ION-CHANNEL INVOLVEMENT IN THE ACUTE VASCULAR EFFECTS OF THIAZIDE DIURETICS AND RELATED-COMPOUNDS

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.