Guanosine-3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (cGMP-PK) plays a central role in the mediation of the vasodilator response to nitric oxide (NO) and other nitrovasodilators. It is unclear whether cGMP-PK affects calcium-activated potassium channels (KCa channels) or any other type of ion channel in smooth muscle. We provide here the first direct evidence that cGMP-PK can activate KCa channels in arterial smooth muscle cells. We demonstrate that NO and a membrane-permeable analogue of cGMP can activate KCa channels in on-cell patches approximately twofold. Furthermore, cGMP-PK, in the presence of ATP and cGMP added directly to the intracellular surface of inside-out patches, increases channel activity by approximately eightfold. These results suggest that cGMP-PK-mediated activation of KCa channels may contribute to the actions of NO and other nitrovasodilators.
Platelet-activating factor (PAF) inhibits single inwardly rectifying
K+ channels in guinea-pig ventricular cells. There
is currently little information as to the mechanism by which these
channels are modulated. The effect of PAF on quasi steady-state
inwardly rectifying K+ currents (presumably of the
IK1 type) of auricular, atrial and ventricular cardiomyocytes from
guinea-pig were studied. Applying the patch-clamp technique in the
whole-cell configuration, PAF (10 nM) reduced the K+
currents in all three cell types. The inhibitory effect of PAF
occurred within seconds and was reversible upon wash-out. It was
almost completely abolished by the PAF receptor antagonist BN 50730.
Intracellular infusion of atrial cells with guanine
5′-(β-thio)diphosphate (GDPS) or pretreatment of cells
with pertussis toxin abolished the PAF dependent reduction of the
currents. Neither extracellularly applied isoproterenol nor
intracellularly applied adenosine 3′,5′-cyclic
monophosphate (cyclic AMP) attenuated the PAF effect. In
multicellular preparations of auricles, PAF (10 nM) induced
arrhythmias. The arrhythmogenic activity was also reduced by BN
50730. The data indicate that activated PAF receptors inhibit
inwardly rectifying K+ currents via a pertussis
toxin sensitive G-protein without involvement of a cyclic
AMP-dependent step. Since IK1 is a major component in
stabilizing the resting membrane potential, the observed inhibition
of this type of channel could play an important role in PAF
dependent arrhythmogenesis in guinea-pig heart.
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