Relaxant Effects of the Potassium Channel Activators BRL 38227 and Pinacidil on Guinea-pig and Human Airway Smooth Muscle, and Blockade of Their Effects by Glibenclamide and BRL 31660
✍ Scribed by D.R. Buckle; J.R.S. Arch; N.E. Bowring; K.A. Foster; J.F. Taylor; S.G. Taylor; D.J. Shaw
- Publisher
- Elsevier
- Year
- 1993
- Tongue
- English
- Weight
- 525 KB
- Volume
- 6
- Category
- Article
- ISSN
- 0952-0600
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✦ Synopsis
SUMMARY: The airways relaxant effects and mechanism of action of the potassium channel activators BRL 38227 and pinacidil have been compared in guinea-pig and human airways. BRL 38227 was a potent relaxant in guinea-pig isolated trachealis ( (\mathrm{IC}{50}=4.9 \times 10^{-7} \mathrm{M}) against spontaneous tone) and human isolated bronchi (\left(\mathrm{IC}{50}=4.75 \times 10^{-7} \mathrm{M}\right.) against histamine-induced tone) and was eight- and six-fold more potent respectively than pinacidil. The relaxant effects of both compounds were shown to be markedly attenuated by glibenclamide (\left(10^{-5} \mathrm{M}\right)) and BRL (31660\left(10^{-5} \mathrm{M}\right)), with the nature of the blockade being species/tissue dependent. Glibenclamide ((20 \mathrm{mg} / \mathrm{kg}) iv) also inhibited the protective effects of BRL (38227(50 \mu \mathrm{g} / \mathrm{kg}) iv) and pinacidil ( (500 \mu \mathrm{g} / \mathrm{kg}) iv) on histamine-induced changes in airways resistance and dynamic compliance in the anaesthetized guinea-pig, although the effects were short-lived. That both BRL 38227 and pinacidil owed their relaxant effects to potassium channel activation was supported by their ability to stimulate ({ }^{42 / 43} \mathrm{~K}) efflux from guinea-pig trachealis preloaded with the radiotracer at concentrations of (10^{-7}-10^{-5} \mathrm{M}) and (10^{-5} \mathrm{M}) respectively. Pretreatment with either glibenclamide (\left(10^{-5} \mathrm{M}\right)) or BRL (31660\left(10^{-5} \mathrm{M}\right)) ablated the response to both compounds. These studies show that two mechanistically distinct potassium channel blockers, glibenclamide and BRL 31660, do not substantially differentiate between the actions of BRL 38227 and pinacidil, although differences do occur, particularly at high concentrations in vitro.