ACTH-induced hypertension is dependent on the ouabain-binding site of the alpha2-Na+-K+-ATPase subunit.
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.
Lorenz
John N
JN
Dept. of Molecular and Cellular Physiology, Univ. of Cincinnati College of Medicine, Cincinnati, OH 45267-0576, USA. john.lorenz@uc.edu
Loreaux
Elizabeth L
EL
Dostanic-Larson
Iva
I
Lasko
Valerie
V
Schnetzer
J Renee
JR
Paul
Richard J
RJ
Lingrel
Jerry B
JB
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
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