Cocaine-Induced Small Vessel Spasm in - Europe PMC

AmericanJournal of Pathology, Vol. 135, No. 1, July 1989 Copyright ©) American Association ofPathologists

Cocaine-Induced Small Vessel Spasm in Isolated Rat Hearts John C. Vitullo, Roger Karam, Nagy Mekhail, Pierre Wicker, Gary L. Engelmann, and Philip A. Khairallah From the Departmen t ofHeart and Hypertension Research, Research Institute and Division of Anesthesiology, The Cleveland Clinic Foundation Cleveland, Ohio

Cocaine abuse has been associated with pathologic cardiovascular events including acute myocardial infarction (AMI) and sudden death. Although coronary vasospasm has been proposed as a possible mechanism, the ability of cocaine to induce coronary spasm has not been conclusively demonstrated. In these studies. isolated rat hearts were perfused with cocaine (100 yg to 500 lig/ml) for I minute, perfusion-fixed with glutaraldebyde, and histologically assessed for evidence of coronary spasm through light and electron microscopy. Light micrographs revealed that cocaine induced spasm in coronary arterioles up to 65 ,Am in diameter, whereas larger caliber vessels did not constrict. Ultrastructurally, vacuolation was observed in the endothelial and smooth muscle cells of constricted arterioles. Endothelial integrity was maintained and interendothelial junctions remained intact. Morphologic evidence of constriction was supported by data obtained from Langendorf-heart preparations in which cocaine reduced myocardial flow rate under constant pressure conditions and increased aortic perfusion pressure under constant flow conditions. Spasm induced by cocaine was prevented by the calcium entry blocker nitrendipine, but not by phentolamine, an alpha-adrenergic antagonist. TheJfinding of small vessel spasm in this study may explain the significant number of clinical cases of cocaine-associated AMI in which the main coronary arteries appear angiographically normal. (Am fPathol 1989, 135:85-91)

With the advent of a less expensive and more potent freebase form of cocaine, the incidence of apparently cocaine-related cardiac events has risen. Several clinical

studies have suggested a link between cocaine usage and acute myocardial infarction (AMI), but the underlying mechanisms have remained elusive in part because the cardiovascular effects of cocaine have not been well studied.1-9 Known pharmacologic properties of cocaine suggest possible explanations for the adverse cardiovascular events attributed to this drug. Cocaine augments the effects of catecholamines by inhibiting their reuptake at adrenergic nerve terminals,'° and its sympathomimetic action distinguishes it from the other local anesthetics that have no effect on reuptake. The sympathomimetic effects have been implicated in cocaine-related Ml, resulting from prolonged ischemia secondary to sudden increases in myocardial oxygen demand, particularly in individuals with preexisting coronary artery disease.2.1 There are reports, however, that cocaine can precipitate Ml in those without underlying cardiovascular disease and in these individuals coronary vasospasm due to either sympathomimetic effects or to a direct effect on vascular smooth muscle is suspected. The ability of cocaine to induce vasospasm in the coronary vasculature, however, has never been conclusively shown. In this communication, we examine vascular responsiveness to cocaine in isolated rat heart preparations and describe the morphologic alterations in coronary vessels after acute exposure to the drug.

Materials and Methods

Morphologic Assessment of Vascular Reactivity In Response to Cocaine Adult Sprague-Dawley rats (300 to 400 g) obtained from Hilltop Farms, Scottsdale, N.J., were used throughout the study. Under sodium amytal anesthesia (100 mg/kg intraperitoneally), hearts from 12 rats were excised, placed in a Petri dish containing cold (1 C to 2 C) Krebs buffer (02: This study was supported by a grant-in-aid from the American HeartAssociation, Northeast Ohio Affiliate. Accepted for publication March 30, 1989. Address reprint requests to John C. Vitullo, PhD, Department of Heart and Hypertension, Research Institute (FF1), The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195-5069.

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C02, 95:5), and immediately perfused with Krebs buffer retrogradely through the aorta. Perfusion was carried out at a constant pressure of 80 mmHg and maintained using a compressed air perfusion pump. After the heart was cleared of blood, cocaine hydrochloride (Roxanne Laboratories, Columbus, OH) was infused at final concentrations of 100, 300, or 500 ,ug/ml for 1 minute. The hearts were then perfusion-fixed with 1% glutaraldehyde/0. 13 M phosphate buffer for 15 minutes at 80 mmHg. Control hearts were perfused with Krebs buffer alone for 3 to 4 minutes at 80 mmHg, and then perfusion fixed as described. Samples (mm3) were taken from the left ventricle, placed in 1% glutaraldehyde overnight, postfixed in 1% osmium tetroxide (4 C for 2 hours), dehydrated in a series of ethanols, and embedded in Spurr's resin. Five 1 um thick sections from the left ventricle of each heart were stained with 1% toluidene blue in 1% borax and examined with an Olympus light microscope (Tokyo, Japan). Vascular constriction was assessed histologically at the light microscopic level using the following criteria: 1) irregular luminal outlines with puckered endothelial cells bulging into the lumen, 2) tortuous internal elastic lamina (IEL) compared with the smooth IEL in relaxed vessels, 3) the nuclei of both endothelial and vascular smooth muscle cells are more rounded, and 4) constricted vessels appear pulled away from the surrounding tissue. Vessels that possess smooth luminal outlines and high lumen-to-wall ratios were considered to be perfusion fixed in the relaxed state.12 To approximate the original lumen diameters of constricted vessels, measurements of internal elastic lamina (IEL) length were obtained on a digitizing pad using Bioquant IV (R & M Biometrics, Nashville, TN) morphometry software system and luminal diameters calculated. For ultrastructural examination, sections of silver-gray interference color were obtained on a Sorvall MT5000 ultramicrotome, collected on 200-mesh copper grids, stained with uranyl and lead salts,13 and examined in a Zeiss EM10 electron microscope

Assessment of Cocaine's Constrictor Actions in Langendorff-Perfused Hearts Hearts were electrically paced (260 beats per minute) to counter the direct depressant effect of cocaine on the myocardium. Rats were given 500 units of heparin intraperitoneally at least 30 minutes before pentobarbital anesthesia (30 mg/kg intraperitoneally). Hearts were excised, quickly placed in cold (1 C to 2 C) Krebs-Henseleit buffer, and attached securely to the plastic grooved tip cannula of the Langendorff apparatus through the aortic stump. Hearts were perfused retrogradely with an oxygenated modified Krebs-Henseleit buffer maintained at 37 C. Two sets of experiments were performed. In one, pressure

was kept constant while myocardial flow rates were determined. In the other, a Harvard peristaltic pump was used to maintain constant flow while perfusion pressure was recorded. For the constant pressure series, the perfusate reservoir was placed at a height of 70 cm above the level of the heart (a pressure equivalent to approximately 50 mmHg). The perfusate contained (in mM): NaCI (1 17), KCI (4.70), CaCI2 (2.5) plus 0.5 to balance EDTA, KH2PO4 (1.2), NaHCO3 (25.0), Na2EDTA (0.5), and dextrose (8.5) at a pH of 7.4 when oxygenated with 95% 02 and 5% CO2. Immediately after the start of perfusion, the base of the pulmonary artery was incised to allow drainage of the fluid accumulating from the coronary sinus and thebesian vessels into the right ventricle. After baseline control values were established, cocaine was infused at a dose of 20 ug per minute for 5 minutes. After a 5-minute recovery period, the calcium channel blocker nitrendipine (1 0-5M) was infused for 10 minutes, followed by a 5-minute concomitant infusion of cocaine and nitrendipine. Myocardial flow was recorded at 5-minute intervals. Left ventricular pressure and its first derivative (+dp/dt), both indices of cardiac contractility, were continuously recorded. In the second set of Langendorff perfusions, myocardial flow was maintained at 12 ml per minute. Cocaine was infused at 100 ,g per minute for 5 minutes, followed by a 5-minute recovery period. The alpha-adrenergic blocker phentolamine (10-5M) was then infused for 10 minutes, followed by a 5-minute concomitant infusion of cocaine and phentolamine. Aortic pressure, left ventricular pressure, and dp/dt were continuously recorded. The dose of cocaine used in the Langendorff experiments was the lowest dose required to effect a response in the three parameters measured. Although this differed in the two experiments for reasons that are unclear, it is known that there is tremendous individual variability to effective levels of cocaine.14

Results

Morphological Assessment of Vascular Reactivity Light microscopic evaluation of Krebs-perfused control hearts revealed that coronary vessels possessed little tone as evidenced by smooth luminal outlines and a large lumen-to-wall ratio (Figure 1 A). In five control hearts, all vessels were perfusion-fixed in their relaxed state and absolutely no constriction was observed. Ultrastructurally, these vessels were characterized by elongated cellular structure, with smooth plasmalemmal and nuclear outlines (Figures 2A). When cocaine was added to the perfusion buffer, constrictor responses were observed in medium- and small-sized arterioles ranging in size from 10 ,m

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Figure 1. A: Light micrograph of coronary arteriole from control heart stained with 1% Toluidine Blue. Note the smooth luminal outlines and large lumen to wall ratio indicative of a relaxed vessel, (X850). B: Light micrograph of coronary arteriole from heart perfused with cocaine (300 g/iml) stained with 1% Toluidine Blue. Endothelial cells bulge into the lumen as the vessel constricts. The internal elastic lamina is scalloped and the vessel appearspulledawayfrom the surrounding tissue (X850).

to 65 um in diameter (Figure 1 B). Not all arterioles in this size range constricted in response to cocaine. For each dose of cocaine used, between 60 and 90 arterioles (10 ,um to 65 gm) were surveyed for constrictor responses. At 100 ,ug/ml, only two of four hearts exhibited constriction when exposed to cocaine. In these two hearts, only 7.3% of arterioles surveyed were constricted. This percentage increased to 75.6% and 74.6% at concentrations of 300 ,ug/ml and 500 Ag/ml, respectively. Constriction was observed in all hearts (N = 8) exposed to higher concentrations of cocaine. In many of the constricted vessels, vacuolation was clearly seen at the light microscopic level (Figure 1 B). Ultrastructural examination of cocaineconstricted vessels revealed that vacuolation was confined to the cytoplasm of both endothelial and smooth muscle cells (Figure 2B). Vacuoles were generally bound by a single membrane. Some contained membraneous elements and cellular debris, whereas others appeared to be devoid of any such material. The internal elastic laminae of these vessels were scalloped and plasmalemmal, and nuclear outlines of endothelial and smooth muscle cells were tortuous and contorted. However, interendothelial junctions remained intact and endothelial integrity was maintained.

Assessment of Myocardial Flow Rate in Langendorff Perfused Hearts In hearts electrically paced at 260 beats per minute to counter the anesthetic effects of cocaine, a significant decrease in myocardial flow rate was observed (P < 0.01) under constant pressure conditions (Table 1). Left ventricular pressure and dp/dt, indices of cardiac contractility, were also significantly lowered during cocaine infusion (P < .01). After exposure to cocaine, hearts were infused

for 5 min with Krebs-Henselheit buffer before beginning a 10 min preperfusion with nitrendipine during which time flow, LVP, and dp/dt returned to control values. Subsequent exposure of the hearts to cocaine together with nitrendipine resulted in a significant attenuation of cocaine's constrictor activity (P < 0.05), as well as significant attenuation of cocaine-induced decreases in LVP (P < 0.05) and dp/dt (P < 0.05). When myocardial flow was kept constant at 12 ml per minute, cocaine infusion produced a consistent rise in aortic perfusion pressure (P < 0.01), indicative of coronary constriction, and significant decreases in left ventricular pressure (P < 0.01) and dp/dt (P < 0.01) (Table 2). The alpha-adrenergic blocker phentolamine did not block or attenuate these effects.

Discussion The direct effects of cocaine on the coronary circulation have not been well studied, although cocaine-induced spasm of coronary arteries has been hypothesized as an underlying mechanism of AMI in persons with no predisposing cardiovascular factors.1' 257 The vasoactive mechanism most often suggested is the well-known sympathomimetic effect, in which cocaine prolongs the effect of norepinephrine by inhibiting its reuptake back into the adrenergic nerve terminal.15 However, two important concepts make this characteristic of cocaine unlikely to affect the coronary circulation. First, there appears to be a functional predominance of beta- over alpha-adrenergic receptors in the main coronary vessels, which would result in beta-mediated relaxation after sympathetic stimulation.16 Second, catecholamines increase the rate and force of contraction, thereby increasing myocardial oxygen demand and initiating an autoregulatory response

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Table 1. Effect of Cocaine Infusion on Myocardial Flow Rate, Left Ventricular Pressure, (L VP), and dp/dt in Langendorff-Perfused Hearts Under Constant Perfusion Pressure (Mean ± SD) Variable Myocardial flow rate (ml/5 minutes) Control Cocaine Recovery Nitrendipine Nitrendipine plus cocaine Left ventricular pressure (mmHg) Control Cocaine Recovery Nitrendipine Nitrendipine plus cocaine dp/dt Control Cocaine Recovery Nitrendipine Cocaine plus nitrendipine

Significance

Significance

vs. control

vs. treated

79.5 ± 61.8 ± 74.5 ± 76.5 ± 74.8 ±

6.4 1.7 9.9 6.9 7.0

0.01 NS NS NS

0.05 0.05 0.05

109.1 ± 37.3 ± 108.3 ± 103.1 ± 74.0 ±

17.9 27.2 14.2 13.5 7.9

0.01 NS NS 0.05

0.01 0.01 0.05

0.01 NS NS 0.01

0.01 0.01 0.05

2488 759 2632 2393 1578

with resultant vasodilatation. These concepts taken together seem to suggest that cocaine-induced constriction of large vessels in the heart, if it does occur, does not result from catecholaminergic mechanisms. Instead, cocaine may exert a direct action on smaller caliber coronary vessels, as suggested by Pierre et al.17 In this context, we report that cocaine induced focal spasm in the coronary circulation, but only in arterioles up to 65 ,m in diameter. Larger caliber vessels did not constrict in response to cocaine. The reasons for the heterogeneity of response to cocaine based on vessel size are unclear. What is intriguing is that cocaine can induce constriction in a specialized vasculature, ie, the coronary, in which constriction has no physiologic advantage given the high metabolic demand of the heart. Current theories of coronary constriction and vasospasm emphasize the importance of endothelial damage or malfunctioning as a prerequisite for spasm.16 Cocaine, however, can induce constriction in the presence of an intact endothelium as described in this study and others."8 Whether cocaine is acting through endothelial factors or through a direct effect on coronary vascular smooth muscle is not known. Endothelial factors may not play a role in cocaine-induced relaxation of preconstricted large proximal canine coronary artery rings, but rather may be due to enhanced uptake of cytosolic calcium by the sarcoplasmic reticulum in vascular smooth muscle and not to soluble endothelial factors.'9

± 404 ± 560 ± 343 ± 270 ± 196

-

Although the calcium entry blocker nitrendipine has been reported to reduce the cardiovascular toxicity associated with cocaine,20 the source of activator calcium mobilized during cocaine-induced spasm is not known. In the present study, nitrendipine attenuated cocaine-induced decreases in myocardial flow rate, left ventricular pressure, and dp/dt, suggesting that cocaine is capable of mobilizing extracellular calcium stores for contraction. However, it should be pointed out that calcium entry blockers also induce preferential dilatation in the coronary circulation through antagonistic alpha-1 adrenergic mechanisms,2' thus making it difficult to determine if cocaine is being opposed by the direct dilator actions of nitrendipine or if there is direct interference with cocaine's ability to mobilize extracellular calcium. The inability of phentolamine, an alpha-adrenergic antagonist, to inhibit the cocaine-induced rise in coronary perfusion pressure suggests the lafter possibility is more likely. This also suggests that cocaine may be acting independently of adrenergic mechanisms, at least in these isolated hearts. In this context, perfusion of norepinephrine (1 ug/ml) in five additional hearts did not induce coronary constriction (data not shown). In addition to a direct or sympathomimetic-mediated mechanism of vasospasm, a third possibility is that cocaine, in subpressor dosages, can cause structural damage to the vascular endothelium with resulting aggregation of platelets. This pathogenic mechanism has been

Figure 2 A: Electron micrograph of coronary arteriole from perfused-fixed control heart. Nuclear and cytoplasmic membranes of both endothelial (E) and smooth (S) muscle cells are smooth in outline. Endothelialjunctions (arrows) are intact and no vacuolation can be observed (uranyl acetate and lead citrate, X 11,000). B: Electron micrograph of constricted coronary arteriole from heart perfused with cocaine (300 ,ug/ml). Endothelial cells bulge into the lumen as contraction occurs, but endothelialjunctions have remained intact (arrows). Vacuoles (V) can be observed in both endothelial and the underlying smooth muscle cells (uranyl acetate and lead citrate, X 11,000).

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Effects of Cocaine on Aortic Perfusion Pressure, Left Ventricular Pressure, and dp/dt in Isolated Langendorf -Perfused Rat Hearts Under Constant Flow (12 ml/min ute)

Table 2.

Significance vs. control

Variable

Aortic perfusion pressure (mmHg) Control

Cocaine Recovery Phentolamine Phentolamine plus cocaine Recovery LVP (mmHg)

Control Cocaine Recovery Phentolamine Phentolamine plus cocaine Recovery dp/dt

Control Cocaine Recovery Phentolamine Phentolamine plus cocaine Recovery

Significance vs. treated

50 79.8 ± 10.8 59.0 ± 1.2 60.5 ± 3.3 89.5 ± 8.2 59.8 ± 8.0

0.01 0.01 0.01 NS

0.05 0.05 0.05

95.9 ± 8.4 59.8 ± 7.5 104.5 ± 7.8 98.6 ± 9.5 65.5 ± 15.9 102.4 ± 10.1

-

-

0.01 0.05 NS 0.05 NS

2147 1296 2372 2223 1443 2355

suggested for both chronic and acute coronary obstructive lesions observed at autopsy in a 21-year-old cocaine abuser.22 Serotonin, released from aggregating platelets and a vasodilator in the presence of an intact endothelium, becomes a potent coronary vasoconstrictor when endothelial integrity is interrupted.16 Aggregating platelets also release thromboxane A2, another potent coronary vasoconstrictor. However, on short exposure to cocaine in the present studies, endothelial integrity remained intact both in constricted and nonconstricted vessels. The only vascular damage observed was the presence of cytoplasmic vacuoles in both endothelial and smooth muscle cells of constricted vessels, which were absent in nonconstricted vessels. It is likely that vacuolation resulted from the focal protrusion of one cell upon another during arteriolar contraction as suggested by Joris and Majno,23 although free radical mechanisms have been suspected.24 That nonconstricted arterioles exposed to cocaine exhibited normal morphology suggests that vacuolation was not due to a direct effect of the drug, but a secondary result of the drug-induced constriction. Although vacuolation has been shown to be reversible,23 it has been suggested that repeated episodes of spasm could lead to a summation of effects resulting in necrosis.25 This raises the possibility that chronic use of cocaine may interrupt the endothelial lining and predispose the coronary vasculature to vasoactive stimuli. It is impossible to ascertain from these short-term studies whether cocaine-induced small vessel spasm could result in focal areas of myocardial necrosis. Multiple focal areas of left ventricular myocardial necrosis resulting from microvascular spasm have been described in cardiomyo-

0.01 0.05

0.01 0.01

NS 0.01

± 244

-

-

+ 170

0.01 0.01 NS 0.01 NS

0.01 0.01 NS 0.01

± 147 ± 265 ± 366 ± 293

pathic Syrian hamsters and hypertensive-diabetic rats,26 and in rats subjected to hypothalamic stimulation.27 It is tempting to suggest that the focal microvascular spasm observed in our study may be the initiating event for contraction band necrosis that has been observed at autopsy in several cases of cocaine-associated sudden death.928 Dosages of cocaine used in these studies to induce coronary vasoconstriction at first glance may seem quite high. It must be pointed out that, although the lethal dosages of cocaine are still disputed, the LD1oo for rats and mice appear to be much higher than for larger mammals, including humans.14 In rats, the LD1oo of cocaine has been reported to be 35 mg to 100 mg/kg,14 which corresponds to between 600 ,ug/ml to 1500 ,g/ml of blood for the 400g rats used in this study. Unusually high blood concentrations of cocaine and its metabolites have been reported even in humans, exceeding 130,gg/ml.29 The mechanisms of cardiac toxicity attributed to cocaine are still unknown. Its actions in the cardiovascular system are complex and often opposing.30 In this communication, we have reported, using histologic methods and isolated heart preparations, that cocaine possesses the ability to induce small vessel spasm in the coronary circulation, although larger caliber vessels do not respond. Although these in vitro studies are not sufficient to make categorical statements regarding cocaine's vasoactive properties in the heart, they are supported by studies in the intact, conscious dog model that suggest that cocaine has coronary constrictor properties, and, at the very least, is capable of interfering with autoregulatory dilatation.0 Taken together, these findings may explain the significant number of clinical cases in which MI associated

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with cocaine abuse have reported angiographically normal coronary arteries.

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systemic hemodynamics after intravenous injection of cocaine (abstr). Anesthesiology 1985, 63:A28 18. Rongione AJ, Steg G, Gal D, Isner JM: Cocaine causes endothelium-independent vasoconstriction of vascular smooth muscle. Circulation 1988, 78:11-436 19. Karam R, Brum J, Bond M, Vitullo JC, Ferrario C: Cocaine potentiates caffeine-induced contraction of canine coronary arteries (manuscript submitted for publication) 20. Trouve R, Nahas G: Nitrendipine: An antidote to cardiac and lethal toxicity of cocaine. Proc Soc Exp Biol Med 1986, 183: 392-397 21. Knight DR, Vatner SF: Calcium channel blockers induce preferential coronary vasodilation by an alpha-1 mechanism. Am J Physiol 1987, 253:H604-H613 22. Simpson RW, Edwards WD: Pathogenesis of cocaine-induced ischemic heart disease. Arch Pathol Lab Med 1986, 110:479-484 23. Joris I, Majno G: Endothelial changes induced by arterial spasm. Am J Pathol 1981,102:346-358 24. Kontos HA, Wei EP, Dietrich WD, Navari RM, Povlishock JT, Ghatak NR, Ellis EF, Patterson JL: Mechanism of cerebral arteriolar abnormalities after acute hypertension. Am J Physiol 1981, 240:H511 -H527 25. Kobori K, Suzuki K, Yoshida Y, Ooneda G: Light and electron microscopic studies on rat arterial lesions induced by experimental arterial contraction. Virchows Arch [A] 1979, 385:29-39 26. Sonnenblick EH, Fein F, Capasso JM, Factor SM: Microvascular spasm as a cause of cardiomyopathies and the calcium-blocking agent verapamil as potential primary therapy. Am J Cardiol 1985, 55:179B-184B 27. Gutstein WH, Anversa P, Guideri G: Spasm of small coronary arteries and ischemic myocardial injury induced by hypothalamic stimulation in the rat. Am J Pathol 1987,129:287-294 28. Tazalaar H, Karch SB, Stephens BG, Billingham ME, et al: Cocaine and the Heart. Hum Pathol 1987,18:195-199 29. Winek CL, Wahba WW, Rozin L, Janssen JK: An unusually high blood cocaine concentration in a fatal case. J Anal Toxicol 1987,11:43-46 30. Wilkerson RD: Cardiovascular toxicity to cocaine, Mechanisms of Cocaine Abuse and Toxicity. Edited by D Clouet, K Asghar, R Brown. NIDA Research Monograph Series, 1988, pp 304-324

Acknowledgment The authors thank Dr. Fetnat Fouad-Tarazi for use of her laboratory and consultation on the Langendorff studies, Mr. Milo Milovanovic for expert technical assistance, Mr. Jim Lang for photographic expertise, and Ms. Tina Ours for help in preparing of the manuscript.