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ACTH-induced hypertension is dependent on the ouabain-binding site of the ₂-Na⁺-K⁺-ATPase subunit

¹Department of Molecular and Cellular Physiology and ²Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio

Submitted 20 February 2008 ; accepted in final form 8 May 2008

ACTH-induced-hypertension is commonly employed as a model of stress-related hypertension, and despite extensive investigation, the mechanisms underlying elevated blood pressure (BP) are not well understood. We have reported that ACTH treatment increases tail-cuff systolic pressure in wild-type mice but not in mutant mice expressing ouabain-resistant ₂-Na⁺-K⁺-ATPase subunits (2^R/R mice). Since tail-cuff measurements involve restraint stress, the present study used telemetry to distinguish between an effect of ACTH on resting BP vs. an ACTH-enhanced stress response. We also sought to explore the mechanisms underlying ACTH-induced BP changes in mutant 2^R/R mice vs. wild-type mice (ouabain-sensitive ₂-Na⁺-K⁺-ATPase, 2^S/S mice). Baseline BP was not different between the two genotypes, but after 5 days of ACTH treatment, BP increased in 2^S/S (104.0 ± 2.6 to 117.7 ± 3.0 mmHg) but not in 2^R/R mice (108.2 ± 3.2 to 111.5 ± 4.0 mmHg). To test the hypothesis that ACTH hypertension is related to inhibition of ₂-Na⁺-K⁺-ATPase on vascular smooth muscle by endogenous cardiotonic steroids, we measured BP and regional blood flow. Results suggest a differential sensitivity of renal, mesenteric, and cerebral circulations to ACTH and that the response depends on the ouabain sensitivity of the ₂-Na⁺-K⁺-ATPase. Baseline cardiac performance was elevated in 2^S/S but not 2^R/R mice. Overall, the data establish that the ₂-Na⁺-K⁺-ATPase ouabain-binding site is of central importance in the development of ACTH-induced hypertension. The mechanism appears to be related to alterations in cardiac performance, and perhaps vascular tone in specific circulations, presumably caused by elevated levels of circulating cardiotonic steroids.

cardiac glycosides; telemetry; blood flow; vascular resistance; hemodynamics

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