HD co-administration. Histological analysis showed significant neuron preservation with Nicorandil pretreatment, which was attenuated by 5HD co-administration. Three days administration of Nicorandil 1.0 mg/kg showed near-total motor function preservation in a murine spinal cord ischemia-reperfusion model, mediated by the mitochondrial KATP channel.

  • reactive oxygen species mediate Nicorandil induced metabolic tolerance to spinal cord injury
    The Annals of Thoracic Surgery, 2020
    Co-Authors: Yuki Ikeno, Christian V Ghincea, Gavriel F Roda, Linling Cheng, Xianzhong Meng, Micheal J Weyant, Joseph C Cleveland, David A Fullerton, Muhammad Aftab, Brett T Reece
    Abstract:

    Abstract Background Spinal cord injury remains a devastating complication of thoracoabdominal aortic surgery. We previously demonstrated that pretreatment with Nicorandil preserved motor function in a murine SCI model via mitochondrial ATP-sensitive potassium (KATP) channel activation. We hypothesized that the neuroprotective effect of Nicorandil is mediated by downstream generation of reactive oxygen species. Methods SCI was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Five groups were evaluated: ischemic control (n=19), Nicorandil 1.0 mg/kg (n=17), Nicorandil 1.0 mg/kg + N acetyl L-cysteine 150 mg/kg (NAC: reactive oxygen species scavenger, n=18), NAC 150 mg/kg (n=13), and sham (n=10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated. Results Mice in the sham group showed no functional deficits following surgery. Compared to ischemic control, motor function was significantly preserved in the Nicorandil pretreatment group at every time point after ischemia. In the Nicorandil+NAC group, the motor preserving effect of Nicorandil was completely abolished (p Conclusions Reactive oxygen species generation plays a key role in the Nicorandil induced metabolic tolerance to spinal cord injury. Manipulation of mitochondrial KATP channels may lead to improvement in preventing spinal cord injury after thoracoabdominal aortic interventions.

C. Beermann - One of the best experts on this subject based on the ideXlab platform.

  • Venodilatory effects of Nicorandil in healthy volunteers.
    Journal of Cardiovascular Pharmacology, 1992
    Co-Authors: G. G. Belz, C. Beermann
    Abstract:

    The effects of a single dose of Nicorandil (40 mg orally) on human dorsal hand veins in vivo were assessed and compared with the effect of nitroglycerin (0.8 mg sublingually). The hand veins had been preconstricted with norepinephrine to approximately one-third of their initial size. We demonstrated that a venous relaxation occurred after administration of Nicorandil and nitroglycerin. In the doses studied, the effect was more pronounced and lasted longer after Nicorandil. The pharmacodynamic effects of Nicorandil in humans may be explained in party by the venous relaxation

  • Venodilatory effects of Nicorandil in healthy volunteers.
    Journal of cardiovascular pharmacology, 1992
    Co-Authors: G. G. Belz, C. Beermann
    Abstract:

    The effects of a single dose of Nicorandil (40 mg orally) on human dorsal hand veins in vivo were assessed and compared with the effect of nitroglycerin (0.8 mg sublingually). The hand veins had been preconstricted with norepinephrine to approximately one-third of their initial size. We demonstrated that a venous relaxation occurred after administration of Nicorandil and nitroglycerin. In the doses studied, the effect was more pronounced and lasted longer after Nicorandil. The pharmacodynamic effects of Nicorandil in humans may be explained in part by this venous relaxation.

Ryozo Oishi - One of the best experts on this subject based on the ideXlab platform.

  • Influence of footshock stress on pharmacokinetics of Nicorandil in rats.
    Life Sciences, 1991
    Co-Authors: Motoo Yamori, Yutaka Gomita, Ryozo Oishi
    Abstract:

    Abstract The influence of footshock stress on the pharmacokinetics of Nicorandil was examined in rats. In the group exposed to a 30-min period of footshock immediately after the oral administration of Nicorandil (10 mg/kg), plasma Nicorandil levels were markedly lower than those in the control group 30–120 min after administration. Plasma levels after the subcutaneous injection of Nicorandil (5 mg/kg) were also slightly but significantly lower in stressed rats than in control rats. When footshock was applied from 60 min after oral administration or 30 min after subcutaneous injection (the time when the plasma Nicorandil level was maximum), it also significantly decreased the plasma levels thereafter. Furthermore, footshock applied immediately after intravenous injection of Nicorandil (3 mg/kg) significantly decreased the plasma levels 30–60 min after injection. Plasma levels of N-(2-hydroxyethyl) nicotinamide, one of the main metabolites of Nicorandil, were slightly increased 30 min after the intravenous injection of Nicorandil (10 mg/kg) by footshock. Nicorandil levels in the heart, kidney, and skin were significantly lower in the stressed rats similar to the change in the plasma level, but levels in the muscle, liver, and thymus showed no significant difference. The urinary excretion of Nicorandil tended to be higher in the stressed rats. These results suggest that footshock stress affects not only the absorption of Nicorandil but also its distribution, metabolism, and excretion.

Muhammad Aftab - One of the best experts on this subject based on the ideXlab platform.

  • optimizing Nicorandil for spinal cord protection in a murine model of complex aortic intervention
    Seminars in Thoracic and Cardiovascular Surgery, 2021
    Co-Authors: Yuki Ikeno, Christian V Ghincea, Gavriel F Roda, Linling Cheng, Xianzhong Meng, Micheal J Weyant, Joseph C Cleveland, David A Fullerton, Muhammad Aftab, Brett T Reece
    Abstract:

    There are currently no clinically utilized pharmacological agents for the induction of metabolic tolerance to spinal cord ischemia-reperfusion injury in the setting of complex aortic intervention. Nicorandil, a nitric oxide donor and ATP-sensitive potassium (KATP) channel opener, has shown promise in neuroprotection. However, the optimized clinical application of the drug and its mechanism of neuroprotection remains unclear. We hypothesized that 3-days pretreatment would confer the most effective neuroprotection, mediated by mitochondrial KATP channel activation. Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Time course: mice received 0.1 mg/kg Nicorandil for 10 min, 4 hours, and 3 consecutive days prior to ischemia compared with control. Dose challenge: mice received 3-days Nicorandil pretreatment comparing 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, and saline administration. Mitochondrial KATP channel blocker 5-hydroxy-decanoate (5HD) was co-administered to elucidate mechanism. Limb motor function was evaluated, and viable anterior horn neurons quantified. Nicorandil pretreatment at 4 hours and 3 days before ischemia demonstrated significant motor function preservation; administration 10 min before ischemia showed no neuroprotection. All Nicorandil doses showed significant motor function preservation. Three days administration of Nicorandil 1.0 mg/kg was most potent. Neuroprotection was completely abolished by 5HD co-administration. Histological analysis showed significant neuron preservation with Nicorandil pretreatment, which was attenuated by 5HD co-administration. Three days administration of Nicorandil 1.0 mg/kg showed near-total motor function preservation in a murine spinal cord ischemia-reperfusion model, mediated by the mitochondrial KATP channel.

  • reactive oxygen species mediate Nicorandil induced metabolic tolerance to spinal cord injury
    The Annals of Thoracic Surgery, 2020
    Co-Authors: Yuki Ikeno, Christian V Ghincea, Gavriel F Roda, Linling Cheng, Xianzhong Meng, Micheal J Weyant, Joseph C Cleveland, David A Fullerton, Muhammad Aftab, Brett T Reece
    Abstract:

    Abstract Background Spinal cord injury remains a devastating complication of thoracoabdominal aortic surgery. We previously demonstrated that pretreatment with Nicorandil preserved motor function in a murine SCI model via mitochondrial ATP-sensitive potassium (KATP) channel activation. We hypothesized that the neuroprotective effect of Nicorandil is mediated by downstream generation of reactive oxygen species. Methods SCI was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Five groups were evaluated: ischemic control (n=19), Nicorandil 1.0 mg/kg (n=17), Nicorandil 1.0 mg/kg + N acetyl L-cysteine 150 mg/kg (NAC: reactive oxygen species scavenger, n=18), NAC 150 mg/kg (n=13), and sham (n=10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated. Results Mice in the sham group showed no functional deficits following surgery. Compared to ischemic control, motor function was significantly preserved in the Nicorandil pretreatment group at every time point after ischemia. In the Nicorandil+NAC group, the motor preserving effect of Nicorandil was completely abolished (p Conclusions Reactive oxygen species generation plays a key role in the Nicorandil induced metabolic tolerance to spinal cord injury. Manipulation of mitochondrial KATP channels may lead to improvement in preventing spinal cord injury after thoracoabdominal aortic interventions.