Abstract
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 alpha(2)-Na(+)-K(+)-ATPase subunits (alpha2(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 alpha2(R/R) mice vs. wild-type mice (ouabain-sensitive alpha(2)-Na(+)-K(+)-ATPase, alpha2(S/S) mice). Baseline BP was not different between the two genotypes, but after 5 days of ACTH treatment, BP increased in alpha2(S/S) (104.0 +/- 2.6 to 117.7 +/- 3.0 mmHg) but not in alpha2(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 alpha(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 alpha(2)-Na(+)-K(+)-ATPase. Baseline cardiac performance was elevated in alpha2(S/S) but not alpha2(R/R) mice. Overall, the data establish that the alpha(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.