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Effects of BRL55834 in rat portal vein and bovine trachea: evidence for the induction of a glibenclamide‐resistant, ATP‐sensitive potassium current
Author(s) -
Edwards G.,
Schneider J.,
NiedersteHollenberg A.,
Noack Th.,
Weston A.H.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15914.x
Subject(s) - trachealis muscle , charybdotoxin , glibenclamide , chemistry , potassium channel , apamin , tetraethylammonium , biophysics , patch clamp , iberiotoxin , potassium channel blocker , medicine , cromakalim , membrane potential , endocrinology , biochemistry , potassium , biology , receptor , organic chemistry , diabetes mellitus
1 The effects of the benzopyran K‐channel opener, BRL55834, on mechanical activity in bovine trachealis and rat portal vein were studied together with membrane currents in freshly‐isolated single cells derived from these tissues. 2 BRL55834 (3nM‐l μ m ) produced a concentration‐dependent relaxation of bovine trachealis precontracted with 100 μm histamine and reduced the spontaneous mechanical activity of rat portal veins, effects which were antagonized by glibenclamide (1–10 μ m ) but were not reversible on washing. In contrast, charybdotoxin (250 nM) did not modify the spasmolytic effect of BRL55834 in bovine trachealis. 3 BRL55834 (10 nM‐10 μ m ) did not relax segments of bovine trachealis precontracted with 80 mM KC1. 4 In some freshly‐isolated single cells from bovine trachealis held at −10 mV, BRL55834 (3 μ m ) induced a time‐independent outward K‐current which was partially resistant to inhibition by glibenclamide (10 μ m ). In other cells, a very noisy, outwardly‐rectifying and charybdotoxin‐sensitive current developed in the presence of BRL55834 (3 μ m ) and in time‐matched control cells. 5 In freshly‐isolated single cells from rat portal vein held at −10 mV, BRL55834 (3 μ m ) induced a time‐and calcium‐independent outward K‐current which was partially resistant (approximately 25% inhibition at +40 mV) to subsequent inhibition by glibenclamide (10 um). In contrast, levcromakalim induced a time‐independent outward K‐current which was completely inhibited by glibenclamide 10 μm. 6 With the non‐hydrolysable ATP analogue, AMP‐PCP (5 mM), in the pipette, the ability of BRL55834 to induce a time‐independent K‐current in portal vein cells was markedly reduced (approximately 80% inhibition at +40 mV) whereas the effects of 10 um levcromakalim were totally inhibited. 7 The glibenclamide‐resistant current component induced by BRL55834 was totally inhibited by phentolamine (100 μ m ), a concentration that had no effect on the peak current ( I BK(Ca) ) induced by NS1619 (33 μ m ). 8 Stationary fluctuation analysis of the noise associated with the glibenclamide‐insensitive K‐current induced by BRL55834 in rat portal vein cells indicated that the unitary current flowing through the underlying channels was 0.26 pA at −10 mV, a value inconsistent with the involvement of BK ca . 9 It is concluded that the relaxations of both bovine trachea and rat portal vein produced by BRL55834 are associated with the opening of K‐channels. These are probably identical to the ATP‐sensitive K‐channel opened by levcromakalim, although the involvement of an additional K‐channel cannot be excluded. The reduced sensitivity of the BRL55834‐induced changes to glibenclamide and to AMP‐PCP may result from avid binding of BRL55834 to its site of action.