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ACTH-induced hypertension is dependent on the ouabain-binding site of the alpha2-Na+-K+-ATPase subunit.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2008 Jul; Vol. 295 (1), pp. H273-80. Date of Electronic Publication: 2008 May 16. - Publication Year :
- 2008
-
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.
- Subjects :
- Adrenergic beta-Agonists pharmacology
Adrenocorticotropic Hormone
Aldosterone blood
Animals
Binding Sites
Blood Pressure Monitoring, Ambulatory
Cerebrovascular Circulation
Corticosterone blood
Disease Models, Animal
Drug Resistance
Enzyme Inhibitors pharmacology
Genotype
Hypertension chemically induced
Hypertension physiopathology
Hypertension prevention & control
Mice
Mice, Transgenic
Muscle, Smooth, Vascular drug effects
Muscle, Smooth, Vascular physiopathology
Mutation
Ouabain pharmacology
Phenotype
Regional Blood Flow
Renal Circulation
Sodium-Potassium-Exchanging ATPase antagonists & inhibitors
Sodium-Potassium-Exchanging ATPase genetics
Splanchnic Circulation
Telemetry
Time Factors
Vascular Resistance
Vasoconstrictor Agents pharmacology
Ventricular Function, Left
Blood Pressure drug effects
Enzyme Inhibitors metabolism
Hypertension enzymology
Muscle, Smooth, Vascular enzymology
Myocardium enzymology
Ouabain metabolism
Sodium-Potassium-Exchanging ATPase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0363-6135
- Volume :
- 295
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 18487447
- Full Text :
- https://doi.org/10.1152/ajpheart.00183.2008