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(Circulation. 1998;98:385-390.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Cocaine Increases the Endothelial Release of Immunoreactive Endothelin and Its Concentrations in Human Plasma and Urine

Reversal by Coincubation With -Receptor Antagonists

Ute Wilbert-Lampen, MD; Christian Seliger, MS; Thomas Zilker, MD; ; Rainer M. Arendt, MD

From the Medizinische Klinik and Poliklinik I, Klinikum Großhadern, Ludwig-Maximilian-University (U.W.-L., C.S., R.M.A.) and the II. Medizinische Klinik and Poliklinik, Department of Toxicology, Klinikum rechts der Isar, Technical University (T.Z.), Munich, Germany.

Correspondence to Dr Rainer M. Arendt, Med. I, Klinikum Großhadern, University of Munich, Marchioninistr 15, 81366 Munich, Germany. E-mail rainer.arendt{at}med1.med.uni-muenchen.de

	Abstract

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Background—Cocaine-associated vascular events are not completely explained by adrenergic stimulation. The purposes of this study were to investigate whether vasoconstrictive endothelin-1 is released by cocaine and to elucidate the mechanisms involved.

Methods and Results—Endothelin-1 was measured by radioimmunoassay and high-performance liquid chromatography (1) in the supernatant of porcine aortic endothelial cells after treatment with cocaine (10^-7 to 10^-4 mol/L) and a -receptor antagonist, haloperidol (10^-6 mol/L) or ditolylguanidine (10^-5 mol/L) and (2) in plasma and urine of 12 cocaine-intoxicated patients and 13 healthy control subjects. Radioligand binding assays were performed on endothelial membrane preparations. In cell culture, cocaine significantly increased endothelin accumulation above baseline at 3 to 24 hours; endothelin release rates per hour increased dose-dependently, reaching a plateau of 175±23% of control at hour 4 to 5. Coincubation of cocaine with haloperidol or ditolylguanidine abolished or reduced cocaine-induced endothelin release. Endothelial membrane preparations specifically and displaceably bound the highly selective -ligand [³H]ditolylguanidine (25x10^-9 mol/L), with 1400 binding sites estimated per cell. Endothelin-1 levels in plasma (22.7±5.6 versus 7.3±0.8 pmol/L) and urine (41.5±10.1 versus 12.7±3.8 pmol/L) of cocaine-intoxicated patients were significantly increased compared with control values.

Conclusions—The data suggest that cocaine increases the endothelin-1 release in vitro and in vivo. The cocaine-induced vasoconstriction/vasospasm may therefore be facilitated by the release of endothelin-1. Cocaine appears to be an exogenous stimulator at endothelial -receptors. The endogenous ligands of this antiopioid system may prove to play a role in vasospastic angina, acute myocardial infarction, and sudden cardiac death.

Key Words: cocaine • endothelin • receptors, sigma • death, sudden • vasospasm

	Introduction

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Chest pain is the most common cocaine-related medical problem, leading to >35 000 hospital admissions per year in the United States at an estimated annual cost of $83 million.^{1 2}

As cocaine abuse has become more common, reports of acute myocardial infarction after the use of cocaine have appeared with increasing frequency.^{3 4 5} However, the actual frequency of cardiovascular complications, including myocardial ischemia and infarction, arrhythmias and sudden death, myocarditis and cardiomyopathy, arterial hypertension, rupture of the aorta, arterial thrombosis, and cerebrovascular events is not established.^{5 6 7 8 9 10}

Cocaine appears to cause acute myocardial ischemia and/or infarction not only in patients with preexisting coronary artery disease but also unassociated with obstructive coronary artery disease in 33% of cases.^{10 11} Acute myocardial infarction has even been reported in neonates whose mothers used the drug,¹² and acute myocardial infarction or sudden cardiac death occurs in young adults.^{7 13 14}

Cocaine may induce acute myocardial ischemia or infarction by at least 2 mechanisms: (1) increasing myocardial oxygen demand through increases in heart rate and blood pressure and (2) diminishing coronary artery flow resulting from either local coronary vasospasm, increased vasoconstrictor tone, and/or thrombosis.^{7 8 9}

It has often been suggested that cocaine causes -adrenergically mediated coronary constriction.¹⁵ However, the pharmacological effects of cocaine are more diverse and include (1) increased (central) neurotransmission by reuptake inhibition of dopamine and serotonin,^{2 16 17 18} (2) local anesthetic effects by inhibition of sodium channels,^{2 16} (3) peripheral sympathomimetic effects by reuptake inhibition of epinephrine and norepinephrine and by stimulation of presynaptic norepinephrine release,^{2 18} (4) direct or baroreflex-mediated inhibition of sympathetic neural outflow from the central nervous system^{19 20} and of neurotransmission at sympathetic ganglia,¹⁹ (5) transient vagotonic effects on the cardiovascular system,² and (6) stimulation of the hypothalamic-pituitary-adrenal axis²¹ and of the stress response.^{2 16}

Furthermore, cocaine exerts direct, ie, not neurally mediated, effects that may have been underestimated: (7) enhanced platelet aggregation,²² (8) catecholamine-independent induction of stress-protein synthesis²³ and accelerated atherosclerosis,² (9) direct constrictor effects on the vessel wall,^{24 25} and (10) impaired endothelium-dependent vasorelaxation.^{26 27}

The direct vascular effects of cocaine are not fully understood. Our objective was to test whether cocaine induces the endothelial release of endothelin-1, the most potent endogenous vasoconstrictor,²⁸ which has been implicated in coronary vasoconstriction/vasospasm, myocardial ischemia, and infarction^{29 30 31 32 33} and as a risk factor for survival in heart failure.³⁴ To evaluate the plausibility of endothelin-1 mediating cocaine effects in vivo, we complemented the in vitro data by measurements of endothelin-1 concentrations in plasma and urine of patients with acute cocaine intoxication.

	Methods

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Materials
Rabbit antiserum RAS 6901 N against endothelin-1 was purchased from Peninsula Laboratories, big endothelin antiserum (46/10) and endothelin-1 standard from Medor Laboratories, and ¹²⁵I-labeled endothelin-1 from Biotrend Chemicals GmbH; haloperidol, cocaine, and procaine were obtained from Sigma; and 1,3-di(2-tolyl)guanidine (ditolylguanidine) was synthesized in our laboratory and radioactively labeled ([³H]ditolylguanidine) by Biotrend.

Cell Isolation and Culture
Endothelial cells were isolated from porcine aorta by established methods.³⁵ Studies were performed on confluent monolayers 3 days after the last passage in a serum-free medium. During the experiments, culture medium containing test substances (cocaine 10^-7, 10^-6, 10^-5, or 10^-4 mol/L; procaine 6x10^-7, 6x10^-6, 6x10^-5, or 6x10^-4 mol/L; haloperidol 10^-6 mol/L; ditolylguanidine 10^-5 mol/L) or blanks was renewed at 0, 4, or 23 hours. Culture medium was then sampled at 5 and 24 hours for determinations of immunoreactive endothelin release rates for the preceding hour. Endothelial cells were counted by use of a conventional grid micrometer (Carl Zeiss).

Radioligand Binding
Cultured endothelial cells were scratched from culture flasks, homogenized in 10 volumes (wt/vol) of 0.32 mol/L saccharose/10 mmol/L Tris-HCl, pH 7.4. The supernatant was collected, centrifuged, and resuspended in 10 volumes of Tris-HCl, pH 7.4, incubated at 37°C for 30 minutes, centrifuged, resuspended in 10 volumes of 50 mmol/L Tris-HCl, pH 7.4, and stored at -70°C. For binding assays, 200-µL aliquots of membrane suspension were added to Eppendorf tubes containing 50 µL unlabeled drug or buffer and 50 µL [³H]ditolylguanidine for a final concentration of 25 nmol/L. The protein concentration in the 300-µL incubation volume was 120 to 150 µg, corresponding to 17x10⁶ cells. Nonspecific binding was defined as that remaining in the presence of 25 µmol/L haloperidol. After incubation for 120 minutes at room temperature, the membrane suspension was rapidly filtered under vacuum through Whatman GF/B glass fiber filters. The filters were washed 3 times with 5 mL ice-cold 50 mmol/L Tris-HCl buffer (pH 7.4). Each filter was dissolved in 10 mL liquid scintillation cocktail (CytoScint, ICN), and radioactivity was measured by liquid scintillation spectrometry.

Patients' Characteristics and Sample Collection
Blood and urine samples were obtained from 13 normal subjects (10 men and 3 women, 19 to 42 years old) and 12 cocaine-intoxicated patients (10 men and 2 women, 18 to 41 years old). Cocaine-intoxicated patients had slightly elevated blood pressure readings (141±16/92±12 mm Hg), 8 of 12 patients displayed nonspecific ECG changes, and 2 patients had slightly elevated creatine kinase values but no clinical evidence of myocardial infarction.

In all subjects, peripheral venous blood was drawn with subjects in the supine position and immediately transferred to EDTA polystyrene tubes. After centrifugation, plasma was removed and stored at -80°C. Voided urine was collected from the healthy control subjects and patients and immediately stored at -80°C.

Extraction and Radioimmunoassay
Extraction from cell culture medium, plasma, and urine samples and radioimmunoassay were performed as described previously.^{30 35 36}

Chromatographic Separation
Gel filtration fractions of pooled medium extracts containing endothelin-1 immunoreactivity were characterized further on a reverse-phase high-performance liquid chromatography system as described previously.³⁵

Data Analysis
Immunoreactive endothelin release rates into culture medium were determined in the 5th (hour 4 to 5) and 24th (hour 23 to 24) hours of the experiment as fmol per 2.5x10⁵ cells per hour. Data in individual experiments were related to their respective 5-hour or 24-hour control values and are presented as percentages of control values. All data are expressed as mean±SD with n=9 to 21 observations in 3 to 7 separate experiments. Data were subjected to ANOVA followed by the Tukey test or Student's t test if appropriate. The level of statistical significance was set at P<0.05.

	Results

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Serial determinations after incubation for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 24 hours displayed a time-dependent increase in endothelin immunoreactivity in porcine aortic cell culture medium. Addition of cocaine (10^-4 mol/L) to the cell incubation significantly increased the accumulated endothelin immunoreactivity compared with the corresponding basal 3- to 24-hour values, eg, to 27.0±4.5 versus 17.8±2.5 fmol per plate at 8 hours (Figure 1).

View larger version (16K): [in this window] [in a new window]   Figure 1. Time course of cumulative endothelin immunoreactivity (ET, comprising endothelin-1 and big endothelin) over 24 hours in medium of cultured porcine aortic endothelial cells without () and with () cocaine (10-4 mol/L). Cultured medium was sampled every hour for 10 hours and at 24 hours for determinations of immunoreactive endothelin. Data are mean±SD in fmol per plate (=mL medium); n=9 observations in 3 separate experiments. Statistical comparisons were made by t test; * denotes significantly different from control, P<0.05.

Gel filtration and high-performance liquid chromatography analysis of endothelin immunoreactivities in cell culture medium revealed that endothelin coeluted in 2 fractions, the dominant part corresponding to the elution position of synthetic endothelin-1, which was preceded by a minor peak corresponding to synthetic big endothelin (data not shown). As previously reported, circulating or urinary immunoreactive endothelin consisted almost exclusively of authentic endothelin-1 (data not shown).^{30 36}

After short or long preincubation (for 4 or 23 hours, respectively), the release rates of endothelin (hour 4 to 5 or 23 to 24) increased dose-dependently in the presence of 10^-6 to 10^-4 mol/L cocaine, eg, in the presence of 10^-4 mol/L cocaine to 13.9±0.82 fmol per 2.5x10⁵ cells per hour (hour 4 to 5). Compared with their concurrent control values, endothelin release rates at hour 4 to 5 reached a plateau at 175±23% of control. After the longer preincubation (hour 23 to 24), lower cocaine concentrations were less effective compared with the 5th-hour values (Figure 2).

View larger version (19K): [in this window] [in a new window]   Figure 2. Concentration-dependent effects of cocaine (10-7 to 10-4 mol/L) on immunoreactive endothelin (ET, comprising endothelin-1 and big endothelin) release rates over 1 hour (hour 4 to 5 or 23 to 24). Data are mean±SD in percent of respective control values; n=21 observations in 7 separate experiments. Statistical comparisons were made by ANOVA followed by Tukey's test; * denotes significantly different from control, P<0.05.

Another local anesthetic, procaine, in concentrations of 6x10^-7 to 6x10^-4 mol/L did not affect the endothelin release rates (data not shown).

Cocaine is known to bind to atypical () opioid receptors in the central nervous system, and we had previously demonstrated that endogenous opioid peptides displayed stimulatory effects on endothelial endothelin release mediated by an atypical opioid receptor.³⁵ We therefore tried to antagonize cocaine-induced increases in endothelin release by -receptor antagonists. Neither the nonselective, high-affinity -receptor antagonist haloperidol (10^-6 mol/L) nor the highly selective -receptor antagonist ditolylguanidine (10^-5 mol/L) displayed significant effects on basal endothelin release rates. However, coincubation of cocaine (10^-4 mol/L) with haloperidol (10^-6 mol/L) abolished all cocaine effects on endothelin release rates at hour 4 to 5 and 23 to 24. Coincubation with ditolylguanidine (10^-5 mol/L) also significantly reduced cocaine-induced increases in endothelin release rates at hour 4 to 5 and to a lesser degree but still significantly at hour 23 to 24 (Figure 3).

View larger version (16K): [in this window] [in a new window]   Figure 3. Effects of cocaine (Coca) (10-4 mol/L), the nonselective -receptor antagonist haloperidol (Halo) (10-6 mol/L), and the selective -receptor ligand ditolylguanidine (DTG) (10-5 mol/L) vs combined treatments with cocaine (10-4 mol/L) and haloperidol (10-6 mol/L) or ditolylguanidine (10-5 mol/L) on immunoreactive endothelin (ET, comprising endothelin-1 and big endothelin) release rates over 1 hour (hour 4 to 5 or 23 to 24). Data are mean±SD in percent of respective control values; n=12 observations in 3 separate experiments. Statistical comparisons were made by ANOVA followed by Tukey's test; * denotes significant difference of combined treatments with cocaine and antagonists from incubation with cocaine alone, P<0.05.

Because -receptors had not previously been demonstrated on endothelial cells, we conducted binding experiments on membranes of cultured porcine aortic endothelial cells. Membrane preparations specifically bound the highly selective -receptor ligand [³H]ditolylguanidine. This binding was displaceable by unlabeled ditolylguanidine or haloperidol (Figure 4). Cellular binding sites were estimated as 1400 binding sites per cell.

View larger version (14K): [in this window] [in a new window]   Figure 4. Specific binding of [3H]ditolylguanidine (3H-DTG; 25 nmol/L, 50 Ci/nmol) to membranes from cultured aortic endothelial cells. Data are given as fmol 3H-DTG bound/mg membrane protein. Binding was displaced by haloperidol (Halo) and half saturated at a haloperidol concentration of 1 µmol/L. Nonspecific binding was determined in the presence of 25 µmol/L haloperidol and was always <40% of total binding.

Endothelin concentrations were determined in plasma and urine of patients with cocaine intoxication. The mean concentration of plasma endothelin in the cocaine-intoxicated users was 22.7±5.6 pmol/L compared with 7.3±0.8 pmol/L in a matched control group (P<0.05). In parallel, the mean endothelin concentration in urine was significantly higher in the cocaine-intoxicated compared with the healthy control subjects: 41.5±10.1 versus 12.7±3.8 pmol/L, P<0.05 (Figure 5).

View larger version (14K): [in this window] [in a new window]   Figure 5. Determination of immunoreactive endothelin-1 (ET-1) in plasma and urine of patients intoxicated with cocaine (n=12) compared with a control group (n=13). Data and mean±SD are in pmol/L. Statistical comparisons were made by t test; *P<0.05 vs control.

	Discussion

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The results presented here document stimulatory effects of cocaine on vasoconstrictive endothelin release from cultured porcine aortic endothelial cells. Accumulation of endothelin in cell culture medium is time-dependent but delayed by 3 hours, reaching a plateau at 8 hours' incubation time. This delay is explained by the lack of secretory granules or of preformed peptide precursors in the cultured endothelial cell, defining a predominantly constitutive secretion pattern.

To exclude not easily controllable factors during endothelin accumulation into the cell culture medium, such as substrate consumption, product inhibition, metabolism, or degradation, we measured hourly endothelin release rates after preincubation for 4 or 23 hours. The effect of cocaine on endothelin release rates was clearly concentration-dependent. In contrast to the previously observed tolerance to opioid peptides,³⁵ the cocaine-stimulated endothelin release at hour 23 to 24 was only slightly blunted compared with release at hour 4 to 5.

Cocaine concentrations chosen for the endothelin release experiments (10^-7 to 10^-4 mol/L) covered the range of postmortem plasma concentrations, 2.8x10^-7 to 6.2x10^-5 mol/L, with an average of 2x10^-5 mol/L, in patients who died of cocaine overdose.³⁷ In the Yucatan swine, serum concentrations of 7x10^-7 to 5x10^-6 mol/L were associated with myocardial infarctions.³⁸ In vitro, cocaine concentrations of 10^-8 to 10^-3 mol/L are used to contract ring segments of human umbilical arteries, and the ED₅₀ for cocaine-induced contractile responses in isolated canine basilar or middle cerebral arteries are 7x10^-5 or 10^-4 mol/L, respectively.^{24 25}

Contractile effects of cocaine in the organ bath were immediate and endothelium-independent.^{24 25} However, the delay in endothelium-dependent endothelin release observed in our study corresponds to the clinical situation with, eg, neurovascular complications of cocaine, such as premature rupture of aneurysms, typically occurring with cocaine, whereas ischemic strokes occur with a delay after the use of cocaine.³⁹ The explanation for this phenomenon may be that acute cardiovascular emergencies are mediated by transient excessive adrenergic stimulation, whereas ischemic sequelae are initiated by longer-lasting cocaine-induced effects, the nature of which is unknown.

Accordingly, several reports have shown that myocardial ischemia may occur immediately after the use of cocaine or hours to days later.^{3 11 40} This would not be expected either if transient excessive sympathetic stimulation were followed by a short-lasting catecholamine surge or if immediate, direct vascular and endothelium-independent mechanisms were solely responsible. This view is corroborated by the recent finding of a persistent cocaine-induced decrease in digital blood flow beyond the hypertensive response.⁴¹

We recently reported "nonclassic" ie, naloxone-insensitive, stimulatory effects of certain native opioid peptides on endothelial endothelin release.³⁵ The mechanisms of these paradoxically stimulatory effects of opioids in the presence of opioid receptor antagonists have not been elucidated. However, because the antiopioid -system mediates opposing opioid effects in bioassays and in vivo^{42 43} and the benzomorphans, -receptor ligands, have been reported to induce cerebral vasospasm,⁴⁴ we speculated about involvement of peripheral -receptors in mediation of stimulatory effects on endothelin release. Since cocaine binds to central -receptors and -receptors in rat liver and human placenta,^{45 46 47} we successfully used the -receptor antagonists haloperidol and the highly selective universal -ligand ditolylguanidine to block the cocaine-stimulated endothelial endothelin release. The pharmacological evidence for -receptor involvement in cocaine-induced endothelial endothelin release as presented here is corroborated by our binding data, demonstrating, for the first time, -binding sites on endothelial cells.

-Receptors have generated a great deal of interest on the basis of their possible role in psychosis and behavioral depression.^{48 49} -Receptors also exist in a number of peripheral cells,⁴⁹ eg, in rodent and human tumor cell lines, in which the -receptor subtype 2 has been linked to the proliferative state of tumor cells; in leukocytes⁵⁰; and in cardiac myocytes.⁵¹ In cardiac myocytes, Ca²⁺ influx, contractility, and the contractile rhythm were shown to be modulated by -receptors, ostensibly by action on Ca²⁺ channels or on Ca²⁺ fluxes via modulation of K⁺ channels.⁵¹

Recently, the cDNA of the mammalian -receptor subtype 1 has been cloned.⁵² High densities of the ₁-receptor site mRNA have been found in sterol-producing tissues.⁵² This corresponds to the known ability of ₁-binding sites to interact with steroids such as pregnenolone, progesterone, dehydroepiandrosterone, and testosterone, so far the only known endogenous ligands for -receptors.^{53 54}

If cocaine increases the endothelial endothelin production, then elevated plasma levels by spillover from the abluminal site of secretion should be detectable in cocaine-intoxicated patients. As expected, we found significantly elevated plasma endothelin-1 levels in the cocaine-intoxicated subjects that were considerably higher than plasma levels in heart transplant recipients with coronary allograft vasculopathy that had been measured previously in this laboratory by use of the identical extraction procedure and radioimmunoassay.³⁶ Earlier findings of others indicate similar effects on circulating endothelin-1 in pregnant patients with cocaine-related complications.⁵⁵

Because transient elevations in systemic endothelin-1 may be missed by discontinuous plasma sampling, we measured endothelin-1 in urine samples. Because cocaine-intoxicated patients cannot reliably collect their urine, we determined endothelin-1 concentrations in cocaine-intoxicated patients and in a control group in the freshly voided urine as pmol/L instead of pmol per g creatinine per 24 hours as in previous studies from our laboratory. Despite this reservation, endothelin-1 concentrations in urine of the cocaine-intoxicated patients were almost 4-fold higher than in normal control subjects and more than twice as high as the endothelin-1 concentrations in 24-hour urine in heart transplant recipients with coronary allograft vasculopathy, and still exceeded the highest concentrations measured so far in our laboratory, ie, in urine of patients with coronary artery disease collected immediately after a coronary balloon angioplasty (unpublished data, 1997).³⁶

The origin of urinary endothelin-1 is not clear at present. It has been shown that the contribution of urinary excretion to endothelin-1 elimination is higher when the kidney is exposed to an increased filtered load of this peptide. In an experimental model, however, it increases only 7% when the plasma endothelin-1 concentration is doubled by intravenous infusion.⁵⁶ As cocaine has been associated with renal failure and vasoconstriction,⁵⁷ cocaine-induced or adrenergically mediated renal synthesis of endothelin-1 may further increase urinary endothelin-1 levels in cocaine-intoxicated patients. Conversely, it had been concluded that urinary endothelin-1 concentrations rather than endothelin-1 plasma concentrations reflect endothelin-1 production in the extravascular compartment, eg, in cerebrospinal fluid after subarachnoid hemorrhage.⁵⁸ Furthermore, coronary angioplasty increases urinary endothelin-1 but not plasma endothelin-1, and increased urinary endothelin-1 is associated with graft vasculopathy in heart transplant recipients (unpublished data, 1997).^{36 59}

Whether increased endothelin-1 plasma levels are essential and sufficient for triggering coronary vasospasm cannot be determined from our data. However, because every cocaine-intoxicated patient in this study, without clinical evidence of myocardial ischemia, displayed an elevated endothelin-1 plasma level and because elevated endothelin-1 plasma levels in patients with provocable coronary artery spasms are elevated before coronary spasm is provoked, it may be deduced that increased endothelin-1 plasma levels are not sufficient for triggering coronary vasospasm.^{29 32} However, as endothelin-1 increases the calcium sensitivity of human arteries, it may sensitize the vasculature to other vasoconstrictor stimuli and prolong coronary vasoconstriction or vasospasm, resulting in acute myocardial infarction without anatomic coronary stenosis.³²

It has long been known that there is a relationship between stress and the incidence of myocardial ischemia and morbidity that occurs even in otherwise asymptomatic patients.^{60 61} Because cocaine imitates a stress response, the elucidation of vascular cocaine effects may help to uncover endogenous mechanisms for increased coronary vasoconstriction/vasospasm and be of relevance in stress-related coronary events or sudden cardiac death.^{23 62}

Cocaine appears to act as an exogenous agonist at peripheral/endothelial -receptors, and the cocaine-induced vasospasms in vivo may thus be facilitated by peripheral, catecholamine-independent, -receptor–mediated release of endothelin-1. The in vitro data are supported by in vivo findings of increased endothelin-1 concentrations in plasma and urine of patients intoxicated with cocaine.

The blockade of the -receptor (by sex steroids or peripherally acting "antipsychotic" -antagonists) or of endothelin A and/or B receptors may prove effective in the therapy of cocaine-induced or perhaps endogenously mediated vasospastic disorders.

	Acknowledgments

 
This research was supported by Hans Kröner and the Else Kröner-Fresenius-Foundation, Bad Homburg, Germany. We thank Prof David J. Greenblatt, Boston, for his critical revision of the manuscript. We are grateful to Andrea Plasse, Cornelia Grimm, and Daniela Wiegand for technical assistance and to Lars Heucke, Berlin, for statistical analysis and graphical presentation of the data.

	Footnotes

 
Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10–13, 1996, and published in abstract form (Circulation. 1996;94[suppl I]:I-105). This work contains data from a doctoral thesis by C. Seliger at the Ludwig-Maximilian-University, Munich, Germany. This article is dedicated to Hans Kröner, Bad Homburg, Germany, on the occasion of his 88th birthday.

Received November 10, 1997; revision received January 30, 1998; accepted February 13, 1998.

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