(Circulation. 1998;98:1587-1590.)
© 1998 American Heart Association, Inc.
Acetylcholine and Endothelial Function
Dimitris Tousoulis, MD, PhD;
; Graham Davies, MD, FRCP
Cardiology Unit,
Hammersmith Hospital,
London, UK
Tom Crake, MD, FRCP
Cardiology Unit St Bartholomew's Hospital,
London, UK
To the Editor:
Hasdai et al1 reported that myocardial perfusion
defects are produced in response to acetylcholine
10-4 mol/L IC. However, acetylcholine has dual
effects on coronary artery tone depending on the
intracoronary concentration of acetylcholine and the presence
of coronary atheroma. In normal coronary
arteries, vasodilation, mediated by the endothelial
cells, occurs at low concentrations and vasoconstriction, mediated by a
direct action on the smooth muscle cells, at higher concentrations. In
atheromatous coronary arteries, constriction
and dilation occur at low concentration and only constriction occurs at
high concentrations of acetylcholine.2 3
We have studied the responses of epicardial coronary arteries
to intracoronary infusion of acetylcholine in 15 patients with
normal coronary arteriograms, chest pain, and risk factors for
coronary artery disease.4 In 53% of
patients, there was both constriction and dilation of proximal and
distal segments coexisting not only in different coronary
arteries but also in different segments of the same artery at
10-7 to 10-6 mol/L
acetylcholine. At 10-4 and
10-3 mol/L, the dilatation response was blunted
and constriction predominated.
We also studied the responses of stenotic and
nonstenotic segments to intracoronary infusion of
acetylcholine in 18 patients with coronary artery disease and
stable angina.5 In all the patients and in 90%
to 100% of the stenotic segments, vasoconstriction occurred at
10-5 to 10-3 mol/L
acetylcholine (Figure
). In particular, in
response to 10-4 mol/L acetylcholine, both the
stenotic segments and the adjacent reference segment
constricted significantly (-26.7±4.3 and -11.4±2.0%, respectively;
Figure) with evidence of myocardial ischemia (ST segment change
and/or chest pain in 
50% of patients).
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Figure 1. Responses of stenotic segments to
intracoronary infusion of 10-7 to
10-3 mol/L acetylcholine in patients with coronary
artery disease. c indicates number of constricted segments; d, number
of dilated segments.
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These findings indicate that when acetylcholine is infused in high
doses in the presence of atherosclerosis, its direct
smooth muscle cell constrictor effects are dominant compared with the
endothelial vasodilator effects. These smooth muscle
cell responses to acetylcholine may be exaggerated and contribute to a
reduction of the myocardial perfusion. Furthermore, our preliminary
observations indicate that atherosclerotic segments that constrict in
response to acetylcholine may vasodilate in response to substance P (an
endothelium-dependent
vasodilator).6 Substance P may therefore be a
better test of endothelial function than a high dose of
acetylcholine. It is difficult to conclude from either our studies or
that of Hasdai et al that myocardial ischemia in these patients
is due to microvascular endothelial dysfunction.
References
1.
Hasdai D, Gibbons RJ, Holmes DR, Higano ST, Lerman A.
Coronary endothelial dysfunction in humans is
associated with myocardial perfusion defects.
Circulation. 1997;96:3390–3395.[Abstract/Free Full Text]
2.
El Tamimi H, Mansour M, Wargorich TJ, Hill JA,
Kerensky RA, Conti RC, Pepine CJ. Constrictor and dilator responses to
intracoronary acetylcholine in adjacent segments of the same
coronary artery in patients with coronary artery
disease: endothelial function revisited.
Circulation. 1994;89:45–51.[Abstract/Free Full Text]
3.
Newman CM, Maseri A, Hackett D, El-Tamimi HM, Davies
GJ. Response of angiographically normal and atherosclerotic left
anterior descending coronary arteries to acetylcholine.
Am J Cardiol. 1990;66:1070–1076.[Medline]
[Order article via Infotrieve]
4.
Tousoulis D, Davies G, Lefroy DC, Haider AW, Crake T.
Variable coronary vasomotor responses to acetylcholine in
patients with normal coronary arteriograms: evidence for
localised endothelial dysfunction.
Heart. 1996;75:261–266.[Abstract/Free Full Text]
5.
Tousoulis D, Crake T, Kaski JC, Rosen S, Haider A,
Davies GJ. Enhanced vasomotor responses of complex coronary
stenoses to acetylcholine in stable angina pectoris.
Am J Cardiol. 1995;75:725–728.[Medline]
[Order article via Infotrieve]
6.
Tousoulis D, Tentolouris C, Crake T, Lefroy DC, Habib
F, Toutouzas P, Davies GJ. Segmental
endothelium-dependent and
endothelium-independent coronary vasodilator
responses in patients with stable angina. Eur Heart
J. 1996;17(suppl):464. Abstract.
Response
Amir Lerman, MD;
David Hasdai, MD;
; David Holmes, MD
Mayo Clinic,
Rochester, Minn
We have read with interest the letter to the editor by Dr
Tousoulis and colleagues. They raised several very important issues
regarding the coronary response to infusion of acetylcholine in
humans. Tousoulis and colleagues demonstrated in 15 patients that
acetylcholine infusion resulted in epicardial coronary
vasoconstriction. Moreover, they emphasize an important point: that the
response of the coronary vasculature to acetylcholine may
be heterogeneous.
Their observation underscored the significance of measuring
coronary blood flow and coronary vascular resistance in
response to substances like acetylcholine and substance P, rather than
measuring a single-segment change in diameter. The change in epicardial
coronary artery diameter in response to acetylcholine does not
necessarily correlate with the change in coronary blood flow
(Hasdai et al, unpublished data, 1998). Because control of
coronary blood flow to the myocardium is mainly at
the level of the microcirculation, it is essential to follow the change
in coronary blood flow in response to acetylcholine rather than
the change in epicardial coronary artery diameter.
The next issue that Tousoulis et al raise is the differential response
to acetylcholine versus substance P in patients with normal
coronary arteries and chest pain. Previous investigations by
Quyyumi et al1 compared coronary blood
flow and coronary vascular rate in response to acetylcholine
and substance P. They suggested that the dysfunction of the stimulatory
capacity of the endothelial cell layer is not
restricted to the muscarinic receptors and extends to others such as
substance P. Thus, acetylcholine may serve as a clinically useful tool
to assess the integrity of the endothelium. Moreover,
previous studies established the relationship between the
pharmacological response to acetylcholine and the
physiological vasodilation response to
metabolic stresses such as mental stress, exercise, and
hyperemia.
Another issue raised by Tousoulis et al is the correlation
between the degree of atherosclerosis and the response
to acetylcholine. We have previously demonstrated that there is no
relationship between the degree of coronary
atherosclerosis by intravascular ultrasound and the
response to acetylcholine.2 Thus, it is difficult
to predict the response of the endothelium to
pharmacological stimuli on the basis of the degree of coronary
atherosclerosis.
References
1.
Quyyumi AA, Mulcahy D, Andrews NP, Husain S, Panza JA,
Cannon RO III. Coronary vascular nitric oxide activity in
hypertension and hypercholesterolemia.
Circulation. 1997;95:104–110.[Abstract/Free Full Text]
2.
Nishimura RA, Lerman A, Chesebro JH, Ilstrup DM,
Higano ST, Holmes DR Jr, Tajik AJ. Endothelial function
is not predicted by coronary atherosclerosis
assessed by intracoronary ultrasonography. J Am
Coll Cardiol. 1995;26:41–49.[Abstract]
