Although serotonin (5-hydroxytryptamine; 5-HT) is used for provocation of coronary spasm, 5-HT receptor subtypes in spastic coronary arteries remain undetermined. We demonstrated the supersensitivity of isolated coronary artery to ergonovine, 5-HT, and sumatriptan, a 5-[HT.sub.ID]) receptor agonist, in a patient with variant angina. Furthermore, we detected gene expression of 5-[HT.sub.1D[Beta]] and 5-[HT.sub.2A] receptors in spastic coronary artery using RNase protection assay. These findings suggest that the leftward shift of the dose-response curve for 5-HT, which plays an important role in the pathogenesis of coronary spasm, is mediated by activation of 5-[HT.sub.1D[Beta]] receptor. (CHEST 1998; 113:243-44)
Key words: coronary artery; coronary spasm; ergonovine; 5-[HT.sub.1D[Beta]] receptor; serotonin; sumatriptan; variant angina
Abbreviations: 5-HT=5-hydroxytryptamine, serotonin; mRNA= messenger RNA; RCA= right coronary artery
Coronary spasm, which usually occurs at the site of an atherosclerotic lesion, has been shown to play an important role in the pathogenesis of ischemic heart disease.[1] Atherosclerotic arteries[2] exhibit enhanced susceptibility to the constrictive effects of ergonovine and serotonin (5-hydroxytryptamine; 5-HT). We previously reported the supersensitivity in contractile response of isolated coronary artery from a patient with variant angina to ergonovine.[3] Ergonovine provokes coronary spasm in susceptible patients mainly via activation of 5-HT receptors. However, the 5-HT receptor subtypes in spastic coronary arteries remain undetermined. In the present report, we demonstrated the supersensitivity of isolated coronary artery to sumatriptan, a 5-[HT.sub.ID] receptor agonist, and characterized the 5-HT receptor messenger RNA (mRNA) expression in a patient with variant angina.
CASE REPORT
A 63-year-old woman was admitted to our hospital with the sensation of anterior chest pain at rest in 1976. Spontaneous coronary spasm with severe chest pain and ST-segment elevations in inferior leads, which were also detected during her spontaneous anginal episodes, was detected in the right coronary artery (RCA) during coronary angiography. After sublingual nitroglycerin alleviated her symptoms and ST elevations, coronary angiography exhibited no organic stenotic lesions. She was diagnosed as having variant angina occurring at the RCA. Treated with oral nitrate and nifedipine, she remained generally well for 20 years. In June 1996, she suddenly died of acute myocardial infarction. Postmortem pathologic examination revealed severe stenotic lesions in the proximal segment of left anterior descending coronary artery with fresh thrombus. Diffuse minimal atherosclerotic lesions were observed in the RCA. Cross-sections of the RCA revealed diffuse intimal thickening with fibromuscular accumulation.
With approval of the institutional review board on human research at Kobe University Hospital and informed consent from her family, pharmacologic and molecular experiments were performed using the coronary arteries of the patient. Proximal and distal portions of the RCA were used for recording isometric tension. Concentration-response curves for phenylephrine, 5-HT, sumatriptan, and ergonovine were determined by cumulative addition of each drug to the organ baths. In our previous study? the threshold concentrations of isolated control human coronary arteries to 5-HT, ergonovine, and phenylephrine were reported to be as follows: 2.9 [+ or -] 1.0 x [10.sup.-10] mol/L; 8.7 [+ or -] 3.1 x [10.sup.-10]) mol/L; and 2.9 [+ or -] 0.9 x [10.sup.-10] mol/L, respectively. These values are almost the same as those in another report.[4] In the present study, 5-HT and ergonovine contracted helical strips of the RCA at extremely low concentrations: [10.sup.-12] mol/L and [10.sup.-15] mol/L, respectively. Interestingly, these coronary strips were also supersensitive to sumatriptan. The threshold concentration for sumatriptan was [10.sup.-12] mol/L, which is much lower than that in a published study.[4] These strips exhibited neither enhanced sensitivity nor reactivity to phenylephrine (Fig 1). However, the strip of left anterior descending coronary artery was supersensitive to none of these agents (data not shown).
[Figure 1 ILLUSTRATION OMITTED]
We extracted total RNA from the coronary arteries of this patient after denuding the endothelium and performed RNase protection assay using the riboprobes for 5-[HT.sub.1A/1D[Alpha]/1D[Beta]/1E] and 5-[HT.sub.2A/2B] receptors to clarify which subtypes of 5-HT receptors are expressed in the coronary arteries. 5-[HT.sub.1D[Beta]] and 5-[HT.sub.2A] receptor mRNAs were found, but 5-[HT.sub.1A], 5-[HT.sub.1D[Alpha]], 5-[HT.sub.1E], and 5-[HT.sub.2B] receptor mRNAs were not detected in the coronary arteries of this patient (Fig 2). The presence of 5-[HT.sub.1F/2C] receptors was excluded by reverse transcription-polymerase chain reactions (data not shown).
[Figure 2 ILLUSTRATION OMITTED]
DISCUSSION
To our knowledge, this is the first report of a patient with variant angina showing the supersensitivity of isolated coronary arteries to sumatriptan, and the expression of 5-[HT.sub.1D[Beta]] and 5-[HT.sub.2A] receptor mRNAs in coronary arteries. These findings suggest that 5-[HT.sub.1D[Beta]] receptor is expressed functionally and may mediate the supersensitivity to 5-HT in spastic coronary arteries, since sumatriptan is devoid of agonist properties at the 5-[HT.sub.2A] receptor. Diffuse intimal thickening and fibromuscular accumulation were observed in the RCA, and the supersensitivity to 5-HT associated with these atherosclerotic changes appears to be a fundamental mechanism in coronary spasm. 5-HT has been reported to contract human coronary arteries through 5-[HT.sub.1]-like and 5-[HT.sub.2] receptors,[4] and this agent is used to provoke coronary spasm. Ketanserin, a 5-[HT.sub.2A] receptor antagonist, failed to block 5-HT-induced coronary artery contraction and coronary spasm in patients with variant angina.[5] In addition, effects mediated by 5-[HT.sub.1]-like receptors, but not those by 5-[HT.sub.2] receptors, are preserved in patients with ischemic heart disease.[6] Therefore, it is suggested that 5-HT receptor subtypes are altered in coronary arteries with atherosclerosis or coronary spasm, and that 5-[HT.sub.1]-like receptors rather than 5-[HT.sub.2] receptors may be involved in the enhanced vascular reactivity to 5-HT. Our findings contribute to the characterization of 5-[HT.sub.1] receptors in spastic coronary arteries. We speculate that the leftward shift of the dose-response curve for 5-HT, which may be a crucial mechanism in the pathogenesis of coronary spasm, is mediated by activation of 5-[HT.sub.1D[Beta]] receptor.
REFERENCES
[1] Maseri A, Davies G, Hackett D, et al. Coronary artery spasm and vasoconstriction: the case for a distinction. Circulation 1990; 81:1983-91
[2] Henry PD, Yokoyama M. Supersensitivity of atherosclerotic rabbit aorta to ergonovine: mediation by a serotonergic mechanism. J Clin Invest 1980; 66:306-13
[3] Yokoyama M, Akita H, Hirata K, et al. Supersensitivity of isolated coronary artery to ergonovine in a patient with variant angina. Am J Med 1990; 89:507-15
[4] Kaumann AJ, Frenken M, Posival H, et al. Variable participation of 5-HTldike receptors and 5-HT2 receptors in serotonin-induced contraction of human isolated coronary arteries: 5-[HT.sub.1]-like receptors resemble cloned 5-[HT.sub.1D[Beta]] receptors. Circulation 1994; 90:1141-53
[5] Caterina RD, Carpeggiani C, Abbate AL. A double-blind, placebo-controlled study of ketanserin in patients with Prinzmetal's angina: evidence against a role for serotonin in the genesis of coronary vasospasm. Circulation 1984; 69:889-94
[6] Chester AH, Martin GR, Bodelsson M, et al. 5-Hydroxytryptamine receptor profile in healthy and diseased human epicardial coronary arteries. Cardiovasc Res 1990; 24:932-37
(*) From the First Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan.
Manuscript received March 12, 1997; revision accepted April 23.
Reprint requests: Mitsuhiro Yokoyama, MD, First Department of Internal Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650, Japan
COPYRIGHT 1998 American College of Chest Physicians
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