High ouabain affinity α2 Na+ pumps are expressed in arterial smooth muscle (ASM). They help regulate blood pressure (BP) in several forms of hypertension, but their influence on basal BP is controversial. We determined basal BP (telemetry), and the effects of subcutaneous (sc) angiotensin II (Ang II) and dietary salt on BP in: 1) α2SM/Tg mice, which express an α2 transgene controlled by an α-actin smooth muscle (SM) promoter; 2) α2SM/DN mice, which express a truncated α2 gene, dominant negative for native α2 Na+ pumps, controlled by the SM myosin heavy chain promoter. Expression (immunoblots) of α2 was significantly up- and down-regulated in SM from α2SM/Tg and α2SM/DN mice, respectively.
Basal 24 hr mean BP (MBP) was reduced in α2SM/Tg mice: 103±1 (n=15) vs 110±2 mm Hg (n=9) in WT controls; P<0.01. Ang II, 400 ng/kg/min sc x 2 wks, increased MBP in both WT and transgenic mice (n=5 each; P<0.01), but the increase (Δ) was smaller in α2SM/Tg, Δ=20.3±3.3, than in WT mice, Δ=30.9±6.4 mm Hg . Also, a high (2% x 2 wks) NaCl diet, along with a sc 300 ng/kg/min (low dose) Ang II infusion, elevated systolic BP (SBP) in the WT mice (Δ=12.6±1.8 mm Hg; n=4; P<0.05), but not in the α2SM/Tg mice (Δ=7.2±2.0 mm Hg; n=9; NS=not significant).
In contrast, in α2SM/DN mice, basal SBP was elevated: 128±4 mm Hg (n=11) vs 109±4 mm Hg (n=10) in WT; P<0.01. Furthermore, both high NaCl (HS, 6% x 10 days), and low dose sc Ang II infusion (240 ng/kg/min x 8 days), individually induced significantly greater increases in MBP in α2SM/DN than in WT mice. In α2SM/DN mice, the HS diet raised MBP by Δ=6.8±0.7 mm Hg (n=5; P<0.01); Ang II elevated MBP by Δ=17.1±3.7 mm Hg (n=5; P<0.05). In WT mice, however, HS did not elevate MBP (Δ=2.6±1.4; n=5; NS), and Ang II elevated MBP by only Δ=6.9±4.0 mm Hg; n=5; P<0.05).
Conclusion: ASM α2 Na+ pumps help regulate basal BP and vascular reactivity. Reduced α2 expression raises basal BP and augments arterial responses to salt and Ang II; increased ASM α2 expression has the opposite effects. The α2 Na+ pumps co-localize with Na/Ca exchangers in plasma membrane (PM) microdomains at MP-sarcoplasmic reticulum junctions; they are a crucial link between circulating endogenous ouabain and the control of ASM Ca2+ homeostasis, arterial contraction and tone.