Mechanistic Interactions Between Potassium Channel Openers, U-37883A and Glyburide in Vascular Smooth Muscle
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Authors
Ohrnberger, Corinna
Issue Date
1991
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
The vascular pharmacology of ATP-sensitive potassium channels
([K+] ATP) was studied in isolated rabbit mesenteric artery (RMA) using
[K+] ATP channel blockers, U-37883A and glyburide against potassium
channel openers (PCas) pinacidil (1µ M), minoxidil sulfate (5µ M),
cromakalim (0.5µM) and RP-49356 (1µM). Time courses for each PCO
induced relaxation in norepinephrine (NE) precontracted RMA were found
to be very similar. Each PCO induced immediate relaxation. Within 15
minutes, the tissue reached approximately 80% relaxation. Pretreatment
of RMA for 75 minutes with U-37883A (0.1µM to 10.µM) caused a
dose-dependent inhibition of PCO relaxation time course. Using the data
for PCO relaxation at t = 15 minutes, it was found that the, U-37883A
IC 50 (concentration of U-37883A to produce 50% of maximum inhibition
of PCO relaxation) for pinacidil was about 780nM; for minoxidil sulfate
was about 840nM; for cromakalim was about 1400nM; and for
RP-49356 was about 1000nM, with maximum inhibition occurring at
5µM to 7.5µM. This is the first report to establish the inhibition
dose-response curves for U-37883A against four PCOs. Comparison
with glyburide induced inhibition dose response curves against the same
PCOs shows that U-37883A is ten times less potent than glyburide.
Subsequent experiments investigated the effects of various pre- and
post-treatments of U-37883A (5µM) on 1µM pinacidil-induced relaxation
in NE precontracted RMA. The onset of U-37883A [K+] ATP channel
inhibiting effects occurred approximately 3 minutes after U-37883A
administration. Full reversal of relaxation occurred in 15 minutes. The
rate of action of U-37883A was much faster than glyburide. When
glyburide (0.05µM) was added to the U-37883A pretreatment, the
potency of the K+ channel blockers was increased eight times. Glyburide
potentiated the effect of U-37883A on minoxidil sulfate and cromakalim,
also, but had no effect on Ca2+ antagonist, D600. The combined effect
of U-37883A and glyburide was observed only when PCOs !were used as
the vasodilators. These data were interpreted to suggest that PCO induced relaxation occurred via the converging pathways mechanism.
[K+] ATP channel blockade by U-37883A and glyburide may occur at
different sites on a [K+] ATP channel associated protein, essential to
channel function.
In summary, the result of this study should provide a basis for further
experimental understanding of the characteristics of U-37883A, the
mechanism of PCO-induced relaxation of smooth muscle via [K+] ATP
channels and the mechanism of [K+] ATP channel blockade by [K+] ATP
antagonists, U-37883A and glyburide.
Description
vii, 57 p.
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