Acetylcholine and Endothelial Function
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).
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.
- Copyright © 1998 by American Heart Association
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.
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.
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.
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.
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 alR1 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.R2 Thus, it is difficult to predict the response of the endothelium to pharmacological stimuli on the basis of the degree of coronary atherosclerosis.