title: Transgenic mice expressing Na+-K+-ATPase in smooth muscle decreases blood pressure.
abstract: 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(1 sm+) or alpha(2 sm+) 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(1 sm+) mice) to 7-fold (alpha(2 sm+) mice). The increase in total NKA alpha-isoform protein was accompanied by a 2.5-fold increase in NKA activity in alpha(2 sm+) gastric antrum. Immunocytochemistry of the alpha(1)- and alpha(2)-isoforms in alpha(2 sm+) aortic smooth muscle cells indicated that alpha-isoform distributions were similar to those shown in wild-type cells. alpha(2 sm+) Mice (high expression) were hypotensive (109.9 +/- 1.6 vs. 121.3 +/- 1.4 mmHg; n = 13 and 11, respectively), whereas alpha(1 sm+) mice (low expression) were normotensive (122.7 +/- 2.5 vs. 117.4 +/- 2.3; n = 11 or 12). alpha(2 sm+) Aorta, but not alpha(1 sm+) 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.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0576, USA.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Pritchard
authors.forename: Michelle
authors.initials: M
authors.lastname: Parvatiyar
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Bullard
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Lynch
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Paul
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007022:Hypotension / Q000201:enzymology* / Q000503:physiopathology; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D010042:Ouabain / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011706:Pyloric Antrum / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000199:Actins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D010042:Ouabain; D011189:Potassium Chloride; C499075:Atp1a1 protein, rat; C498532:Atp1a2 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase