Two alpha1-adrenergic receptor subtypes regulating the vasopressor response have differential roles in blood pressure regulation.
To study the functional role of individual alpha1-adrenergic (AR) subtypes in blood pressure (BP) regulation, we used mice lacking the alpha1B-AR and/or alpha1D-AR with the same genetic background and further studied their hemodynamic and vasoconstrictive responses. Both the alpha1D-AR knockout and alpha1B-/alpha1D-AR double knockout mice, but not the alpha1B-AR knockout mice, had significantly (p < 0.05) lower levels of basal systolic and mean arterial BP than wild-type mice in nonanesthetized condition, and they showed no significant change in heart rate or in cardiac function, as assessed by echocardiogram. All mutants showed a significantly (p < 0.05) reduced catecholamine-induced pressor and vasoconstriction responses. It is noteworthy that the infusion of norepinephrine did not elicit any pressor response at all in alpha1B-/alpha1D-AR double knockout mice. In an attempt to further examine alpha1-AR subtype, which is involved in the genesis or maintenance of hypertension, BP after salt loading was monitored by tail-cuff readings and confirmed at the endpoint by direct intra-arterial recording. After salt loading, alpha1B-AR knockout mice developed a comparable level of hypertension to wild-type mice, whereas mice lacking alpha1D-AR had significantly (p < 0.05) attenuated BP and lower levels of circulating catecholamines. Our data indicated that alpha1B- and alpha1D-AR subtypes participate cooperatively in BP regulation; however, the deletion of the functional alpha1D-AR, not alpha1B-AR, leads to an antihypertensive effect. The study shows differential contributions of alpha1B- and alpha1D-ARs in BP regulation.
Hosoda
Chihiro
C
Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University Faculty of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Koshimizu
Taka-Aki
TA
Tanoue
Akito
A
Nasa
Yoshihisa
Y
Oikawa
Ryo
R
Tomabechi
Takashi
T
Fukuda
Shinya
S
Shinoura
Hitomi
H
Oshikawa
Sayuri
S
Takeo
Satoshi
S
Kitamura
Tadaichi
T
Cotecchia
Susanna
S
Tsujimoto
Gozoh
G
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D003001:Cloning, Molecular; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D011189:Potassium Chloride / Q000494:pharmacology; D011224:Prazosin / Q000493:pharmacokinetics; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D018340:Receptors, Adrenergic, alpha-1; D011994:Recombinant Proteins; D011189:Potassium Chloride; D011224:Prazosin