Vasorelaxant actions of 5-OH-indapamide, a major metabolite of indapamide: comparison with indapamide, hydrochlorothiazide and cicletanine.
5-OH-Indapamide is a principal metabolite of indapamide, and possesses similar antihypertensive and diuretic properties. This study investigated the mechanisms of the acute vasodilator actions of 5-OH-indapamide, indapamide, hydrochlorothiazide and cicletanine and their interaction with ion channels in isolated guinea pig mesenteric arteries. Hydrochlorothiazide, cicletanine and 5-OH-indapamide relaxed noradrenaline-constricted vessels significantly more than K(+)-constricted vessels (P < 0.001) and the relaxations were reduced in the presence of charybdotoxin (P < 0.001). 5-OH-Indapamide-induced relaxation was reduced (by 42% at 30 microM) by glibenclamide (P < 0.001). Hydrochlorothiazide, cicletanine and 5-OH-indapamide (all at 10 microM) were weak Ca2+ antagonists shifting the Ca2+ dose-response curves half a log unit to the right (P < 0.01). Indapamide was a more potent inhibitor, a 10 microM concentration shifting the Ca2+ dose-response curve three log units to the right and reducing maximal-induced Ca2+ contraction by 72% (P < 0.001). Hydrochlorothiazide, cicletanine and 5-OH-indapamide-induced relaxations appear to be partly mediated via Ca(2+)-activated K+ channels; 5-OH-Indapamide-induced relaxation is also partly mediated via ATP-sensitive K+ channels. Indapamide is a potent Ca2+ antagonist.
Calder
J A
JA
Department of Clinical Pharmacology, St. Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, UK.
Schachter
M
M
Sever
P S
PS
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D004576:Electromyography; D004730:Endothelium, Vascular / Q000502:physiology; D006168:Guinea Pigs; D006852:Hydrochlorothiazide / Q000494:pharmacology; D066298:In Vitro Techniques; D007190:Indapamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D013152:Splanchnic Circulation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D015220:Calcium Channels; D015221:Potassium Channels; D011725:Pyridines; D014665:Vasodilator Agents; D006852:Hydrochlorothiazide; C064096:5-hydroxyindapamide; C038068:cicletanine; D007190:Indapamide; D011188:Potassium; D009638:Norepinephrine