Subtype specific regulation of human vascular alpha(1)-adrenergic receptors by vessel bed and age.
BACKGROUND
alpha(1)-adrenergic receptors (alpha(1)ARs) regulate blood pressure, regional vascular resistance, and venous capacitance; the exact subtype (alpha(1a), alpha(1b), alpha(1 d)) mediating these effects is unknown and varies with species studied. In order to understand mechanisms underlying cardiovascular responses to acute stress and chronic catecholamine exposure (as seen with aging), we tested two hypotheses: (1) human alpha(1)AR subtype expression differs with vascular bed, and (2) age influences human vascular alpha(1)AR subtype expression.


RESULTS
Five hundred vessels from 384 patients were examined for alpha(1)AR subtype distribution at mRNA and protein levels (RNase protection assays, ligand binding, contraction assays). Overall vessel alpha(1)AR density is 16+/-2.3fmol/mg total protein. alpha(1a)AR predominates in arteries at mRNA (P<0.001) and protein (P<0.05) levels; all 3 subtypes are present in veins. Furthermore, alpha(1)AR mRNA subtype expression varies with vessel bed (alpha(1a) higher in splanchnic versus central arteries, P<0.05); competition analysis (selected vessels) and functional assays demonstrate alpha(1a) and alpha(1b)-mediated mammary artery contraction. Overall alpha(1)AR expression doubles with age (<55 versus > or = 65 years) in mammary artery (no change in saphenous vein), accompanied by increased alpha(1b)>alpha(1a) expression (P< = 0.001).


CONCLUSIONS
Human vascular alpha(1)AR subtype distribution differs from animal models, varies with vessel bed, correlates with contraction in mammary artery, and is modulated by aging. These findings provide potential novel targets for therapeutic intervention in many clinical settings.
Rudner
X L
XL
Department of Anesthesiology, Duke UniversityMedical Center, Durham, NC 27710, USA. Medical Center, Durham, NC.
Berkowitz
D E
DE
Booth
J V
JV
Funk
B L
BL
Cozart
K L
KL
D'Amico
E B
EB
El-Moalem
H
H
Page
S O
SO
Richardson
C D
CD
Winters
B
B
Marucci
L
L
Schwinn
D A
DA
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D001011:Aorta / Q000737:chemistry / Q000502:physiology; D001158:Arteries / Q000737:chemistry* / Q000502:physiology*; D002445:Celiac Artery / Q000737:chemistry / Q000502:physiology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005260:Female; D005263:Femoral Artery / Q000737:chemistry / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006499:Hepatic Artery / Q000737:chemistry / Q000502:physiology; D006801:Humans; D007083:Iliac Artery / Q000737:chemistry / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008323:Mammary Arteries / Q000737:chemistry / Q000502:physiology; D008875:Middle Aged; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism; D012077:Renal Artery / Q000737:chemistry / Q000502:physiology; D012501:Saphenous Vein / Q000737:chemistry / Q000502:physiology; D013134:Spiperone / Q000494:pharmacology; D013157:Splenic Artery / Q000737:chemistry / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018492:Dopamine Antagonists; D010879:Piperazines; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; C057446:5-methylurapidil; D010656:Phenylephrine; D013134:Spiperone; C053428:BMY 7378; D011224:Prazosin