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

Lorenz JN, Loreaux EL, Dostanic-Larson I, Lasko V, Schnetzer JR, Paul RJ, Lingrel JB. ACTH-induced hypertension is dependent on the ouabain-binding site of the 2-Na -K -ATPase subunit. Am J Physiol Heart Circ Physiol 295: H273–H280, 2008. First published May 16, 2008; doi:10.1152/ajpheart.00183.2008.—ACTH-inducedhypertension 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 ouabainresistant 2-Na -K -ATPase subunits ( 2 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 mice vs. wild-type mice (ouabain-sensitive 2-Na -K -ATPase, 2 mice). Baseline BP was not different between the two genotypes, but after 5 days of ACTH treatment, BP increased in 2 (104.0 2.6 to 117.7 3.0 mmHg) but not in 2 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 but not 2 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.