Mode of action of cyclothiazide and triamterene. Ex vivo effect on 22Na and 86Rb efflux from arterial smooth muscle

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

“…A recent study has shown that hydrochlorothiazide increased 86Rb+ efflux, a marker of K+ efflux, from guinea-pig mesenteric arteries (Calder et al, 1994). A similar effect has also been seen using another thiazide drug, cyclothiazide, in tail artery smooth muscle (Moura & Worcel, 1983). Both these findings are consistent with the notion that thiazides increase the permeability of smooth muscle membranes to K+, probably by opening KCa.…”

How do thiazide and thiazide-like diuretics lower blood pressure?

“…The authors' proposal that thiazides act via K + channels is consistent with an earlier report of increased (86Rb) efflux from ex vivo tail artery following in vivo treatment of normal and nephrectomised rats with cyclothiazide. 86 The ability of hydrochlorothiazide to reduce intracellular Ca 2+ and tone in noradrenaline-contracted guinea-pig mesenteric arteries was also attributed to K Ca opening. [87][88][89] Further studies 90 showed that the relaxant effects of hydrochlorothiazide were not shared by bendroflumethiazide, but that inhibitors of carbonic anhydrase also relaxed guinea-pig mesenteric arteries via opening K Ca and both hydrochlorothiazide and acetazolamide increased intracellular pH (pH i ).…”

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

“…This vasorelaxant response to hydrochlorothiazide was abolished by charybdotoxin and iberiotoxin, both selective blockers of large-conductance Ca 2ϩ -activated potassium (K Ca ) channels, but not by inhibitors of other vascular K ϩ channels. 2 On the basis of the fact that thiazide-like drugs such as cicletanine and diazoxide lead to hyperpolarization in vascular smooth muscle cells 3 and the fact that hydrochlorothiazide increases 86 Rb efflux as a marker of K ϩ efflux, 2,4 it was proposed that hydrochlorothiazide opens K Ca channels, thereby leading to K ϩ efflux and membrane hyperpolarization. The resultant closure of voltage-dependent Ca 2ϩ channels leads to a fall in [Ca 2ϩ ] i and vasorelaxation.…”