Possible protein binding displacement interaction between glibenclamide and metolazone

George, S; McBurney, A; Cole, A. F. D.

doi:10.1007/bf00314813

Cited by 6 publications

(2 citation statements)

References 8 publications

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“…The current dose of 5 mg/kg for rats of a mean body mass of 366 g equates to a blood concentration of ϳ140 mol/l. Given that 98 -99% of GLI is bound to plasma protein, the effective blood concentration of GLI is ϳ2-3 mol/l (19), which is in the range for GLI to be selective for K ATP channels without possible inhibition of Ca ϩ channel current (41). This dosing strategy, based on SMC investigations, has been shown to elicit a degree of KATP channel blockade for swine in vivo (60 -70%) (16).…”

Section: Methodsmentioning

confidence: 97%

Acute inhibition of ATP-sensitive K⁺ channels impairs skeletal muscle vascular control in rats during treadmill exercise

Holdsworth

Copp

Ferguson

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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The ATP-sensitive K(+) (KATP) channel is part of a class of inward rectifier K(+) channels that can link local O2 availability to vasomotor tone across exercise-induced metabolic transients. The present investigation tested the hypothesis that if KATP channels are crucial to exercise hyperemia, then inhibition via glibenclamide (GLI) would lower hindlimb skeletal muscle blood flow (BF) and vascular conductance during treadmill exercise. In 27 adult male Sprague-Dawley rats, mean arterial pressure, blood lactate concentration, and hindlimb muscle BF (radiolabeled microspheres) were determined at rest (n = 6) and during exercise (n = 6-8, 20, 40, and 60 m/min, 5% incline, i.e., ~60-100% maximal O2 uptake) under control and GLI conditions (5 mg/kg intra-arterial). At rest and during exercise, mean arterial pressure was higher (rest: 17 ± 3%, 20 m/min: 5 ± 1%, 40 m/min: 5 ± 2%, and 60 m/min: 5 ± 1%, P < 0.05) with GLI. Hindlimb muscle BF (20 m/min: 16 ± 7%, 40 m/min: 30 ± 9%, and 60 m/min: 20 ± 8%) and vascular conductance (20 m/min: 20 ± 7%, 40 m/min: 33 ± 8%, and 60 m/min: 24 ± 8%) were lower with GLI during exercise at 20, 40, and 60 m/min, respectively (P < 0.05 for all) but not at rest. Within locomotory muscles, there was a greater fractional reduction present in muscles comprised predominantly of type I and type IIa fibers at all exercise speeds (P < 0.05). Additionally, blood lactate concentration was 106 ± 29% and 44 ± 15% higher during exercise with GLI at 20 and 40 m/min, respectively (P < 0.05). That KATP channel inhibition reduces hindlimb muscle BF during exercise in rats supports the obligatory contribution of KATP channels in large muscle mass exercise-induced hyperemia.

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Section: Methodsmentioning

confidence: 97%

Acute inhibition of ATP-sensitive K⁺ channels impairs skeletal muscle vascular control in rats during treadmill exercise

Holdsworth

Copp

Ferguson

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…In 30-kg pigs, this dose corresponds to 90 mg in ϳ2 liters of circulating blood volume, i.e., 90 mol/l (M w ϭ 494). However, 98-99% of glibenclamide is bound to plasma proteins (12), so that the concentration of free glibenclamide is in the range of 1-2 M. These concentrations are well within the range where glibenclamide is selective for K ATP ϩ channels (2,26). Moreover, we observed that glibenclamide attenuated the bimakalim-mediated vasodilation without blunting the sodium nitroprusside-mediated vasodilation, indicating that glibenclamide in a dose of 3 mg/kg iv selectively inhibited K ATP ϩ channels without nonspecifically blunting vascular smooth muscle relaxation.…”

Section: Methodological Considerationsmentioning

confidence: 99%

Role of K_ATP ⁺ channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine

Duncker

Oei

et al. 2001

American Journal of Physiology-Heart and Circulatory Physiology

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The role of ATP-sensitive K(+) (K(ATP)(+)) channels in vasomotor tone regulation during metabolic stimulation is incompletely understood. Consequently, we studied the contribution of K(ATP)(+) channels to vasomotor tone regulation in the systemic, pulmonary, and coronary vascular bed in nine treadmill-exercising swine. Exercise up to 85% of maximum heart rate increased body O(2) consumption fourfold, accommodated by a doubling of both cardiac output and body O(2) extraction. Mean aortic pressure was unchanged, implying that systemic vascular conductance (SVC) also doubled, whereas pulmonary artery pressure increased almost in parallel with cardiac output, so that pulmonary vascular conductance (PVC) increased only 25 +/- 9% (both P < 0.05). Myocardial O(2) consumption tripled during exercise, which was paralleled by an equivalent increase in O(2) supply so that coronary venous PO(2) was maintained. Selective K(ATP)(+) channel blockade with glibenclamide (3 mg/kg iv), decreased SVC by 29 +/- 4% at rest and by 10 +/- 2% at 5 km/h (both P < 0.05), whereas PVC was unchanged. Glibenclamide decreased coronary vascular conductance and hence myocardial O(2) delivery, necessitating an increase in O(2) extraction from 76 +/- 2% to 86 +/- 2% at rest and from 79 +/- 2% to 83 +/- 1% at 5 km/h. Consequently, coronary venous PO(2) decreased from 25 +/- 1 to 17 +/- 1 mmHg at rest and from 23 +/- 1 to 20 +/- 1 mmHg at 5 km/h (all values are P < 0.05). In conclusion, K(ATP)(+) channels dilate the systemic and coronary, but not the pulmonary, resistance vessels at rest and during exercise in swine. However, opening of K(ATP)(+) channels is not mandatory for the exercise-induced systemic and coronary vasodilation.

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Drug Interactions with Agents Used in the Treatment of Cardiovascular Disease

Griffin

D’Arcy²

1997

A Manual of Adverse Drug Interactions

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Possible protein binding displacement interaction between glibenclamide and metolazone

Cited by 6 publications

References 8 publications

Acute inhibition of ATP-sensitive K⁺ channels impairs skeletal muscle vascular control in rats during treadmill exercise

Acute inhibition of ATP-sensitive K⁺ channels impairs skeletal muscle vascular control in rats during treadmill exercise

Role of K_ATP ⁺ channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine

Drug Interactions with Agents Used in the Treatment of Cardiovascular Disease

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Possible protein binding displacement interaction between glibenclamide and metolazone

Cited by 6 publications

References 8 publications

Acute inhibition of ATP-sensitive K+ channels impairs skeletal muscle vascular control in rats during treadmill exercise

Acute inhibition of ATP-sensitive K+ channels impairs skeletal muscle vascular control in rats during treadmill exercise

Role of KATP + channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine

Drug Interactions with Agents Used in the Treatment of Cardiovascular Disease

Contact Info

Product

Resources

About

Acute inhibition of ATP-sensitive K⁺ channels impairs skeletal muscle vascular control in rats during treadmill exercise

Acute inhibition of ATP-sensitive K⁺ channels impairs skeletal muscle vascular control in rats during treadmill exercise

Role of K_ATP ⁺ channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine