Direct vascular actions of hydrochlorothiazide and indapamide in isolated small vessels.
The mechanism by which thiazides lower peripheral resistance is unresolved. The aim of this study was to investigate the mechanisms of the acute vasodilator action of hydrochlorothiazide and the 'thiazide-like' diuretic indapamide on human, guinea pig and rat small arteries. Vessels were mounted on a myograph and the relaxation profile of both drugs and interactions with K+ channels and the vascular eicosanoid system were studied. Neither drug had any relaxant effect in rat mesenteric vessels and indapamide did not relax human arteries. Hydrochlorothiazide in both human and guinea pig vessels produced significantly more relaxation of noradrenaline than K(+)-constricted vessels (P less than 0.001). Relaxation to hydrochlorothiazide was reduced in the presence of charybdotoxin. Maximal-induced hydrochlorothiazide relaxation was reduced by 64% in human arteries (P less than 0.001) and by 91% in guinea pig vessels (P less than 0.001). Incubation with glibenclamide and indomethacin had no effect on the relaxant activity of hydrochlorothiazide and indapamide. Indapamide-induced relaxation was unaffected in the presence of charybdotoxin. These results show marked differences in the acute vasodilator action of hydrochlorothiazide and indapamide. There appears to be involvement of Ca(2+)-activated K+ channels in the acute vasorelaxant activity of hydrochlorothiazide.
Calder
J A
JA
Department of Clinical Pharmacology, St. Mary's Hospital, Imperial College of Science Technology and Medicine, London, UK.
Schachter
M
M
Sever
P S
PS
D000818:Animals; D001158:Arteries / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015777:Eicosanoids / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007190:Indapamide / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D012604:Scorpion Venoms / Q000494:pharmacology; D014118:Toxins, Biological / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D015777:Eicosanoids; D010455:Peptides; D015221:Potassium Channels; D012604:Scorpion Venoms; D014118:Toxins, Biological; D014665:Vasodilator Agents; D006852:Hydrochlorothiazide; C064719:iberiotoxin; D007190:Indapamide