Abstract Body: Background: Salt plays a major role in blood pressure homeostasis and the pathogenesis of arterial hypertension. While numerous mechanisms have been described by which Na⁺ can influence arterial blood pressure, the role of Cl^- in blood pressure regulation is still largely unexplored. The Na⁺-K⁺-2Cl^- cotransporter NKCC1 is an important Cl^- import pathway in vascular smooth muscle cells (VSMC). To investigate the role of NKCC1 in blood pressure regulation, we generated mice with an inducible VSMC-specific disruption of Slc12a2.
Methods: Mean arterial blood pressure and heart rate were measured by radiotelemetry in unrestrained mice lacking vascular NKCC1 (KO) and wildtype littermates (WT). Cardiac function was assessed by echocardiography. Plasma renin activity and aldosterone concentrations were quantified by radioimmunoassay. Protein expression of renal sodium transporters and channels was analyzed by Western blotting.
Results: Mean arterial blood pressure was markedly decreased in Nkcc1-deficient mice 6 weeks after induction of gene disruption (from 116±2 mm Hg to 103±4 mm Hg, n=18, p<0.001, 2-way ANOVA and Bonferroni post-test), while it did not change in WT control animals (n=17). Heart rate, stroke volume, fractional shortening, and ejection fraction remained unchanged compared to non-induced controls. We did not observe a compensatory increase in plasma renin activity or aldosterone levels, and the blood pressure response to ANG II receptor 1 antagonism by losartan treatment for 7 days was similar in both groups (ΔMAP KO -8.8±3.0 mm Hg, n=8, ΔMAP WT -12.4±1.9 mm Hg, n=7; p>0.05, 2-way ANOVA). In the kidney, the relative expression of total NCC (1.5-fold, n=7-8; p=<0.05, Student’s t-test) and pNCCThr53 (1.9-fold, n=7-8; p=<0.05, Student’s t-test) were modestly increased. The hypotensive effect of Nkcc1 disruption was maintained after induction of hypertension by either infusion of ANG II for 10 days (ΔMAP KO 43.8±6.5 mm Hg, n=6, ΔMAP WT 50.2±7.2 mm Hg, n=4; p>0.05, 2-way ANOVA) or a high salt diet for 10 days (ΔMAP KO 21.7±7.0 mm Hg, n=8, ΔMAP WT 34.0±7.3 mm Hg, n=5; p>0.05, 2-way ANOVA).
Conclusions: Our findings indicate that NKCC1 in vascular smooth muscle contributes significantly to the maintenance of arterial blood pressure. Inhibition of NKCC1 in VSMC may provide additional blood pressure reduction in resistant hypertension.