Inhibition of Carbonic Anhydrase Accounts for the Direct Vascular Effects of Hydrochlorothiazide

Author:

Pickkers Peter1,Garcha Robinder S.1,Schachter Michael1,Smits Paul1,Hughes Alun D.1

Affiliation:

1. From the Department of Pharmacology, University Hospital Nijmegen, Nijmegen, Netherlands (P.P., P.S.), and Department of Clinical Pharmacology, National Heart and Lung Institute, Queen Elizabeth the Queen Mother Wing, St. Mary’s Hospital, Imperial College of Science, Technology, and Medicine, London, UK (R.S.G., M.S., A.D.H.).

Abstract

Abstract —Hydrochlorothiazide has been shown to exert direct vasodilator effects by activation of calcium-activated potassium (K Ca ) channels in human and guinea pig isolated resistance arteries. Since hydrochlorothiazide binds to and inhibits the enzyme carbonic anhydrase and because K Ca channel activation is pH sensitive, we investigated the role of intracellular and extracellular carbonic anhydrase in the vascular effects of thiazide diuretics. Small arteries were isolated from guinea pig mesentery and studied by use of a microvascular myograph technique. In some experiments, tone and intracellular pH (pH i ) were measured simultaneously with 2′,7′-bis(2-carboxyethyl)-5(6)′-carboxyfluorescein (BCECF- am) . Bendroflumethiazide, a thiazide diuretic with minimal inhibitory effects on carbonic anhydrase, had little effect on noradrenaline-induced tone (16±8% relaxation) compared with hydrochlorothiazide (74±12% relaxation). In contrast to hydrochlorothiazide, the action of bendroflumethiazide was unaffected by 100 nmol/L charybdotoxin, a selective blocker of K Ca channels. All inhibitors of carbonic anhydrase relaxed noradrenaline-induced tone in a concentration-dependent manner, and this effect was blocked by charybdotoxin. Hydrochlorothiazide and the inhibitors of carbonic anhydrase failed to relax tone induced by a depolarizing potassium solution. Acetazolamide and hydrochlorothiazide increased pH i by 0.27±0.07 and 0.21±0.04, respectively, whereas bendroflumethiazide had a much smaller effect: 0.06±0.03. The rise in pH i induced by any agent was not inhibited by charybdotoxin. The vasorelaxant effect of hydrochlorothiazide is shared by other inhibitors of carbonic anhydrase. Inhibitors of carbonic anhydrase, but not bendroflumethiazide, cause intracellular alkalinization, which is associated with K Ca channel opening. These data suggest that the vasodilator effect of thiazide diuretics results primarily from inhibition of vascular smooth muscle cell carbonic anhydrase, which results in a rise in pH I , leading to K Ca channel activation and vasorelaxation.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

Reference40 articles.

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2. Potassium Channel Opening Properties of Thiazide Diuretics in Isolated Guinea Pig Resistance Arteries

3. Siegel G Schnalke F Schultz G Stock G. K + channel opening and vascular tone. In: Mulvany MJ Aalkjær C Heagerty AM Nyborg NCB Standgaard S eds. Resistance Arteries Structure and Function . Amsterdam Netherlands: Elsevier; 1991:130–139.

4. Relaxation and decrease in [Ca2+]i by hydrochlorothiazide in guinea-pig isolated mesenteric arteries

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