Lack of thiazide diuretic inhibition of agonist constriction of mouse mesenteric arterioles ex vivo
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The chronic reduction of arterial blood pressure by thiazide diuretics (TZD) in hypertensive patients is mediated through an extra-renal mechanism. It is widely held that this extra-renal mechanism is a direct TZD inhibition of vasoconstriction. This study tested whether the TZD, hydrochlorothiazide (HCTZ), inhibited agonist constriction of mesenteric arterioles ex vivo. Mice deficient in the kidney distal convoluted tubule Na+/Cl− cotransporter (NCC), i.e., the target of thiazide inhibition–mediated diuresis, and wild type (WT), were subjected to Na+-restricted diet. Mesenteric arterioles from NCC knockout and WT mice were then isolated, placed under constant pressure, and the inhibitory effects of HCTZ (100 μM) on phenylephrine constriction determined. HCTZ did not inhibit phenylephrine constriction of arterioles from NCC knockout and wild type (WT) mice subjected to Na+-restricted diet. This study suggests that future investigations to identify the extra-renal site of chronic TZD treatment should (1) focus on indirect inhibition of vascular constriction and (2) be determined under clinically relevant conditions. These conditions include chronic TZD at relevant concentrations in hypertensive animals.
KeywordsNa+/Cl− cotransporter (NCC) Hydrochlorothiazide (HCTZ) Mesentery Constriction Phenylephrine
We thank Glenn Doerman (University of Cincinnati) for the figure.
This study was financially supported by Merit Review 5 I01 BX001000-06 award from the Department of Veterans Affairs and funds from the Center on Genetics of Transport and Epithelial Biology at the University of Cincinnati, and US Renal Care Inc. (MS), R01 AG053585 from NIA, Jewish Heritage Fund for Excellence, and the Gheens Foundation (AJL), and a Professional Development Grant from the University of Cincinnati (RMR).
RMR and MS conceived of the research. RMR, AJL, and JEB designed the research and conducted the experiments. MS contributed the mouse model. RMR, AJL, and JEB analyzed data. RMR wrote the manuscript. All authors read and approved the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
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