title: An activated renin-angiotensin system maintains normal blood pressure in aryl hydrocarbon receptor heterozygous mice but not in null mice.
abstract: It has been postulated that fetal vascular abnormalities in aryl hydrocarbon receptor null (ahr(-/-)) mice may alter cardiovascular homeostasis in adulthood. We tested the hypothesis that blood pressure regulation in adult heterozygous mice (ahr(+/-)) would be normal, compared to ahr(-/-) mice, since no vascular abnormalities have been reported in the heterozygote animals. Mean arterial blood pressure (MAP) was measured using radiotelemetry prior to and during treatment with inhibitors of the autonomic nervous system, nitric oxide synthase (NOS), angiotensin converting enzyme (ACE), or endothelin-1 A receptor (ET(A)). Also, indices of renin-angiotensin system (RAS) activation were measured. ahr(+/-) and ahr(-/-) mice were normotensive and hypotensive, respectively, compared to wild-type (ahr(+/+)) littermates. Responses of all genotypes to autonomic nervous system inhibition were normal. ahr(+/-) mice responded normally to NOS inhibition, while the responses of ahr(-/-) mice were significantly blunted. In contrast, ahr(+/-) mice were significantly more responsive to inhibition of ACE, an ET(A) antagonist, or both, while ahr(-/-) mice were significantly less responsive to ACE inhibition and more responsive to an ET(A) antagonist. ahr(+/-) mice also exhibited significant increases in plasma renin and ACE activity, plasma sodium, and urine osmolality, indicative of RAS activation. Thus, normotension in ahr(+/-) mice appears to be maintained by increased RAS and ET-1 signaling, while hypotension in ahr(-/-) mice may result from decreased RAS signaling. In conclusion, despite the lack of overt fetal vascular abnormalities in ahr(+/-) mice, the loss of a single ahr allele has a significant effect on blood pressure regulation.
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, 87131, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Larry N
authors.initials: LN
authors.lastname: Agbor
authors.forename: Jason A
authors.initials: JA
authors.lastname: Scott
authors.forename: Tyler
authors.initials: T
authors.lastname: Zalobowski
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Elased
authors.forename: Alicia
authors.initials: A
authors.lastname: Trujillo
authors.forename: Melissa Skelton
authors.initials: MS
authors.lastname: Duke
authors.forename: Valerie
authors.initials: V
authors.lastname: Wolf
authors.forename: Mary T
authors.initials: MT
authors.lastname: Walsh
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Born
authors.forename: Linda A
authors.initials: LA
authors.lastname: Felton
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Kanagy
authors.forename: Mary K
authors.initials: MK
authors.lastname: Walker
mesh_terms: D000804:Angiotensin II / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology*; D004149:Dioxoles / Q000494:pharmacology; D065130:Endothelin A Receptor Antagonists; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006579:Heterozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000502:physiology*; D013686:Telemetry
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004149:Dioxoles; D065130:Endothelin A Receptor Antagonists; C093322:PD 155080; D044022:Receptor, Endothelin A; D018336:Receptors, Aryl Hydrocarbon; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D007703:Peptidyl-Dipeptidase A