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

¹Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and ²Department of Physiology, University of Arizona Health Sciences Center, Tucson, Arizona

Submitted 6 March 2007 ; accepted in final form 25 April 2007

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 ₁- or ₂-isoform (_1sm+ or _2sm+ mice) driven by the smooth muscle-specific -actin promoter SMP8. Interestingly, both -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 -isoform protein was increased from 1.5-fold (_1sm+ mice) to 7-fold (_2sm+ mice). The increase in total NKA -isoform protein was accompanied by a 2.5-fold increase in NKA activity in _2sm+ gastric antrum. Immunocytochemistry of the ₁- and ₂-isoforms in _2sm+ aortic smooth muscle cells indicated that -isoform distributions were similar to those shown in wild-type cells. _2sm+ Mice (high expression) were hypotensive (109.9 ± 1.6 vs. 121.3 ± 1.4 mmHg; n = 13 and 11, respectively), whereas _1sm+ mice (low expression) were normotensive (122.7 ± 2.5 vs. 117.4 ± 2.3; n = 11 or 12). _2sm+ Aorta, but not _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 -isoforms. Increasing smooth muscle NKA decreases blood pressure and is dependent on the degree of increased -isoform expression.

vascular contractility; hypertension; Na⁺-K⁺-ATPase -isoforms

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