Ja. Calder et al., ION-CHANNEL INVOLVEMENT IN THE ACUTE VASCULAR EFFECTS OF THIAZIDE DIURETICS AND RELATED-COMPOUNDS, The Journal of pharmacology and experimental therapeutics, 265(3), 1993, pp. 1175-1180
The involvement of calcium and potassium channels in mediating the vas
cular actions of hydrochlorothiazide, indapamide and cicletanine were
investigated in guinea pig small vessels mounted on the Mulvany myogra
ph. Hydrochlorothiazide (10 muM) and cicletanine (10 muM) were weak ca
lcium antagonists shifting the calcium dose-response curve half a log
unit to the right. Indapamide was a far more potent inhibitor, a 10 mu
M concentration shifting the calcium dose-response curve 3 log units t
o the right and reducing maximal calcium contraction by 72% (P < .001)
. Relaxations to hydrochlorothiazide and cicletanine were reduced in t
he presence of charybdotoxin, a blocker of calcium-activated potassium
channels (K(Ca)). Maximal relaxation induced by hydrochlorothiazide (
30 muM) was reduced by 91% and cicletanine-induced relaxation by 63%.
In the presence of iberiotoxin, a more selective K(Ca) inhibitor, maxi
mal hydrochlorothiazide and cicletanine-induced relaxations were reduc
ed by 73 and 60%, respectively. Neither drug's action was affected by
incubation with glibenclamide, which inhibits ATP-sensitive K+ channel
s. Incubation with glibenclamide, charybdotoxin or iberiotoxin had no
effect on the indapamide-induced relaxation. These results show differ
ences in the involvement of ion channels in the acute vasorelaxation p
roduced by these drugs. Hydrochlorothiazide and cicletanine-induced re
laxations appear to be mediated via K(Ca), whereas indapamide is a pot
ent calcium antagonist.