Ion channel involvement in the acute vascular effects of thiazide diuretics and related compounds.
The involvement of calcium and potassium channels in mediating the vascular actions of hydrochlorothiazide, indapamide and cicletanine were investigated in guinea pig small vessels mounted on the Mulvany myograph. Hydrochlorothiazide (10 microM) and cicletanine (10 microM) were weak calcium antagonists shifting the calcium dose-response curve half a log unit to the right. Indapamide was a far more potent inhibitor, a 10 microM concentration shifting the calcium dose-response curve 3 log units to the right and reducing maximal calcium contraction by 72% (P < .001). Relaxations to hydrochlorothiazide and cicletanine were reduced in the presence of charybdotoxin, a blocker of calcium-activated potassium channels (KCa). Maximal relaxation induced by hydrochlorothiazide (30 microM) was reduced by 91% and cicletanine-induced relaxation by 63%. In the presence of iberiotoxin, a more selective KCa inhibitor, maximal hydrochlorothiazide and cicletanine-induced relaxations were reduced by 73 and 60%, respectively. Neither drug's action was affected by incubation with glibenclamide, which inhibits ATP-sensitive K+ channels. Incubation with glibenclamide, charybdotoxin or iberiotoxin had no effect on the indapamide-induced relaxation. These results show differences in the involvement of ion channels in the acute vasorelaxation produced by these drugs. Hydrochlorothiazide and cicletanine-induced relaxations appear to be mediated via KCa, whereas indapamide is a potent calcium antagonist.
Calder
J A
JA
Department of Clinical Pharmacology, St. Mary's Hospital Medical School, Imperial College of Science Technology and Medicine, London, England.
Schachter
M
M
Sever
P S
PS
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D018999:Charybdotoxin; D004232:Diuretics / Q000494:pharmacology; D004347:Drug Interactions; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007190:Indapamide / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D012604:Scorpion Venoms / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects*
D015220:Calcium Channels; D004232:Diuretics; D010455:Peptides; D015221:Potassium Channels; D011725:Pyridines; D012604:Scorpion Venoms; D006852:Hydrochlorothiazide; D018999:Charybdotoxin; C064719:iberiotoxin; C038068:cicletanine; D007190:Indapamide; D005905:Glyburide