Relaxation and decrease in [Ca2+]i by hydrochlorothiazide in guinea-pig isolated mesenteric arteries.
1. We examined the effect of the thiazide diuretic, hydrochlorothiazide, on on intracellular calcium concentration ([Ca2+]i) and tone in guinea-pig mesentery arteries. Vessels were mounted on a microvascular myograph and loaded with the Ca(2+)-sensitive fluorescent dye, Fura-2. 2. Hydrochlorothiazide caused relaxation of noradrenaline-precontracted arteries associated with a fall in [Ca2+]i. Preincubation of arteries with hydrochlorothiazide inhibited both contraction and rise in [Ca2+]i in response to noradrenaline. Hydrochlorothiazide did not affect tone and [Ca2+]i when this was elevated by a combination of depolarizing potassium solution and noradrenaline. 3. Hydrochlorothiazide-induced vasorelaxation and decrease of [Ca2+]i was abolished by charybdotoxin, a blocker of large conductance Ca(2+)-activated K channels. 4. The rise in [Ca2+]i elicited by caffeine in Ca(2+)-free physiological salt solution, and presumably reflecting Ca2+ release from intracellular stores, was not altered by preincubation with hydrochlorothiazide. 5. Under depolarizing conditions hydrochlorothiazide did not alter the relationship between the extracellular concentration of Ca2+ and [Ca2+]i; however, hydrochlorothiazide caused a small reduction in the contraction produced for a given rise in [Ca2+]i suggesting hydrochlorothiazide may cause a slight desensitization of the contractile machinery. 6. These findings suggest that hydrochlorothiazide opens Ca(2+)-activated K channels leading to hyperpolarization and consequent closing of voltage-operated calcium channels. The result of this is an impaired influx of extracellular Ca2+, a decrease in [Ca2+]i and vasorelaxation.
Pickkers
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Department of Clinical Pharmacology, St. Mary's Hospital Medical School, Imperial College of Science Technology and Medicine, London.
Hughes
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AD
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D018999:Charybdotoxin; D006168:Guinea Pigs; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D012604:Scorpion Venoms / Q000494:pharmacology
D015221:Potassium Channels; D012604:Scorpion Venoms; D006852:Hydrochlorothiazide; D018999:Charybdotoxin; D002110:Caffeine; D002118:Calcium; D009638:Norepinephrine