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(Circulation. 1999;100:2336.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Subtype Specific Regulation of Human Vascular ₁-Adrenergic Receptors by Vessel Bed and Age

Xiaowen L. Rudner, PhD; Dan E. Berkowitz, MD; John V. Booth, MB, ChB; Bonita L. Funk, RN; Kelli L. Cozart, RN; Elizabeth B. D’Amico, RN; Habib El-Moalem, PhD; Stella O. Page; Charlene D. Richardson, PhD; Bradford Winters, MD; Leo Marucci; Debra A. Schwinn, MD

From the Departments of Anesthesiology (X.L.R., J.V.B., B.L.F., K.L.C., E.B.D., H.E.M., S.O.P., C.D.R., D.A.S.), Pharmacology/Cancer Biology (D.A.S.), Surgery (D.A.S.), and Biostatistics (H.E.-M.), Duke University Medical Center, Durham, NC; and Department of Anesthesiology (D.E.B., B.W., L.M.), The Johns Hopkins Medical School, Baltimore, Md.

Correspondence to Debra A. Schwinn, MD, Box 3094, DUMC, Durham, NC 27710. E-mail Schwi001{at}mc.duke.edu

	Abstract

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Background—₁-adrenergic receptors (₁ARs) regulate blood pressure, regional vascular resistance, and venous capacitance; the exact subtype (_1a, _1b, _{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 ₁AR subtype expression differs with vascular bed, and (2) age influences human vascular ₁AR subtype expression.

Methods and Results—Five hundred vessels from 384 patients were examined for ₁AR subtype distribution at mRNA and protein levels (RNase protection assays, ligand binding, contraction assays). Overall vessel ₁AR density is 16±2.3fmol/mg total protein. _1aAR predominates in arteries at mRNA (P<0.001) and protein (P<0.05) levels; all 3 subtypes are present in veins. Furthermore, ₁AR mRNA subtype expression varies with vessel bed (_1a higher in splanchnic versus central arteries, P<0.05); competition analysis (selected vessels) and functional assays demonstrate _1a and _1b-mediated mammary artery contraction. Overall ₁AR expression doubles with age (<55 versus 65 years) in mammary artery (no change in saphenous vein), accompanied by increased _1b>_1a expression (P0.001).

Conclusions—Human vascular ₁AR 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.

Key Words: catecholamine • stress • arteries • veins • hypertension

	Introduction

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Alpha₁-adrenergic receptor (₁AR) stimulation mediates sympathetic nervous system responses such as vascular smooth muscle contraction and myocardial hypertrophy. ₁AR-mediated vasoconstriction contributes to baseline (tonic) vessel tone, modulates systemic vascular resistance/venous capacitance, and is important in cardiovascular responses to shock.¹ In addition, during fight and flight responses, elevated catecholamines result in constriction of nonessential vascular beds (eg, splanchnic) while blood flow to vital organs (eg, brain, heart) remains uncompromised.^{2 3} We recently cloned cDNAs encoding 3 human ₁AR subtypes (_1a, _1b, and _{1 d}),^{4 5} pharmacologically characterized each expressed receptor,⁴ and identified species heterogeneity in ₁AR subtype tissue distribution.^{6 7} All 3 ₁ARs couple predominantly via Gq to phospholipase C-ß activation, resulting in formation of inositol trisphosphate, calcium release from intracellular stores, and ultimately to smooth muscle contraction.⁸

Although reasons for existence of 3 ₁AR subtypes remain elusive, recent findings suggest subtype and tissue-specific regulation may be important.^{9 10} Whereas all ₁AR subtypes mediate smooth muscle contraction, hypertrophic pathways demonstrate subtype-specific signaling.¹¹ ₁AR agonist exposure to neonatal rat myocytes results in _1aAR mRNA/protein upregulation (doubling) concurrent with _1b and _{1 d} downregulation, correlating with induction of myocardial hypertrophy.¹² In contrast, insulin and insulin-like growth factor I induces _{1 d}AR expression in cultured rat vascular smooth muscle cells.¹³ Thus, agonist exposure, disease states, and drugs alter ₁AR subtype expression. In order to understand mechanisms underlying cardiovascular responses to acute stress and chronic catecholamine exposure (eg, aging), we examined human vascular ₁AR subtype distribution and function. Specifically, we tested 2 hypotheses: (1) human ₁AR subtype expression differs with vascular bed, and (2) age influences human vascular ₁AR subtype expression. Our results demonstrate human vascular ₁AR subtype distribution differs from animal models, varies with vessel bed, correlates with contraction in mammary artery, and is modulated by aging, all novel findings.

	Methods

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Human Vessels
Vessels were obtained after approval from the Duke University institutional review board and individual agencies. Sources included discarded tissues from surgery (0 to 60 minutes from isolation), Duke University rapid autopsy program (0 to 3 hours postmortem), National Disease Research Interchange (Philadelphia, Pa; 0 to 5 hours postmortem), and the International Institute for the Advancement of Medicine (Scranton, Pa; within 12 hours postmortem). Except for functional assays, vessels were snap-frozen in liquid nitrogen and stored at -70°C for later use.

Membrane Preparation and Radioligand Binding
Vessels were weighed, lumen diameter measured, pulverized under liquid nitrogen, and suspended in cold lysis buffer (5 mmol/L Tris HCl and 5 mmol/L EDTA, pH 7.4) with protease inhibitors.¹⁴ After lysate preparation, membranes were resuspended in cold binding buffer (150 mmol/L NaCl, 50 mmol/L Tris HCl, 5 mmol/L EDTA, with protease inhibitors, pH 7.4) as previously described;¹⁴ protein concentration was determined using the bicinchoninic acid method (Pierce). Full saturation binding isotherms were performed in selected human vessels (aorta, mammary artery, saphenous vein) in 250 µL binding buffer (20- to 60-µg vessel membrane protein) using the ₁-adrenergic antagonist [¹²⁵I]HEAT(2-[ß-(hydroxy-3[¹²⁵I]iodophenyl)ethyl-aminomethyl]-tetralone; DuPont-NEN; Boston, Mass) as previously described.¹⁴ To measure total ₁AR density in all vessels, a saturating concentration (300 pmol/L) of the [¹²⁵I]HEAT was used. A Kd concentration (130 pmol/L [¹²⁵I]HEAT) was used in competition analysis with antagonists 5-MU, WB4101 and BMY7378 (10^-12 to 10^-4 mol/L).

RNase Protection Assays
RNA isolation and human ₁AR cDNA constructs have previously been described by our laboratory.¹⁴ RNase protection assays were performed as previously described; control ß-actin consisted of 0.104 kb (HinP1I/TaqI) fragment in pGEM-4Z (GenBank No. AB004047; nucleotide 119-222).¹⁴ [³²P]CTP (DuPont-NEN) was incorporated into RNA probes at the time of synthesis. After digestion with RNase A and T1, RNA samples were separated electrophoretically through a 6% polyacrylamide gel, dried, and exposed to X-Omat film (Eastman Kodak Company) for 18 to 24 hours and PhosphorImager plates (Molecular Dynamics) for 72 hours. Volume integration of protected fragments was corrected for background using ImageQuant image analysis software (Molecular Dynamics) and counts were normalized for ß-actin signal and ³²P-CTP incorporation (CTPs: _1a–97, _1b–219, _{1 d}–133). Final mRNA data are scaled +1 to +10, with +10 (100 arbitrary units) assigned _1aAR mRNA in liver (human tissue known to contain maximal ₁AR mRNA); thus PhosphorImager counts/10000x1.8 defined PhosphorImager units. _1aAR mRNA is highest in mesenteric artery (26 U); therefore, +3=20 to 29 U; +2=10 to 19 U; +1=4 to 9 U; (-)=almost undetectable signal (3 U PhosphorImager, negative autoradiograph); -=lack of signal on both.

Functional Assays
Because the presence of receptor protein does not always correlate with functional response,¹⁵ ₁AR-mediated contractility in mammary artery was tested using phenylephrine dose-response curves in the absence or presence of subtype selective and nonselective antagonists. Mammary arteries were immersed in cold oxygenated Krebs-Ringer bicarbonate solution (118.3 mmol/L NaCl, 4.7 mmol/L KCl, 1.2 mmol/L MgSO₄, 1.2 mmol/L KHPO₄, 42.5 mmol/L CaCl₂, 25 mmol/L NaHCO₃, 16 mmol/L CaEDTA, 1.1 mmol/L glucose), cleaned of loose connective tissue, and cut into 4 to 5 mm long rings, and suspended for isometric tension recording in organ chambers. One stirrup was anchored to the chamber and the other connected to a strain gauge (FT-102) for measurement of isometric force (MacLab, CB Sciences). All concentration effect curves were performed at optimum resting tone (3 g in pilot studies). Contractile response to 60 mmol/L KCl was performed; this determined vessel viability and facilitated normalization of phenylephrine response across vessel rings. Phenylephrine dose-response curves were generated (10^-4-10^-9 mol/L) in one-half log order concentrations in the absence/presence of competitive ₁AR antagonists. Contraction assays using vessel rings from an individual patient were performed simultaneously in separate baths for each antagonist; hence, each vessel ring was exposed to 3 dose-response curves. Antagonist potency was expressed as the dissociation constant (K_B) determined from pK_B=log[B]log(DR-1), where [B] is antagonist concentration and DR the dose ratio produced by antagonist. Dose-response curves were analyzed using DOSE RESPONSE software (MacLab, CB Sciences).

Statistical Analysis
Data were tested for normal distribution using Shapiro-Wilke test of normality. Overall ₁AR density was compared between vessels using a general linear multivariate model, and where significant differences were identified between specific vascular beds, the exact P value was determined using Wilke’s test; P<0.05 was considered significant. Because determination of ₁AR subtype expression involved 3 subtypes (_1a, _1b, _{1 d}), critical was reduced to 0.0167 for these studies. Similarly, when comparing ₁AR subtype expression between different vascular beds, pairwise comparisons were made using a Wilcoxon 2-sample rank sum test, and critical set at 0.0167. Competition binding and functional assays were analyzed using least squares regression analysis with Prism software (GraphPad). Final data were analyzed using SAS system (release v.6.12, SAS Institute Inc) and presented as mean±SEM to 2 significant figures.

	Results

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Characterization of Human Vessels
500 vessels from 384 patients (male, n=257; female, n=127; 64±0.82 years [range 12 to 92]) were used. The majority (83%) were collected from operating room specimens, 17% from autopsy (cause of death: gun shot, automobile accident, myocardial infarction, cancer). Ninety-five percent of vessels were obtained 3 hours from tissue isolation or death (within 12-hour postmortem mRNA/protein stability period in rats/humans).^{16 17} Vessels were obtained only from patients without coexisting disease (eg, no chronic renal failure, congestive heart failure, diabetes, hypertension, thyroid disease), or potentially confounding drugs (eg, no estrogen supplementation, catecholamines, sympathetic stimulants, antidepressants, or AR drugs); 5 years was required to collect enough vessels to complete the study. Due to limited vessel RNA/protein, n=1 vessel from a single individual whenever possible, but sometimes represents pooled samples from 2 to 6 patients with similar patient characteristics.

Human Vascular Total ₁AR Expression
The fight and flight (stress) response results in redistribution of blood from splanchnic and nonessential organs toward vital organs.^{2 3} In order to test the hypothesis that ₁AR density in splanchnic versus somatic vessels may be responsible for these effects, we determined Kd and Bmax for ¹²⁵I-HEAT binding in selected human vessels (nonspecific binding 30% to 70%). Kd is 130±0.20 (aorta), 130±3.1 (mammary artery), and 130±0.65 (saphenous vein) pmol/L (n=2 to 4 each, Figure 1), similar to cloned human ₁ARs.⁴ Overall human vascular ₁AR expression is 16±2.3fmol/mg total protein; central (conduit) and small somatic arteries express significantly lower ₁AR density than splanchnic arteries, P<0.05, Table 1). In contrast, venous ₁AR density does not change with vessel diameter or vascular bed.

View larger version (13K): [in this window] [in a new window]   Figure 1. Representative saturation-binding isotherms for human mammary artery, aorta, and saphenous vein.

View this table: [in this window] [in a new window]   Table 1. Total 1AR Density in Human Vasculature: Influence of Vessel Type

₁AR Subtype mRNA in Human Vessels
We next examined ₁AR subtypes; due to limited tissue, molecular approaches were used. All 3 ₁AR mRNAs are present in human vessels (Figure 2), with _1aAR predominating overall in arteries (P<0.001); epicardial coronary arteries express _1a exclusively (Table 2). _1aAR subtype density is significantly higher in splanchnic versus central vessels (P<0.05; Figure 3). These findings suggest ₁AR subtype expression varies with vessel type.

View larger version (23K): [in this window] [in a new window]   Figure 2. Representative RNase protection assay. Autoradiograph (24-hour exposure) demonstrating specific hybridization of 1AR subtype radiolabeled antisense riboprobes with total RNA isolated from tRNA (negative control), human aorta, vena cava, iliac artery, and renal artery.

View this table: [in this window] [in a new window]   Table 2. Distribution of 1AR Subtype mRNA in Human Vessels

View larger version (20K): [in this window] [in a new window]   Figure 3. PhosphorImager counts from RNase protection assays for each 1AR subtype. 1aAR mRNA expression is significantly higher overall in arteries compared with 1bAR and 1 dAR (**P<0.001), particularly splanchnic (SPL) versus central arteries (CEN) (*P<0.05).

₁AR Subtype Protein in Human Vessels
To ensure mRNA and protein expression correlate, competition analysis was performed. Selected vessels were chosen for availability and expression of only 1 or 2 ₁AR subtypes (to facilitate interpretation of results). Because _1aAR mRNA predominates, 5-MU (_1a-selective antagonist) was used. Figure 4 shows results from competition analysis in 4 vessels; Table 3 summarizes pKi values (-logKi; measure of receptor affinity for antagonist). 5-MU binds to 2 sites in mammary, renal, splenic arteries, and vena cava, with the high affinity pKi site consistent with interactions at cloned _1aARs.⁴ Although designation of the high-affinity binding site is straightforward, low-affinity ₁AR site identification was aided by mRNA data in Table 2 and confirmed in mammary artery (and aorta) using BMY7378 (_{1 d}-selective antagonist). Only 1 binding site was detected in aorta, coronary artery, and hepatic artery, with pKi values consistent with _{1 d}, _1a, and _1aARs, respectively. These data suggest mRNA and protein expression correlate closely in human vessels.

View larger version (19K): [in this window] [in a new window]   Figure 4. 1AR subtype protein expression in 4 representative human vessels determined by competition analysis with 5-MU (1a-selective antagonist). n=3 experiments per vessel, each performed in triplicate. See Table 3 for pKi values.

View this table: [in this window] [in a new window]   Table 3. 1AR Subtype Expression in Human Vessels: Competition Analysis With 5-MU

Human Mammary Artery Contraction
Phenylephrine dose-response curves were completed in 10 mammary arteries (patient age 60±2.2 years [range 37 to 73]), vessels which contain only _1a and _1bARs; isometric contraction occurs with pD₂ 6.0±0.093. ₁AR competitive antagonists produce a concentration-dependent shift in potency of phenylephrine contraction without reducing maximum response (Figure 5). Potency in inhibiting mammary artery contraction is 9.2±0.046 (prazosin, nonselective), 8.4±0.63 (5-MU, _1a-selective), and 8.6±0.19 (spiperone, relatively _1b-selective), similar to affinities for each antagonist at cloned human ₁ARs.⁴ BMY7378 (_{1 d}-selective) does not produce a shift in dose response. These data suggest _1a and _1bARs mediate contraction in human mammary artery.

View larger version (23K): [in this window] [in a new window]   Figure 5. Phenylephrine-induced mammary artery contraction. Antagonists prazosin (nonselective), 5-MU (1a-selective), and spiperone (relatively 1b-selective) demonstrate concentration-dependent shift in potency without reducing maximum response. BMY7378 (1 d-selective) does not produce a significant shift. Two concentrations of antagonist are shown: indicates control; , low (prazosin–10-9 mol/L; 5-MU/spiperone/BMY7378–10-8 mol/L);higher (prazosin–10-8 mol/L; 5-MU/spiperone/BMY7378–10-7 mol/L).

Regulation of Vascular ₁AR Subtype Expression by Age
Mammary artery ₁AR density increases significantly with age (4.4±0.78 <55 years versus 9.3±1.7 65 years, P=0.003, fmol/mg total protein) (Table 4). In contrast, saphenous vein ₁AR density does not change with age. Competition analysis with 5-MU and WB4101 reveals _1aARs are the major subtype in mammary artery in patients <55 years of age (Figure 6). However, with aging _1bAR expression significantly increases (3-fold, P=0.0001), becoming the major subtype in patients 65 years; _1aARs also significantly increase with age (1.5-fold, P=0.001). _{1 d}AR expression is virtually absent in younger and older patients.

View this table: [in this window] [in a new window]   Table 4. Correlation of Age With 1AR Expression in Mammary Artery and Saphenous Vein

View larger version (19K): [in this window] [in a new window]   Figure 6. 1AR subtype expression in mammary artery from young (<55 years, n=6) versus older (65 years, n=6) patients. Competition analysis with 5-MU (1a>1b1 d) or WB4101 (1a=1 d>1b). See Table 4 for pKi values.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This is the first study to characterize ₁AR subtype distribution in humans across different vascular beds. Our results demonstrate ₁AR subtype expression varies according to vessel bed, providing support for our first hypothesis. Specifically, _1aAR mRNA/protein predominates in coronary, splanchnic, renal, and pulmonary arteries, whereas central arteries and veins express all 3 ₁ARs. With aging (<55 versus 65 years), a 2-fold increase in overall mammary artery (but not saphenous vein) ₁AR expression occurs (_1b>_1a), providing support for our second hypothesis. Robust _1a and _1b-mediated contraction for all ages studied suggests these findings have functional significance. In summary, human vascular ₁AR subtype distribution is different from other animal models, varies with vessel bed, correlates with contraction in mammary artery, and varies with age, all novel findings.

₁AR-mediated smooth muscle contraction is important in determining tonic and reflex changes in arterial and venous diameter. Instantaneous changes in vessel tone are responsible for maintenance of blood pressure and venous return to the heart during stress (eg, hypovolemia [hemorrhage], shock, and sepsis).¹ At rest, adult splanchnic vessels contain 30% total circulating blood volume;³ acute sympathetically mediated constriction is a primary mechanism underlying maintenance of blood pressure during shock or hemorrhage. Robustness of compensatory mechanisms is illustrated by blood pressure stability until >20% blood volume is lost.¹⁸

Vascular ₁ARs have been studied in animals using a variety of techniques (Table 5). After initial controversy, it has been generally agreed that _{1 d}ARs mediate vasoconstriction in rat aorta;^{15 19} in contrast, contraction in dog, rabbit, and mouse aorta occurs via _1bARs.^{20 21 22} ₁AR subtype-mediated contraction also differs along mesenteric bed; _{1 d}ARs mediate contraction in rat superior mesenteric artery (proximal), whereas _1bARs function in distal mesenteric arteries.¹⁹ Only a few studies in human vessels have been performed to date; these identify all 3 ₁AR subtype mRNAs in human mesenteric artery,²³ _1b and _{1 d} in human aorta,⁶ and _1a in saphenous vein²⁴ and vena cava.⁶ _1b-mediated contraction occurs in human superior vesicle and obturator arteries,²⁵ and _1a-mediated contraction in human mesenteric artery.²⁶ Our findings go further, suggesting _1aAR-mediated contraction may account for generalized splanchnic vasoconstriction during stress in humans, although this hypothesis must be confirmed by further contraction studies. Other findings of clinical relevance include _1aARs in renal, pulmonary, and coronary vasculature as possible targets for treatment of renal insufficiency, pulmonary hypertension, and angina. Because veins contain all 3 ₁AR subtypes, potential for pharmacologically isolating preload (venous return) and afterload (arterial vascular resistance) exists. Note that all experiments performed in the present study used normal vessels; it will be interesting to examine potential alterations of ₁AR subtype distribution by disease.

View this table: [in this window] [in a new window]   Table 5. Vascular 1AR Subtype Distribution Reported in Various Species

Sympathetically mediated vascular responsiveness changes with age, although precise mechanisms underlying this observation remain unknown.⁸ Although overall aortic ₁AR density remains unchanged with age in rat, subtype modulation occurs (increased _1a, decreased _1b, unchanged _{1 d})²⁷ ; other studies suggest age decreases all ₁ARs in rat²⁸ but increases in sheep.²⁹ Age-related changes are vessel-specific, with rat renal _1bAR mRNA declining without change in mesenteric/pulmonary ₁ARs.²⁸ Furthermore, age increases functional _{1 d}ARs in resistance vessels compared with _1aAR predominance in young rats.³⁰ In humans, age increases in-hospital mortality associated with major surgery³¹ ; risks include vascular-associated conditions such as gastrointestinal infarction and limb ischemia.^{2 32 33} Our results reveal age-related increases in mammary artery ₁AR density (but not saphenous vein) and a switch from _1a predominance in younger adults to _1b>_1a in older patients. Other arteries need to be tested to determine whether age-induced arterial changes are global or mammary artery-specific. In support of a global interpretation of our findings, a recent clinical study demonstrates less blood pressure perturbation in elderly patients with tamsulosin (_1a/_{1 d}-selective antagonist) compared with alfuzosin (nonselective),³⁴ suggesting importance of _1bARs with aging in resistance vessels.

In summary, our results demonstrate human vascular ₁AR subtype distribution differs from animal models, varies with vessel bed, correlates with contraction in mammary artery, and is modulated by aging. This information provides potential targets for therapeutic intervention in many clinical settings.

	Acknowledgments

 
The authors acknowledge helpful comments by Jim Faber (UNC-Chapel Hill), Nicholas Flavahan (Ohio State); initial assistance with RNase protection assays by Robert Fremeau; assistance with tissue collection by Darryl Atwell, Rita Ongjoco, Christine Hulette, Mari H. Szymanski, Nancy Sinclaire, Pamela Vollmer, Claudia Brady; discussions with Madan Kwatra; and secretarial assistance by Beth Barbee.

This work was funded in part by NIH grants HL49103, AG00745 (to D.A.S.), and Yamanouchi Europe (to D.A.S.). Organizations facilitating human tissue collection include Duke rapid autopsy program (NIH-AG05128 and GlaxoWellcome), Duke General Clinical Research Center (NIH-M01RR30), NDRI (NIH-RR06042), and IIAM. Dr Schwinn is a senior fellow in the Center for the Study of Aging and Human Development at Duke University.

Received August 2, 1998; revision received July 23, 1999; accepted July 28, 1999.

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