Urocortin 2 lowers blood pressure and reduces plasma catecholamine levels in mice with hyperadrenergic activity.
Exaggerated adrenergic activity is associated with human hypertension. The peptide urocortin 2 (Ucn 2) inhibits catecholamine synthesis and secretion from adrenal chromaffin cells in vitro and administration to mammals lowers blood pressure (BP). The chromogranin A-null mouse (Chga-/-) manifests systemic hypertension because of excessive catecholamine secretion from the adrenal and decreased catecholamine storage. In the present study, we investigated whether systemic administration of Ucn 2 could reduce BP and adrenal and plasma levels of catecholamines in vivo. Ucn 2 peptide was administered to freely moving, conscious Chga-/- and wild-type control mice. Telemetry and HPLC measured changes in BP and catecholamine levels, respectively. In both groups of mice, Ucn 2 dose-dependently decreased BP, and this effect was mediated by corticotropin factor-receptor type 2. However, in Chga-/- mice, the maximal percentage decrease of systolic BP from basal systolic BP was 37% compared with only a 23% reduction in wild-type mice (P=0.04). In Chga-/- mice only, Ucn 2 decreased adrenal and plasma levels of catecholamines as well as adrenal levels of tyrosine hydroxylase protein and phosphorylation. In vitro mechanistic studies demonstrated that Ucn 2 reduces both catecholamine secretion and tyrosine hydroxylase promoter activity, suggesting that the exaggerated action of Ucn 2 to reduce BP in the Chga-/- mouse is mediated through inhibition of both catecholamine synthesis and secretion. The data suggest that Ucn 2 may be therapeutically useful in regulating the exaggerated sympathoadrenal function of hyperadrenergic hypertension.
Gu
Yusu
Y
Department of Medicine, University of California and Veterans Affairs San Diego Healthcare System, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0838, USA.
Zhang
Kuixing
K
Biswas
Nilima
N
Friese
Ryan S
RS
Lin
Dennis H
DH
Mahata
Sushil K
SK
Hoshijima
Masahiko
M
O'Connor
Daniel T
DT
Peterson
Kirk L
KL
Brar
Bhawanjit K
BK
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000320:Adrenergic Fibers / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D002395:Catecholamines / Q000097:blood* / Q000378:metabolism; D053379:Chromogranin A / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D054832:Urocortins / Q000008:administration & dosage / Q000494:pharmacology*
C101531:CRF receptor type 2; D002395:Catecholamines; D053379:Chromogranin A; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C506155:chromogranin A, mouse; D014446:Tyrosine 3-Monooxygenase