Endothelin A-receptors and the coronary circulation

doi:10.4236/wjcd.2013.35057

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World Journal of Cardiovascular Diseases, 2013, 3, 371-376 WJCD

http://dx.doi.org/10.4236/wjcd.2013.35057 Published Online August 2013 (http://www.scirp.org/journal/wjcd/)

Endothelin A-receptors and the coronary circulation

Evangelos Polymeropoulos1, Mesele Valenti1, Zenon S. Kyriakides1,2*

12nd Department of Cardiology, Hellenic Red Cross General Hospital, Athens, Greece

2Cardiovascular Research Institute, Athens, Greece

Email: *[email protected]

Received 3 June 2013; revised 3 July 2013; accepted 20 July 2013

tion License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly

cited.

ABSTRACT

We review the role of endothelin (ET) A-receptors (R)

on the coronary circulation. ET-1 maintains the nor-

mal coronary artery tone. ET-1 plasma levels are in-

creased during and after coronary angioplasty and

this increase is related to myocardial ischaemia rather

than to mechanical artery injury. ETAR antagonists

inhibit coronary artery vasoconstriction induced by

ET release after coronary angioplasty in humans. ET

promotes neointimal formation and ETAR antago-

nism has been shown to inhibit restenosis after angio-

plasty in the animal model but not in humans. ETAR

blockade increases coronary blood flow, dilates distal

coronary arterial segments and decreases coronary

vascular resistance. Coronary collaterals are less sen-

sitive than other coronary vessels to ET-1. ETAR bloc-

kade decreases collateral blood flow and, consequent-

ly, perfusion of the ischemic myocardium.

Keywords: Endothelin; Coronary Circulation

1. INTRODUCTION

Diseases of the cardiovascular system account for the

majority of morbidity and mortality in Western countries.

Most forms of cardiovascular disease are associated with

impaired vascular function in the cerebral, coronary, re-

nal or peripheral circulation. Enhanced intermittent and/

or persistent vasoconstriction is one of the most impor-

tant features of several forms of cardiovascular disease.

An important local vascular regulator is the 21-amino

acid peptide endothelin (ET) with potent and characteris-

tically sustained vasoconstrictor and vasopressor actions

[1]. In the blood vessel wall, only endothelial cells pro-

duce the peptide and exclusively ET-1, except in disease

states such as atherosclerosis, where smooth muscle cells

may also contribute. Most of the ET-1 produced in the

endothelium interacts with vascular smooth muscles,

while only about one-third circulates and can be mea-

sured by ra dioimm un oas say techniques [2].

With intraluminal administration of ET-1, a transient

vasodilation due to activation of nitric oxide and prosta-

cyclin is observed followed by profound and sustained

vasoconstriction which is mediated by ETAR receptor

activation and at least in certain blood vessels also by

ETBR receptors [3,4]. With higher concentrations of ET-1,

only vasoconstriction is observed, although even then in-

hibition of a production of endothelium derived relaxing

factors enhances the response to the peptide [5].

Brunner [6] compared coronary and interstitial ET-1

levels in perfused rat hearts under several experimental

conditions. Basal ET-1 releasing into effluent was higher

than in transudate, but basal ET-1 concentration was

four-fold higher in transudate than in effluent. Following

the removal of the endothelial cells, ET-1 release in the

artery lumen decreased dramatically and was completely

abolished in interstitial transudate, indicating that the

peptide originated from the vascular endothelium [6].

When the coronary flow was reduced to an ischemic

level, ET-1 secretion rates into effluent decreased by

60%, but increased 3- to 4-fold after reperfusion at nor-

mal flow. These data do not support a vasoconstrictor

action of ET-1 in rats following ischemia/reperfusion,

but rather point to a possible vasodilator role of the pep-

tide under these conditions.

Thrombin and ischemia increase ET-1 production and

up-regulate its receptors. In patients with unstable angina,

increased staining for ET-1 can be demonstrated in

coronary artery lesions removed by atherectomy [7].

ET-1 levels were measured in blood samples, obtained

from the femoral vein of patients with stable angina, un-

dergoing coronary rotational atherectomy. Patients un-

dergoing plain balloon angioplasty were used as controls.

Plasma levels of ET-1 were higher in patients undergo-

ing balloon angioplasty, whereas in patients undergoing

*Corresponding a uthor.

OPEN ACCESS

E. Polymeropoulos et al. / World Journal of Cardiovascular Diseases 3 (2013) 371-376

372

atherectomy, these were only mildly elevated [8] (Figure

1). The peripheral release of ET-1 during angioplasty is

related to myocardial ischemia, rather than to endoth elial

injury [9] (Figure 2). Possible explanations for the

smaller ET-1 secretion during atherectomy compared

with balloon angioplasty are: 1) more calcified arteries

may secrete less ET-1 during ischemia; 2) more diffusely

diseased arteries may produce less ET-1 during ischemia,

and 3) the destruction of the endothelium during rota-

tional atherectomy is so extensive that it renders itself

unable to produce and excrete ET-1 into the plasma.

Tahara, et al. [10] reported that ET-1 is increased in

the coronary sinus after coronary angioplasty. ET-1 plas-

ma levels have been shown to increase more in normo-

tensive than in hypertensive patients after coronary an-

gioplasty [11]. Thus, ET-l has a weaker vasomotor effect

on the coronary vasculature in hypertensive patients than

in normotensives [12], due to reduced responsiveness to

ET-l by the small resistance arteries in the former. In

patients undergoing angioplasty, ET-1 is increased more

in patients with partially occluded coronary arteries than

in patients with totally occluded vessels. Thus, the in-

crease in ET-1 is another confirmation that ET-1 levels

are related to myocardial ischaemia rather than to me-

chanical artery injury [9].

Biopsies from internal mammary arteries in patients

undergoing coronary artery by-pass grafting showed that

systemic hypertension is associated with increased ET-1

and ETAR receptor mRNA expression, whereas insu-

lin-dependent diabetes down-regulates ETAR receptor

mRNA expression [13]. This could help explain the dif-

ferential response of hypertensive and diabetic animals

and humans to external and internal stimulation and

blockade of ET-1 and its receptors.

Figure 1. Plasma levels of Endotelin-1 were higher in patients

undergoing balloon angioplasty, whereas in patients undergoing

atherectomy, these were insignificantly raised. Letters A to E

denote the phases during which blood samples were drawn. A is

after the coronary artery engagement with the guiding catheter

(baseline), B is after the end of the rotational atherectomy, C is

after the first balloon inflation, D is immediately after the end

of the procedure, and E is 4 hours later [8].

Figure 2. Endothelin-1 during coronary angioplasty in a group

of patients with total (filled circles) and another with partial

(open circles) artery occlusion *<0.05 vs baseline. Letters A to

D denote the phases during which blood samples were drawn.

A is after the coronary artery engagement with the guiding ca-

theter (baseline), B is after the first balloon inflation, C is im-

mediately after the end of the procedure, and D is 4 hours later

[9].

2. ET-1 DURING ANGIOPLASTY

In a study utilizing the selective ETAR antagonist

BQ-123 in patients undergoing angioplasty [14], acute

ETAR receptor antagonism prevented the normal reduce-

tion of myocardial ischemia on repeated balloon infla-

tions. This phenomenon may be explained by a “steal”

effect through coronary collaterals; local ETAR receptor

antagonism with BQ-123 causes coronary vasodilatation

(mainly at the distal coronary arterial segments), an in-

crease in coronary blood flow, and a decrease in the

coronary artery resistance [14] (Figure 3). ETAR recep-

tor antagonism may increase coronary blood flow and

decrease coronary artery resistance and distal coronary

pressure by dilating the distal arterial segments and the

resistance arteries in the non-ischemic region and in-

creasing coronary blood flow [15] (Figure 4).

Coronary vasoconstriction after coronary angioplasty

has been attributed to a variety of mechanisms and it can

be prevented by ETA receptor blockade. Quantitative

analysis of coronary angiography of the diameter of the

distal segment of coronary arteries 25 minutes after co-

ronary angioplasty, showed that intracoronary admini-

stration of BQ-123 hindered vasoconstriction of the dis-

tal segment [16] (Figure 5).

3. ET ANTAGONISTS IN CORONARY

BLOOD FLOW

ET-1 and big ET-1 administration in rat hearts reduces

coronary blood flow. However, BQ-123, an ETAR recep-

tor antagonist abolishes the cardiac effect of ET-1 [17].

Cannan, et al. [18] showed that low concentrations of

exogenous ET-1 in dogs, which may mimic pathophysi-

ological concentrations, result in coronary vasoconstric-

tion mediated predominantly via the ETAR, since such

E. Polymeropoulos et al. / World Journal of Cardiovascular Diseases 3 (2013) 371-376 373

Figure 3. Schematic representation of coronary arterial bed,

effects of myocardial ischemia, and possible effects of ETAR

antagonism (BQ-123). Coronary arteries can be divided into 2

functional components: large epicardial conductance arteries

and smaller resistance arterioles. After significant narrowing of

coronary artery, ischemic stimulus results in autoregulation of

small resistance vessels and consequently maximal vasodilation

in ischemic region. ETAR antagonism, in nonischemic region,

dilates distal arterial segments and resistance vessels, causing

decrease in coronary artery resistance, increase in blood flow,

and fall in distal coronary pressure. Fall in pressure at source of

collaterals may diminish collateral flow and perfusion of

ischemic myocardium. This deleterious effect is termed “coro-

nary steal” [14].

Figure 4. Coronary blood flow velocity in a patient with coro-

nary artery disease 15 minutes (top) and 30 minutes (middle)

after the initiation of BQ-123, an ETAR blocker, infusion and

after the end of the infusion (bottom). It can be seen that peak

velocity integral (PVI) increases from 14 to 17 and 22 cm, re-

spectively, while systolic blood pressure decreases from 162 to

154 and 151 mm Hg. Note that the blood flow velocity scale is

different in the three recordings [15].

Figure 5. Line plots of the diameter of the distal arterial seg-

ments at 5 and 25 minutes after completion of angioplasty with

BQ-123 (an ETAR antagonist) (right) or saline control admini-

stration (left). *: p < 0.05 versus 5-minute postangioplasty [16].

vasoconstriction is significantly attenuated by ETAR

blockade. Pernow, et al. [19] showed that intravenous

ET-1 administration decreases coronary sinus blood flow

and increases coronary vascular resistance in humans.

Endogenous ET-1 maintains the normal coronary ar-

tery tone and thus regulates coronary blood flow. In pa-

tients undergoing coronary arteriography, administra-

tion of intracoronary BQ-123 led to an increase in blood

flow in the left anterior descending coronary artery, an

increase in the diameter of the distal segment of the coro-

nary artery and a decrease in coronary vascular resis-

tance (Figure 4) [15]. Moreover, changes in blood flow

were similar in subjects with and without coronary artery

disease [15]. In coronary artery disease patients, coro-

nary artery compliance increased after intracoronary

BQ-123 [20]. ETAR dependent activity is impaired in

diabetic patients; coronary artery diameter in diabetic

patients increased far less in comparison to healthy sub-

jects after administration of intracoronary BQ-123 [21].

In a similar manner, physiologic response to ETAR

blockade was also attenuated in hypertensive patients

[22].

4. ET-1 ON THE CORONARY

COLLATERAL CIRCULATION

Collateral vessels demonstrate heightened sensitivity to

certain vasoconstrictors such as vasopressin, which can

decrease blood flow to the dependent myocardium at

doses that do not affect blood flow to normal myocar-

dium. Rapps, et al. [23] found that collateral vessel rings

constricted smaller-than-normal coronary arterial vessels

to ET-1. An impaired collateral vasoconstrictor response

might be expected to protect collateral blood flow when

ET-1 levels are increased. In the work of Traverse, et al.

[24], collateral blood flow did not significantly change

although coronary sinus ET-1 concentrations exceeded

70 pg/ml. Only at the highest infusion rate, when the

coronary blood concentration was 175 pg/ml, did colla-

E. Polymeropoulos et al. / World Journal of Cardiovascular Diseases 3 (2013) 371-376

374

teral blood flow decrease significantly. It was demon-

strated that in the intact animal collateral vessels con-

strict similarly to normal vessels in response to ET-1.

Coronary collateral vessels can synthesise prostacyclin.

Furthermore, in dogs with long-term coronary occlusion,

prostacyclin appears to cause tonic collateral vessel dila-

tation [25] because cyclooxygenase blockade with indo-

methacin significantly decreased retrograde blood flow

from the cannulated collateral dependent artery. Traverse,

et al. [24] showed that prostacyclin production is impor-

tant in blunting th e vasoconstrictor effects of ET-1 in th e

collateral circulation. In contrast, the response of colla-

teral vascular resistance to ET-1 in the normal zone was

much less affected by inhibition of prostacyclin produc-

tion. This is in agreement with previous findings that

vasodilator prostaglandins are of greater importance in

collateral than in normal coronary vessels.

Well-developed collateral vessels exhibit nitric oxide-

mediated, endothelium-dependent vasodilation in res-

ponse to agonists such as acetylcholine or bradykinin

[26-28]. However, there are indications that vasodila-

tation of collateral vessels resulting from ET-1-stimu-

lated production of nitric oxide could also improve per-

fusion of the collateral-dependent region. ET-1 could al-

ter blood flow to the collateral-dependent myocardium

by influencing vasomotion of the resistance vessels in

the collateral zone. As we know, receptor-mediated, en-

dothelium-dependent dilation has been shown to be im-

paired in microvessels chronically perfused by collateral

vessels [28 ].

Donckier, et al. [29] studied 30 conscious chronically

instrumented dogs before, during and after a 10-min

coronary artery occlusion performed either during ET-1

or during saline infusion. Left anterior descending artery

blood flow decreased equally during occlusion with ei-

ther ET-1 or saline. Both endocardial and epicardial

blood flow in ischemic regions also decreased during

artery occlusion but were threefold greater with ET-1

than with placebo. These results showed that ET-1 in-

creases collateral blood flow in the ischemic myocar-

dium in dogs.

By combining coronary wedge pressure, obtained by

means of a wave wire, with simultaneously recorded

aortic pressure, obtained by means of the guiding cathe-

ter, and central venous pressure at maximum arterial

vasodilation, a quantitative index of collateral flow can

be calculated. This index, called fractional collateral

blood flow, expresses actual collateral flow as a ratio to

normal maximum myocardial perfusion. A lower ratio

indicates a higher impairment in the collateral perfusion

of the ischemic myocardium. After repeated balloon in-

flations, the coronary wedge pressure, in a group of pa-

tients administered BQ-123, decreased, whereas in the

control group it increased. These results indicate that

acute ETAR antagonism decreases coronary collateral

circulation in patients with coronary artery disease du-

ring angioplasty. Therefore, ETAR antagonism may in-

crease coronary blood flow and decrease coronary artery

resistance and distal coronary pressure by dilating the

distal arterial segments and the resistance arteries in the

nonischemic region [14].

5. ETA ANTAGONISTS AND INHIBITION

OF RESTENOSIS

In addition to its actions on vascular smooth muscle cells,

ET-1 is also a potent mitogen in several cultured cell

lines of both cardiovascular and noncardiovascular origin

[30]. ET-1 also induces the expression and release of

several proto-ongogenes and growth factors, the latter of

which may be synergistic [31-34].

Douglas, et al. [35] studied the role of endogenous

ET-1 in neointimal formation after rat carotid artery bal-

loon angioplasty. They showed that ET-1 promotes

neointimal formation in vivo and that it is involved in the

pathogenesis of angioplasty-induced lesion formation in

the rat. They showed also the protective effect of the

nonpeptide ETR an tagonist SB 209670 ( ETAR and ETBR

antagonist) in neointimal formation, indicating that this

substance can serve as a useful adjunct to coronary an-

gioplasty, attenuating the degree of vascular restenosis

observed after vascular wall injury. The same investiga-

tors showed that neither chronic nor acute ETAR bloc-

kade after giving BQ-123, an ETAR blockade, is suffi-

cient to inhibit angioplasty-induced neointima formation

in the rat. They implicated a significant role for the ETBR

subtype, either exclusively or in concert with ETAR acti-

vation, in the pathogenesis of neo intima formation in the

rat. The administration of BQ-123 in patients with stab le

angina undergoing angioplasty, failed to show any dif-

ference in restenosis after 6 months, as analyzed by

quantitative coronary arteriography and intravascular

ultrasound [36].

6. CONCLUSION

ET-1 maintains normal coronary artery tone. ETAR as-

sume a cornerstone role on the regulation of coronary

circulation. There is an upregulation of ETAR in hyper-

tension and a downregulation in diabetes. ET is a potent

promoter of neointimal formation, and ETAR blockade

inhibits restenosis after ang ioplasty in an imal model. The

secretion of ET during myocardial ischemia and reperfu-

sion is related to ischemia, rather than to endothelial in-

jury. ETAR antagonism increases coronary blood flow in

healthy coronary arteries, but may reduce coronary blood

flow in diseased segments, via a coronary steal pheno-

menon. Moreover, ETAR blockade increases the diameter

of distal coronary arterial segments and decreases coro-

nary vascular resistance. Coronary collaterals have de-

creased sensitivity to ET-1, and ETAR antagonism de-

E. Polymeropoulos et al. / World Journal of Cardiovascular Diseases 3 (2013) 371-376 375

creases collateral blood flow and perfusion of the ische-

mic myocardium.

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