Transgenic mice expressing Na⁺-K⁺-ATPase in smooth muscle decreases blood pressure

The Na⁺-K⁺-ATPase (NKA) is a transmembrane protein that sets and maintains the electrochemical gradient by extruding three Na ⁺ in exchange for two K⁺. An important physiological role proposed for vascular smooth muscle NKA is the regulation of blood pressure via modulation of vascular smooth muscle contractility (5). To investigate the relations between the level of NKA in smooth muscle and blood pressure, we developed mice carrying a transgene for either the NKA α₁- or α₂-isoform (α_1sm+ or α_2sm+ mice) driven by the smooth muscle-specific α-actin promoter SMP8. Interestingly, both α-isoforms, the one contained in the transgene and the one not contained, were increased to a similar degree at both protein and mRNA levels. The total α-isoform protein was increased from 1.5-fold (α_1sm+ mice) to 7-fold (α_2sm+ mice). The increase in total NKA α-isoform protein was accompanied by a 2.5-fold increase in NKA activity in α_2sm+ gastric antrum. Immunocytochemistry of the α₁- and α₂-isoforms in α_2sm+ aortic smooth muscle cells indicated that α-isoform distributions were similar to those shown in wild-type cells. α_2sm+ Mice (high expression) were hypotensive (109.9 ± 1.6 vs. 121.3 ± 1.4 mmHg; n = 13 and 11, respectively), whereas α_1sm+ mice (low expression) were normotensive (122.7 ± 2.5 vs. 117.4 ± 2.3; n = 11 or 12). α_2sm+ Aorta, but not α_1sm+ aorta, relaxed faster from a KCl-induced contraction than wild-type aorta. Our results show that smooth muscle displays unique coordinate expression of the α-isoforms. Increasing smooth muscle NKA decreases blood pressure and is dependent on the degree of increased α-isoform expression.