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 alpha(1)- or alpha(2)-isoform ( alpha(1sm+) or alpha(2sm+) mice) driven by the smooth muscle-specific alpha-actin promoter SMP8. Interestingly, both alpha-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 alpha-isoform protein was increased from 1.5-fold (alpha(1sm+) mice) to 7-fold (alpha(2sm+) mice). The increase in total NKA alpha- isoform protein was accompanied by a 2.5-fold increase in NKA activity in alpha(2sm+) gastric antrum. Immunocytochemistry of the alpha(1)- and alpha(2)-isoforms in alpha(2sm+) aortic smooth muscle cells indicated that alpha-isoform distributions were similar to those shown in wild-type cells. alpha(2sm+) Mice (high expression) were hypotensive ( 109.9 +/- 1.6 vs. 121.3 +/- 1.4 mmHg; n = 13 and 11, respectively), whereas alpha(1sm+) mice ( low expression) were normotensive ( 122.7 +/- 2.5 vs. 117.4 +/- 2.3; n = 11 or 12). alpha(2sm+) Aorta, but not alpha(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 alpha-isoforms. Increasing smooth muscle NKA decreases blood pressure and is dependent on the degree of increased alpha-isoform expression.