Ca. Maggi et al., EFFECT OF CROMAKALIM AND GLIBENCLAMIDE ON SPONTANEOUS AND EVOKED MOTILITY OF THE GUINEA-PIG ISOLATED RENAL PELVIS AND URETER, British Journal of Pharmacology, 111(3), 1994, pp. 687-694
1 We have investigated the effect of the potassium (K) channel opener,
cromakalim, on the spontaneous myogenic activity of the guinea-pig is
olated renal pelvis and on myogenic contractions evoked by direct elec
trical stimulation of, the guinea-pig isolated ureter. 2 In the presen
ce of Bay K 8644 (1 mu M), electrical stimulation of the guinea-pig ur
eter (10 Hz for 1 s, pulse width 5 ms, 60 V) produced regular tetrodot
oxin-(1 mu M) resistant phasic contractions which were suppressed by 3
mu M cromakalim. Glibenclamide (0.1-3 mu M), 4-aminopyridine (4-AP, 0
.1-2 mM) and tetraethylammonium (TEA, 1-10 mM) produced a concentratio
n-dependent inhibition of the effect of cromakalim with the rank order
of potency (EC(50) in parentheses): glibenclamide (0.64 mu M)> >4.AP
(1.11 mM) > TEA (6.6 mM), Apamin (0.1-0.3 mu M) was without effect. 3
Cromakalim (0.1-10 mu M) produced concentration-dependent inhibition a
nd suppression of spontaneous contractions of the guinea-pig isolated
renal pelvis and of evoked contractions of the ureter with ECS, values
of 0.71 and 0.47 mu M, respectively. 4 Glibenclamide (1 mu M) produce
d a rightward shift of the concentration-response curve to cromakalim
in both the renal pelvis and ureter, without producing depression of t
he maximal inhibitory effect. Glibenclamide did not affect the spontan
eous activity of the renal pelvis while it produced a slight enhanceme
nt (10-15% increase) of evoked contractions of the ureter. Glibenclami
de did not affect the inhibitory action of the adenylate cylase activa
tor, forskolin, in the renal pelvis or ureter. 5 In electrophysiologic
al experiments (sucrose gap), cromakalim (0.3 and 1 mu m) produced hyp
erpolarization of ureter smooth muscle. Cromakalim also produced a tra
nsient suppression of action potentials and accompanying phasic contra
ctions evoked by electrical stimulation. Before suppression of evoked
contractions, a shortening of action potential duration was observed c
oncomitant with the developing hyperpolarization produced by cromakali
m. A lower concentration (0.1 mu M) of cromakalim did not affect membr
ane potential but shortened action potential duration and reduced the
evoked contraction. 6 Glibenclamide (1 mu M) inhibited the hyperpolari
zing action of cromakalim and prevented its inhibitory action on evoke
d action potentials and contractions of the ureter. Glibenclamide also
produced a slight prolongation of action potential duration and incre
ased the amplitude and duration of the accompanying mechanical respons
e. 7 These findings demonstrate that activation of cromakalim- and gli
benclamide-sensitive K channels produces a powerful mechanism for regu
lation of pyeloureteral motility and suppression of latent pacemakers
of the ureter in guinea-pig. Glibenclamide-sensitive K channels take p
art in determining action potential shape and duration in the guinea-p
ig ureter.