Enhanced vascular contractility in alpha1-adrenergic receptor-deficient mice.
OBJECTIVE
Alpha1-adrenergic receptors (alpha1-ARs) are classified into three subtypes: alpha1A-AR, alpha1B-AR, and alpha1D-AR. Triple disruption of alpha1A-AR, alpha1B-AR, and alpha1D-AR genes results in hypotension and produces no contractile response of the thoracic aorta to noradrenalin. Presently, we characterized vascular contractility against other vasoconstrictors, such as potassium, prostaglandin F2alpha (PGF(2alpha)) and 5-hydroxytryptamine (5-HT), in alpha1A-AR, alpha1B-AR, and alpha1D-AR triple knockout (alpha1-AR triple KO) mice.


METHODS
The contractile responses to the stimulation with vasoconstrictors were studied using isolated thoracic aorta.


RESULTS
As a result, the phasic and tonic contraction induced by a high concentration of potassium (20 mM) was enhanced in the isolated thoracic aorta of alpha1-AR triple KO mice compared with that of wild-type (WT) mice. In addition, vascular responses to PGF(2alpha) and 5-HT were also enhanced in the isolated thoracic aorta of alpha1-AR triple KO mice compared with WT mice. Similar to in vitro findings with isolated thoracic aorta, in vivo pressor responses to PGF(2alpha) were enhanced in alpha1-AR triple KO mice. Real-time reverse transcription-polymerase chain reaction analysis and western blot analysis indicate that gene expression of the 5-hydroxytryptamine 2A (5-HT(2A)) receptor was up-regulated in the thoracic aorta of alpha1-AR triple KO mice while the prostaglandin F2alpha receptor (FP) was unchanged.


CONCLUSIONS
These results suggest that loss of alpha1-ARs can lead to enhancement of vascular responsiveness to the vasoconstrictors and may imply that alpha1-ARs and the subsequent signaling regulate the vascular responsiveness to other stimulations such as depolarization, 5-HT and PGF(2alpha).
Sanbe
Atsushi
A
Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. asanbe@nch.go.jp
Tanaka
Yoshio
Y
Fujiwara
Yoko
Y
Miyauchi
Noriko
N
Mizutani
Reiko
R
Yamauchi
Junji
J
Cotecchia
Susanna
S
Koike
Katsuo
K
Tsujimoto
Gozoh
G
Tanoue
Akito
A
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D015237:Dinoprost / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000502:physiology; D018390:Gene Targeting; D006339:Heart Rate / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000235:genetics* / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D018340:Receptors, Adrenergic, alpha-1; D014662:Vasoconstrictor Agents; D012701:Serotonin; D015237:Dinoprost