Abstract
Thiazide derivatives including Hydrochlorothiazide (HCTZ) represent the most common treatment of mild to moderate hypertension. Thiazides initially enhance diuresis via inhibition of the kidney Na+-Cl- Cotransporter (NCC). However, chronic volume depletion and diuresis are minimal while lowered blood pressure (BP) is maintained on thiazides. Thus, a vasodilator action of thiazides is proposed, likely via Ca2+-activated K+ (BK) channels in vascular smooth muscles. This study ascertains the role of volume depletion induced by salt restriction or salt wasting in NCC KO mice on the non-diuretic hypotensive action of HCTZ. HCTZ (20mg/kg s.c.) lowered BP in 1) NCC KO on a salt restricted diet but not with normal diet; 2) in volume depleted but not in volume resuscitated pendrin/NCC dKO mice; the BP reduction occurs without any enhancement in salt excretion or reduction in cardiac output. HCTZ still lowered BP following treatment of NCC KO on salt restricted diet with paxilline (8 mg/kg, i.p.), a BK channel blocker, and in BK KO and BK/NCC dKO mice on salt restricted diet. In aortic rings from NCC KO mice on normal and low salt diet, HCTZ did not alter and minimally decreased maximal phenylephrine contraction, respectively, while contractile sensitivity remained unchanged. These results demonstrate 1) the non-diuretic hypotensive effects of thiazides are augmented with volume depletion and 2) that the BP reduction is likely the result of HCTZ inhibition of vasoconstriction through a pathway dependent on factors present in vivo, is unrelated to BK channel activation, and involves processes associated with intravascular volume depletion.
Highlights
Thiazide derivatives are the most commonly used diuretics for the treatment of mild and moderate hypertension [1]
Thiazides lowers blood pressure during volume depletion potent diuretics, which implies the non-diuretic mechanisms, there are no in vivo studies distinguishing between diuretic and non-diuretic hypotensive effects of HCTZ
The uncertainty about HCTZ hypotensive mechanisms is likely due to 1) both mechanisms may be operating simultaneously and 2) the paucity of knowledge of pathophysiological circumstances that determine by which mechanism HCTZ reduces the blood pressure (BP)
Summary
Thiazide derivatives are the most commonly used diuretics for the treatment of mild and moderate hypertension [1]. Distinguishing the non-diuretic mechanism of thiazides vs their natriuretic (renal) effect in humans or experimental animals, while very important, is complicated by the fact that both mechanisms may be operating simultaneously, hindering a clear distinction between the two anti-hypertensive modalities. These studies aimed to examine the non-diuretic, BP lowering action of HCTZ, utilizing an in vivo system, which is lacking the renal target, NCC, and volume depletion due to salt wasting or salt restriction
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