title: ACTH-induced hypertension is dependent on the ouabain-binding site of the alpha2-Na+-K+-ATPase subunit.
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.
authors.affiliation: Dept. of Molecular and Cellular Physiology, Univ. of Cincinnati College of Medicine, Cincinnati, OH 45267-0576, USA. john.lorenz@uc.edu
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Loreaux
authors.forename: Iva
authors.initials: I
authors.lastname: Dostanic-Larson
authors.forename: Valerie
authors.initials: V
authors.lastname: Lasko
authors.forename: J Renee
authors.initials: JR
authors.lastname: Schnetzer
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Paul
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone; D000450:Aldosterone / Q000097:blood; D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D018660:Blood Pressure Monitoring, Ambulatory; D002560:Cerebrovascular Circulation; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005838:Genotype; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D009154:Mutation; D009206:Myocardium / Q000201:enzymology*; D010042:Ouabain / Q000378:metabolism* / Q000494:pharmacology; D010641:Phenotype; D012039:Regional Blood Flow; D012079:Renal Circulation; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013152:Splanchnic Circulation; D013686:Telemetry; D013997:Time Factors; D014655:Vascular Resistance; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D016277:Ventricular Function, Left
chemical_list: D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D000450:Aldosterone; D010042:Ouabain; D000324:Adrenocorticotropic Hormone; C401838:Atp1a2 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase; D003345:Corticosterone