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Acute effects of glibenclamide on reactive hyperaemia in the lower limbs in humans
P L Capecchi1, F Guideri, M Colafati
1Department of Clinical Medicine and Immunologcal Sciences, Section of Immunology, University of Siena, Italy. capecchipl@unisi.it
Insights
Brief lower limb ischemia episodes protect against prolonged ischemia by enhancing metabolic debt repayment. This protective effect is mediated by ATP-dependent K(+) channels, as shown by glibenclamide administration blocking this benefit.
Area of Science:
- Physiology
- Cardiovascular Research
Background:
- Repeated brief ischemia can precondition tissues, offering protection against subsequent longer ischemic events.
- The role of ATP-dependent K(+) channels in peripheral circulation's response to ischemia is not fully understood.
Purpose of the Study:
- To investigate the protective effects of repeated brief lower limb ischemia on metabolic debt repayment.
- To determine if ATP-dependent K(+) channels mediate these protective effects.
Main Methods:
- Human participants underwent three 1-minute ischemia episodes in lower limbs.
- Reactive hyperemia was measured to assess metabolic debt repayment.
- The ATP-dependent K(+) channel blocker glibenclamide was administered to assess its effect on protection.
Main Results:
- Repeated brief ischemia reduced metabolic debt repayment following prolonged ischemia.
- Glibenclamide administration significantly reduced reactive hyperemia and abolished the protective effect of brief ischemia.
- Plasma glibenclamide levels peaked at 2 hours, remaining around 1 micromol/l for 3 hours.
Conclusions:
- Brief, repeated lower limb ischemia episodes offer protection against prolonged ischemia.
- This protective mechanism appears to be mediated by ATP-dependent K(+) channels.
- Findings suggest a parallel to ischemic preconditioning observed in cardiac circulation.
Abstract:
Three episodes of 1 min ischemia in the lower limbs in humans reduced the metabolic debt repayment (expressed as AUC of reactive hyperaemia) following more prolonged ischemia (666.6+/-86.6 vs 500.0+/-33.5 ml/100 ml). The administration of the ATP-dependent K(+) channel blocker glibenclamide was associated with a significant reduction in the AUC of reactive hyperaemia (666.6+/-86.6 vs 563.1+/-76.6 ml/100 ml), and with the removal of the protective effect produced by 3 episodes of 1 min ischemia (563.1+/-76.6 vs 551.8+/-71.3 ml/100 ml). Plasma level of glibenclamide reached the peak value of 1.295+/-0.15 micromol/l 2 h after drug administration, ranging around the 1 micromol/l concentration in the following 3 hours. Our findings produce indirect evidence that, similarly to the ischemic preconditioning of the heart, the protective effects towards ischemia of brief repeated episodes of sub-maximal occlusion in the peripheral circulation of the lower limbs in humans are mediated by ATP-dependent K(+) channels.