INCREASED EXPRESSION OF CA2-SENSITIVE K+ CHANNELS IN THE CEREBRAL MICROCIRCULATION OF GENETICALLY HYPERTENSIVE RATS - EVIDENCE FOR THEIR PROTECTION AGAINST CEREBRAL VASOSPASM()
Yp. Liu et al., INCREASED EXPRESSION OF CA2-SENSITIVE K+ CHANNELS IN THE CEREBRAL MICROCIRCULATION OF GENETICALLY HYPERTENSIVE RATS - EVIDENCE FOR THEIR PROTECTION AGAINST CEREBRAL VASOSPASM(), Circulation research, 82(6), 1998, pp. 729-737
The Ca2+-sensitive K+ channel (K-Ca channel) plays a key role in buffe
ring pressure-induced constriction of small cerebral arteries. An ampl
ified current through this channel has been reported in vascular smoot
h muscle cells obtained from hypertensive animals, implying that the e
xpression or properties of K-Ca channels may be regulated by in vivo b
lood pressure levels. In this study, we investigated this hypothesis a
nd its functional relevance by comparing the properties, expression le
vels, and physiological role of K-Ca channels in cerebral resistance a
rteries from normotensive and genetically hypertensive rats, Whole-cel
l patch-clamp experiments revealed a 4.7-fold higher density of iberio
toxin-sensitive K-Ca channel current at physiological membrane potenti
als in spontaneously hypertensive rat (SHR) compared with Wistar-Kyoto
(WKY) rat cerebrovascular smooth muscle cells (n=18 and 21, respectiv
ely), However, additional single-channel analysis in detached patches
showed similar levels of unitary conductance, voltage, and Ca2+ sensit
ivity in K-Ca channels from WKY and from SHR membranes. In contrast, W
estern analysis using an antibody directed against the K-Ca channel al
pha-subunit revealed a 4.1-fold increase in the corresponding 125-kD i
mmunoreactive signal in cerebrovascular membranes from SHR compared wi
th WKY rats, The functional impact of this enhanced K-Ca channel expre
ssion was assessed in SHR and WKY rat pial arterioles, which were moni
tored by intravital microscopy through in situ cranial windows. Progre
ssive pharmacological block of K-Ca channels by iberiotoxin (0.1 to 10
0 nmol/L) dose-dependently constricted pial arterioles from SHR and WK
Y rats (n=6 to 8). The arterioles in SHR constricted 2- to 4-fold more
intensely, and vasospasm occurred in some vessels, These data provide
the first direct evidence that elevated levels of in situ blood press
ure induce K-Ca channel expression in cerebrovascular smooth muscle me
mbranes, This homeostatic mechanism may critically regulate the restin
g tone of cerebral arterioles during chronic hypertension, Furthermore
, the overexpression of distinct K+ channel types during specific card
iovascular pathologies may provide for the upregulation of novel disea
se-specific membrane targets for vasodilator therapies.