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(Circulation. 2004;110:2708-2712.)
© 2004 American Heart Association, Inc.

Vascular Medicine

Heterogeneous ß₂-Adrenoceptor Expression and Dilation in Coronary Arterioles Across the Left Ventricular Wall

Travis W. Hein, PhD^*; Cuihua Zhang, MD, PhD^*; Wei Wang, MD; Lih Kuo, PhD

From the Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, The Texas A&M University System Health Science Center, College Station, Tex.

Correspondence to Lih Kuo, PhD, Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, The Texas A&M University System Health Science Center, 702 Southwest H.K. Dodgen Loop, Temple, TX 76504. E-mail LKUO{at}tamu.edu

Received December 16, 2003; de novo received April 6, 2004; revision received May 24, 2004; accepted May 25, 2004.

	Abstract

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Background— Previous in vivo studies have shown that ß-adrenoceptor agonists cause a redistribution of coronary flow away from the subendocardium; however, the underlying mechanism remains uncertain. We tested the hypothesis that a heterogeneous distribution of ß-adrenoceptors and their vasomotor responses exists in the coronary microcirculation across the left ventricular wall.

Methods and Results— Porcine subepicardial and subendocardial arterioles (<100 µm) were isolated from the left ventricle and pressurized for in vitro study of vasodilation to the nonselective ß-adrenoceptor agonist isoproterenol and the selective ß₂-adrenoceptor agonist procaterol. Both vessel types developed a similar level of basal tone and dilated to isoproterenol and procaterol. However, subepicardial arterioles exhibited a much higher sensitivity and greater dilation capacity to both agonists. The isoproterenol-induced vasodilations were inhibited by glibenclamide, an ATP-sensitive potassium (K_ATP) channel blocker. In contrast to isoproterenol, dilations of subepicardial and subendocardial arterioles to pinacidil, a K_ATP channel opener, were similar. In both vessel types, isoproterenol-induced dilation was inhibited by the ß₂-adrenoceptor blocker ICI-118,551 but was insensitive to the ß₁-adrenoceptor blocker atenolol. Reverse transcription–polymerase chain reaction and immunohistochemical data revealed that ß₂-adrenoceptor mRNA and protein expression, respectively, were markedly greater in subepicardial arterioles.

Conclusions— This study demonstrates that selective activation of ß₂-adrenoceptors elicits dilation of both subepicardial and subendocardial arterioles through opening of K_ATP channels. The higher ß₂-adrenoceptor expression in subepicardial arterioles may contribute to the greater dilation of these vessels to ß₂-adrenoceptor activation.

Key Words: receptors, adrenergic, beta • endocardium • microcirculation • vasodilation

	Introduction

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It has been shown that direct activation of vascular ß-adrenoceptors elicits dilation of both large and small coronary arteries in vitro, suggesting a possible role for these receptors in the regulation of coronary blood flow.^1,2 The physiological relevance of this finding is supported by recent evidence showing that the activation of vascular ß-adrenoceptors plays an important role in mediating feed-forward sympathetic coronary vasodilation in response to exercise.^3,4 Although the contribution of specific ß-adrenoceptors was not determined in this study, it has been shown that the ß₁-adrenoceptors are the predominant subtype in large coronary arteries⁵ and that they mediate dilation of these vessels in vitro.¹ On the other hand, the ß₂-adrenoceptor distribution⁶ and dilation² appear to be predominant in small coronary arterioles. It appears that the coronary circulation exhibits a longitudinal heterogeneity in ß-adrenoceptor distribution. Interestingly, previous in vivo studies have shown that ß₂-adrenoceptor agonists cause redistribution of coronary blood flow away from the subendocardial region in normal^7,8 and ischemic myocardium.⁷ Although the underlying mechanism for this redistribution phenomenon remains uncertain, it was speculated that a heterogeneous transmural distribution of ß-adrenoceptors and their vasomotor response may exist in the coronary microcirculation. However, this hypothesis has not been directly tested, and the distribution of specific ß-adrenoceptor subtypes and their vasomotor function across the left ventricular wall have yet to be determined. Because coronary arterioles are the primary regulators of blood flow in the heart,⁹ it would be important to understand the functional and molecular distribution of ß-adrenoceptor subtypes in the subepicardial and subendocardial arterioles. Therefore, the present study was designed to determine the direct involvement of vascular ß₁- and ß₂-adrenoceptors in the dilation of subepicardial and subendocardial arterioles to the ß-adrenoceptor agonist isoproterenol and the molecular distribution of ß-adrenoceptors in these coronary microvessels. Because ATP-sensitive potassium (K_ATP) channels have been suggested to be involved in the coronary vasodilation in response to ß-adrenoceptor activation,¹⁰ we also investigated the role of K_ATP channels in the transmural vasodilatory response.

	Methods

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Functional Assessment of Isolated Coronary Arterioles
The procedures followed were in accordance with approved guidelines set by the Laboratory Animal Care Committee at Texas A&M University. See the online-only Data Supplement for detailed description of methods. Pigs (Milberger Farms, Kurten, Tex; n=18) were anesthetized with pentobarbital (20 mg/kg), and the heart was quickly excised. Individual left ventricular subepicardial and subendocardial arterioles were carefully dissected out for in vitro study, as described previously.¹¹ Vessels were cannulated and pressurized to 60 cm H₂O intraluminal pressure. After development of stable basal tone, the vascular responses to cumulative extraluminal concentrations of the nonselective ß-adrenoceptor agonist isoproterenol (0.1 pmol/L to 0.1 µmol/L) and of sodium nitroprusside (1 nmol/L to 100 µmol/L) were established. In some vessels, the response to the selective ß₂-adrenoceptor agonist procaterol (0.1 nmol/L to 100 µmol/L) was examined. To determine the contribution of specific ß-adrenoceptor subtypes, the vascular response to isoproterenol was evaluated before and after treatment with the selective ß₁-adrenoceptor antagonist atenolol (1 µmol/L)^2,12 or the selective ß₂-adrenoceptor antagonist ICI-118,551 (1 µmol/L).^2,13 The role of K_ATP channels in mediating vascular responses was assessed by the K_ATP channel blocker glibenclamide (5 µmol/L).¹⁴

RNA Isolation and Reverse Transcription-Polymerase Chain Reaction Analysis
Total RNA was isolated from subepicardial and subendocardial arterioles (50- to 100-µm inner diameter, 3 to 4 vessels per sample) and from myocardial tissue (positive control), as described previously.¹⁵ Using primers specific for ß₁-adrenoceptor, ß₂-adrenoceptor, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) genes, reverse transcription–polymerase chain reaction was conducted as described previously.¹⁵

Immunohistochemical Analysis
Subepicardial and subendocardial arterioles (50- to 100-µm inner diameter) were prepared for immunohistochemical analysis, as described previously.¹⁵ Sections (12 µm thick) were immunolabeled with a rabbit anti-ß₂ antibody (1:40 dilution, Santa Cruz Biotechnology) and observed by means of confocal microscopy, as described previously.¹⁵

Data Analysis
Diameter changes in response to vasodilator agonists were normalized to the maximum diameter changes in response to 100 µmol/L sodium nitroprusside and expressed as a percentage of maximal dilation.¹⁴ Statistical comparisons were performed by means of 2-way ANOVA or Student’s t test, as appropriate. A value of P<0.05 was considered significant. Data are presented as mean±SEM.

	Results

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Vasomotor Function and ß-Adrenoceptor Activation
The isolated subepicardial and subendocardial arterioles had similar levels of basal tone (subepicardial: 70±5 µm, 62±2% of maximal diameter versus subendocardial: 68±7 µm, 66±2% of maximal diameter; P>0.05). Isoproterenol evoked a robust concentration-dependent dilation in the subepicardial vessels and only a modest dilation with the highest concentration (0.1 µmol/L) in the subendocardial vessels (Figure 1A). The vasodilation threshold of subepicardial arterioles was 3 orders of magnitude more sensitive than that of subendocardial arterioles, and the maximal response at 0.1 µmol/L isoproterenol was 4-fold greater in subepicardial microvessels. A significantly greater ß₂-adrenoceptor-mediated dilation to procaterol, a selective ß₂-adrenoceptor agonist, in subepicardial arterioles than in subendocardial arterioles was also observed (Figure 1B). Inhibition of ß₂-adrenoceptors by ICI-118,551 almost completely blocked the isoproterenol-induced dilation of subepicardial arterioles (Figure 1C) and abolished the dilation of subendocardial arterioles (Figure 1C). In contrast, the ß₁-adrenoceptor antagonist atenolol did not affect vasodilation to isoproterenol (Figure 1C and 1D). The subepicardial and subendocardial vessels dilated equally to sodium nitroprusside (1 nmol/L to 100 µmol/L, n=3, see Data Supplement; P>0.05) and the responses were not altered by ICI-118,551, indicating that the ß₂-adrenoceptor antagonist did not exert a nonspecific effect on vasomotor reactivity and that the vessels exhibited similar levels of vasodilatory capacity. The K_ATP channel antagonist glibenclamide (5 µmol/L) also inhibited vasodilation to isoproterenol (Figure 1C and 1D). Both vessel types dilated equally to pinacidil (1 µmol/L) (subepicardial: 78±4% versus subendocardial: 74±6%; n=4), and the dilations were significantly (P<0.05) inhibited by glibenclamide (subepicardial: 13±6% versus subendocardial: 8±3%; n=4). It is noted that ICI-118,551, atenolol, and glibenclamide did not alter resting basal tone.

View larger version (32K): [in this window] [in a new window]   Figure 1. A and B, Vascular reactivity of isolated porcine subepicardial (EPI) and subendocardial (ENDO) arterioles in response to isoproterenol (n=11 for EPI and ENDO) and procaterol (n=4 for EPI and ENDO). C and D, Dilation of EPI and ENDO arterioles to isoproterenol was examined in the absence and the presence of atenolol (n=7 for EPI and ENDO), ICI-118,551 (ICI; n=7 for EPI and ENDO), or glibenclamide (GB; n=4 for EPI and ENDO). n=number of vessels. *P<0.05 vs EPI, control groups, or atenolol groups; P<0.05 vs EPI-GB.

ß-Adrenoceptor Expression in Coronary Arterioles
The reverse transcription-polymerase chain reaction results showed that ß₂-adrenoceptor but not ß₁-adrenoceptor mRNA expression was detected in coronary arterioles, whereas both ß-adrenoceptor subtypes were detected in myocardial tissue (Figure 2A). Normalization of ß₂-adrenoceptor transcripts with GAPDH transcripts exhibited a similar level of expression for all samples evaluated and showed that the expression of ß₂ was nearly 3-fold greater in subepicardial vessels than in subendocardial vessels (Figure 2A). Similarly, immunohistochemical results revealed markedly greater signal intensity for ß₂-adrenoceptor protein expression in subepicardial arterioles (Figure 2B).

View larger version (30K): [in this window] [in a new window]   Figure 2. A, Upper panel: Reverse transcription-polymerase chain reaction analysis of ß-adrenoceptor mRNA in porcine coronary arterioles and myocardial tissue was performed with the use of gene-specific primers for the ß2-adrenoceptor (ß2-AR) and the ß1-adrenoceptor (ß1-AR). Lower panel: ß2-AR transcripts from the subepicardial (EPI, n=3) and subendocardial (ENDO, n=3) arterioles were normalized with the corresponding GAPDH transcripts. *P<0.05 vs EPI arterioles. Marker=X174-DNA marker. n=number of independent experiments. B, Immunohistochemical analysis of ß2-AR protein in EPI and ENDO arterioles, shown as a pseudocolor spectral display, was performed in vessels treated without (–1°) or with (+1°) anti–ß2-AR primary antibody. Level of ß2-AR protein expression was represented by the signal intensity of the color pallet. Similar results were obtained in 3 independent experiments.

	Discussion

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The activation of ß-adrenoceptors in vivo has been shown to regulate myocardial perfusion by causing coronary vasodilation and increases in coronary blood flow.^8,16 Because adrenergic activation in vivo can produce coronary vasodilation indirectly through myocardial ß₁- and/or ß₂-adrenoceptors (ie, increased heart rate and contractility leading to metabolic vasodilation)¹⁷ or directly through vascular ß-adrenoceptors, it can be difficult to discern the exact contribution of the direct vascular component. To gain insight into the involvement of specific vascular ß-adrenoceptor subtypes in vasodilation, an isolated vessel preparation has been used. It has been shown that ß₁-adrenoceptors are primarily responsible for the dilation of isolated large conduit coronary arteries.¹ In contrast, ß₂-adrenoceptor activation mediates dilation of small resistance vessels isolated from the subepicardium.^2,18 However, it has not been established whether specific ß-adrenoceptor activation influences vasomotor tone in the subendocardium. In the present study, the response of ß-adrenoceptor activation was investigated and compared in isolated and pressurized subepicardial and subendocardial arterioles. Isoproterenol (0.1 pmol/L to 0.1 µmol/L), at the concentrations comparable to those used in vivo (10 nmol/L to 1 µmol/L),^8,16 elicited concentration-dependent dilation of isolated coronary arterioles, but the response was considerably greater in the subepicardial vessels. Isoproterenol-induced dilation in both vessel types was inhibited by ICI-118,551 but not by atenolol, indicating the primary functional role of ß₂-adrenoceptors in these microvessels. It seems reasonable to postulate that a heterogeneous distribution of the ß₂-adrenoceptor subtype could contribute to the differential response in the present study.

Further support for a heterogeneous ß₂-adrenoceptor activation was provided by procaterol, a selective ß₂-adrenoceptor agonist. Similar to isoproterenol, we observed a greater dilation of subepicardial arterioles to procaterol, and the dilation of subendocardial arterioles only occurred at higher concentrations (10 µmol/L). This is consistent with the in vivo findings that a relatively higher concentration of another ß₂-adrenoceptor agonist, salbutamol (>1 µmol/L), was required to increase subendocardial blood flow in the nonworking dog hearts after ß₁-adrenoceptor blockade.⁸ The disparity in the vasodilatory capacity to ß₂-adrenoceptor agonists between subepicardial and subendocardial arterioles was apparently not a general phenomenon because the dilations of these vessels to pinacidil and sodium nitroprusside in the present study and to pinacidil and adenosine in our previous study¹¹ were very comparable.

The pharmacological results above support the hypothesis of a heterogeneous transmural distribution of ß₂-adrenoceptors. Although differences in ß₂-adrenoceptor density have been determined between large and small subepicardial coronary arteries by quantitative autoradiography,⁶ it remains unclear whether receptor distribution, in particular at the molecular level, varies across the left ventricular wall. In agreement with the functional results, our molecular data provide the first evidence that ß₂-adrenoceptor mRNA was predominantly expressed in both vessel types. However, the ß₂-adrenoceptor mRNA and protein expression were significantly greater in the subepicardial vessels than in the subendocardial vessels. It appears that the differences in the sensitivity and magnitude of dilation to ß-adrenoceptor agonists between subepicardial and subendocardial arterioles may result from the unequal distribution of ß₂-adrenoceptors.

Although our findings do not support a role for ß₁-adrenoceptors in coronary arteriolar dilation with isoproterenol, an earlier in vivo study has shown that blockade of ß₁-adrenoceptors attenuates the isoproterenol-induced coronary blood flow.¹⁶ A possible explanation for these apparently disparate results is that isoproterenol may stimulate ß₁-adrenoceptors at upstream larger arterioles (>200 µm in diameter), which have been shown to contribute some degree (25%)⁹ of coronary vascular resistance. Moreover, the ß₁-adrenoceptors have been shown to be the predominant subtype in large coronary arteries,⁵ and they mediate dilation of these vessels in vitro.¹ Therefore, it appears that large coronary arterioles/arteries exhibit ß₁-adrenoceptors and possibly ß₂-adrenoceptors, whereas small coronary arterioles, as shown in our present functional and molecular studies, exhibit predominately ß₂-adrenoceptors.

Administration of the K_ATP channel blocker glibenclamide in the coronary circulation has been shown to attenuate ß₂-adrenoceptor-induced increases in myocardial blood flow,¹⁰ suggesting that K_ATP channel activation contributes to the dilation of coronary resistance vessels in response to ß-adrenoceptor stimulation. This earlier study was not able to unequivocally determine whether arteriolar K_ATP channels are directly involved in ß-adrenoceptor-induced dilation because K_ATP channel activations secondary to metabolic and hemodynamic disturbances during adrenoceptor activation are inevitable in the in vivo setting. In the present study, glibenclamide inhibited the dilation of subepicardial and subendocardial arterioles to the K_ATP channel opener pinacidil and to isoproterenol, indicating a critical role for K_ATP channels in the ß₂-adrenoceptor–induced dilation of these vessels. However, it does not appear that K_ATP channel signaling contributes to the transmural difference in vasodilation to ß-adrenoceptor agonists because pinacidil-induced dilation was similar between subepicardial and subendocardial arterioles. These results further support the idea that the differential expression of ß₂-adrenoceptors rather than the downstream signaling is responsible for the observed transmural difference in coronary arteriolar dilation to ß-adrenoceptor activation.

The physiological or pathophysiological implications of the present results could provide further insight into the mechanisms contributing to regional differences in myocardial blood flow. In the normal heart, blood flow to the subendocardium is either equal to or slightly greater than that to the subepicardium. During exercise, sympathetic activation of vascular ß-adrenoceptors can contribute to coronary vasodilation^3,4 and the subendocardial flow is slightly redistributed toward the subepicardium.¹⁹ For healthy individuals, this usually does not pose a grave situation, but for those with cardiovascular complications such as coronary stenosis, the redistribution of flow to the subepicardium is accentuated during exercise.²⁰ It is worth noting that myocardial ischemia is generally associated with elevated levels of norepinephrine.²¹ Under this condition, the transmural difference in ß₂-adrenoceptor activation, with preferential dilation in the subepicardium, could contribute, in part, to the apparent high vulnerability of subendocardium to ischemia. Indeed, in vivo studies indicate that activation of coronary ß₂-adrenoceptors, independent of myocardial ß₁-adrenoceptor activation, increases microvascular perfusion²² and redistributes flow toward the subepicardial region in normal^7,8 and ischemic myocardium.⁷ Our findings may help to explain the observed differences in transmural blood flow during sympathetic activation and the greater susceptibility of subendocardium to ischemia that is exacerbated during exercise.²⁰ A better understanding of the functional and molecular mechanisms regulating subepicardial and subendocardial tone may yield new therapies for optimizing blood flow to different regions of the heart with ischemic disease.

	Acknowledgments

 
This work was supported by National Heart, Lung, and Blood Institute grants HL-48179 and HL-71761 to Dr Kuo.

	Footnotes

 
*The first 2 authors contributed equally to this work.

The online-only Data Supplement is available at http://www.circulationaha.org.

	References

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This Article Abstract Full Text (PDF) Data Supplement All Versions of this Article: 110/17/2708    most recent 01.CIR.0000134962.22830.CFv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hein, T. W. Articles by Kuo, L. Search for Related Content PubMed PubMed Citation Articles by Hein, T. W. Articles by Kuo, L. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Autonomic, reflex, and neurohumoral control of circulation Coronary circulation Other Vascular biology