Abstract
This study was designed to determine the toxicity of cocaine on heart and other organ tissues. To investigate this, in study one, BALB/C mice were injected daily with either saline or one of three doses of cocaine (ip): 10mg/kg, 30mg/kg, or 50mg/kg. Hemodynamic parameters, hepatic biochemical changes, heart and liver apoptosis, and tumor necrosis factor (TNF-α) levels were analyzed after cocaine administration. After administration of cocaine, left ventricular pressure decreased among the three dose groups. Also, +dP/dt was decreased from 7598 mmHg/s in the saline group to 5448, 5198, and 5042 mmHg/s, respectively in the 10, 30, and 50mg/kg groups. Moreover, histopathology demonstrated that hepatocyte necrosis could be observed in the liver. Neutrophils, lymphocytes, and cellular debris surrounded the central area of necrosis in the three cocaine-treated groups. Also, inflammatory cell infiltration and eosinophilic contraction bands were visible in the 50/kgmg groups hearts. TdT-mediated dUTP nick end-labeling (TUNEL) staining and DNA ladder analysis indicated that cocaine caused apoptosis in the heart and liver. The ratio of TUNEL and Hoechst 33258 staining nuclei from the livers were 6.1 ± 2.3, 11.0 ± 2.7 and 12.3 ± 4.2%, respectively in the 10, 30, and 50mg/kg cocaine groups. However, in the heart apoptosis occurred only in the high dose group and the apoptotic percentage was 5.7 ± 1.4%. TNF-α levels were 1.75 ± 0.91 ng/g (saline); 4.13 ± 0.36, 5.03 ± 0.36, and 5.77 ± 0.67 ng/g respectively in the 10, 30, and 50mg/kg cocaine groups, significantly higher in all cocaine-treated mice hearts compared to saline control (p < 0.05). Moreover, in the liver the content of TNF-α was increased from 621.8 ± 73 in the saline group to 867.2 ± 72, 940.8 ± 61, and 1032.8 ± 69 (ng/g) among the three dose groups. However, RT-PCR study showed that there was no significant difference in the levels of mRNA of TNF-α between cocaine and saline groups both in the heart and liver. These results suggest that cocaine impaired cardiac function and caused liver necrosis. In addition, cocaine triggered programmed cell death and induced the production of TNF-α in mouse myocardium and liver. In study two, we investigated whether cocaine can exacerbate viral myocarditis or increase its incidence. Male BALB/c mice were divided into eight groups: saline control, encephalomyocarditis virus (EMCV), Cocaine 10mg/kg (Coc-10), Cocaine 30mg/kg (Coc-30), Cocaine 50mg/kg (Coc-50), EMCV+Coc-10, EMCV+Coc-30, and EMCV+Coc-50. After inoculation with EMCV, the mice were treated daily with cocaine or saline for 90 days. Mice were sacrificed at different days after EMCV inoculation. Mortality was recorded and myocarditis severity was evaluated. The mortality of the myocarditis mice treated with cocaine increased significantly, from 22% (EMCV) to 25.7% (Coc-10+EMCV), 41.4% (Coc-30+EMCV), and 51.4% (Coc-50+EMCV) (p<0.05). The incidence and severity of inflammatory cell infiltration and myocardial lesions was higher in infected mice exposed to cocaine. In conclusion, these results suggested that the liver is more sensitive than the heart to cocaine toxicity, and induction of apoptosis or TNF-α may be an important mechanism related to cocaine s toxicity. Also, exposure to cocaine significantly increased the mortality and exacerbated the severity of viral myocarditis. This enhancing effect of cocaine on viral myocarditis may relate to catecholamines.
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References
Kloner RA, Hale S, Alker K, Rezkalla S. 1992. The effects of acute and chronic cocaine use on the heart. Circulation 85:407–419.
Knuepfer MM, Branch CA, Gan Q, Fischer VW. 1993. Cocaine-induced myocardial ultrasstructural alterations and cardiac output responses in rats. Exp Mol Pathol 59:155–168.
Karch SB, Billingham ME. 1988. The pathology and etiology of cocaine-induced heart disease. Arch Pathol Lab Med 112:225–230.
Roth L, Harrison RD, James BC, Tobin T, Roberts SM. 1992. Cocaine hepatotoxicity: influence of hepatic enzyme inducing and inhibiting agents on the site of necrosis. Hepatology 15:934–940.
Boyer CS, Perterson DR. 1991. Hepatic biochemical changes as a result of acute cocaine administration in the mouse. Hepatology 14:1209–1216.
Thompson ML, Shuster L, Shaw K. 1979. Cocaine-induced hepatic necrosis in mice-The role of cocaine metabolism. Biochem Pharmacol 28:2385–2395.
Aoki K, Ohmori M, Takimoto M, Ota H, Yoshida T. 1997. Cocaine-induced liver injury in mice is mediated by nitric oxide and reactive oxygen species. Eur J Pharmacol 336:43–49.
Devi BG, Chan AWK. 1996. Cocaine-induced peroxidative stress in rat liver: antioxidant enzymes and mitochondria. J Pharmacol Exp Ther 279:359–366.
Veinot JP, Gattinger DA, Fliss H. 1997. Early apoptosis in human myocardial infarcts. Hum Pathol 28:485–492.
Fliss H, Gattinger DA. 1996. Apoptosis in ischemic and reperfusioed rat myocardium. Circ Res 79:949–956.
James TN, Martin E, St. Willis PW, Lohr TO. 1996. Apoptosis as a possible cause of gradual development of complete heart block and fatal arrhythmias associated with absence of the AV node, sinus node, and internodal pathways. Circulation 93:1424–1438.
Ray SD, Mumaw VR, Raje RR, Fariss MW. 1996. Protection of acetaminophen-induced hepatocellular apoptosis and necrosis by cholsteryl hemisuccinate pretreatment. J Pharmacol Exp Ther 279:1470–1483.
Cascales M, Alvarez A, Gasco P, Fernandez-Simon L, Sanz N, Bosca L. 1994. Cocaine-induced liver injury in mice elicits specific changes in DNA ploidy and induces programmed death of hepatocytes. Hepatology 20:992–1001.
Habeebu SSM, Liu L, Klaassen CD. 1998. Cadmium-induced apoptosis in mouse liver. Toxicol Appl Pharmacol 149:203–209.
Kumar A, Thota V, Olson J, Uretz E, Parrillo JE. 1996. Tumor necrosis factor-a and interleukin-lβ are responsible for in vitro myocardial cell depression induced by human septic shock serum. J Exp Med 183:949–958.
Wang JH, Redmond HP, William R, Watson G, Bouchier-Hayes D 1995. Role of lipopolysaccharide and tumor necrosis factor-a in induction of hepatocyte necrosis. Am J Physiol 269:G297–G304.
Virmani R, Robinowitz M, Smialek JE, Smyth DE 1988. Cardiovascular effects of cocaine: An autopsy study of 40 patients. Am Heart J 115:1068–1076.
Jentzen JM. 1989. Cocaine-induced myocarditis. Am Heart J 117:1398–1399.
Matsumori A, Wang H, Abelmann WH, Crumpacker CS. 1985. Treatment of viral myocarditis with ribavirin in an animal preparation. Circulation 71:834–839.
Peng S-K, French WJ, Pelikan PCD. 1989. Direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy. Arch Pathol Lab Med 113:842–845.
Turizzo V, Rubio MC. 1985. Effects of cocaine on several adrenergic system parameters. Gen Pharmacol 16:71–76.
Gay GR, Loper KA. 1988. The use of labetolol in the management of cocaine crisis. Ann Emerg Med 17:282–283.
Shannon RP, Lozano P, Cai Q, Manders WT, Shen YT 1996. Mechanism of the systemic, left ventricular, and coronary vascular tolerance to a binge of cocaine in conscious dogs. Circulation 94:534–541.
Mittleman MA, Mintzer D, Maclure M, Tofler GH, Sherwood JB, Muller JE. 1999. Triggering of myocardial infarction by cocaine. Circulation 99:2737–2741.
Bernards CM, Cullen BF, Powers KM. 1997. Effect of chronic cocaine exposure on the hemodynamic response to vasopression in sheep. J Trama 43:680–686.
Arbeille P, Maulik D, Salihagic A, Locatelli A, Lansac J, Platt JD. 1997. Effect of long-term cocaine administration to pregnant ewes on fetal hemodynamic, oxygenation, and growth. Obstet Gynecol 90:795–802.
Fraker TD, Temesy-Armos PN, Brewster PS, Wilkerson RD. 1990. Mechanism of cocaine-induced myocardial depression in dogs. Circulation 81:1012–1016.
Wilkerson RD. 1988. Cardiovascular effects of cocaine in conscious dogs: Importance of fully func-tional autonomic and central nervous systems. J Pharmacol Exp Ther 246:466–471.
Wilkerson RD, Temesy-Armos PN, Fraker TD. 1991. Pharmacokinetics and time-action profile of cocaine in dogs. In: Cardiovascular toxicity of cocaine: underlying mechanims. Ed. Thadani P, 28–29. Bethesda, MD: National Institute on Drug Abuse.
Pellinen P, Honkakosh P, Stenback F, Niemitz M, Alhava E, Pelkonen O, Lang MA, Pasanen M. 1994. Cocaine N-demethylation and its metabolism-related hepatotoxicity can be prevented by P450 3A inhibitors. Eur J Pharmacol 270:35–48.
Pellinen P, Stenback F, Kojo A, Honkakoski P, Gelboin HV, Pasanen M. 1996. Regenerative changes in hepatic morphology and enhanced expression of CYP2B10 and CYP3A during daily administration of cocaine. Hepatology 23:515–523.
Wu YB, Shen ML, Gu GG, Anderson KM, Ou DW 1997. The effects of cocaine injections on mouse thymocyte population. PSEBM 214:173–179.
Cascales M, Alvarez A, Gasco P, Fernandez-Simon L, Sanz N, Bosca L. 1994. Cocaine-induced liver injury in mice elicits specific changes in DNA ploidy and induces programmed death of hepatocytes. Hepatology 20:992–1001.
Ledda-Columbano GM, Coni P, Curto M, Giacomin L, Faa G, Oliverio S, Piacentini M, Columbano A. 1991. Induction of two different models of cell death, apoptosis and necrosis, in rat liver after a single dose of thioacetamide. Am J Pathol 139:1099–1109.
Mallat Z, Tedgui A, Fontaliran F, Frank R, Durigon M, Fontaine G. 1996. Evidence of apoptosis in arrhythemogenic right ventricular dysplasia. N Eng J Med 335:1190–1196.
Meldrum DR. 1998. Tumor necrosis factor in the heart. Am J Physiol 274:R577–R595.
Ing DJ, Zang J, Dzau VJ, Webster KA, Bishopric NH. 1999. Modulation of cytokine-induced cardiac myocyte apoptosis by nitric oxide, Bak, and Bcl-x. Circ Res 84:21–33.
Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KJ, Glembotski CC, Quintana PJE, Sabbadini RA. 1996. Tumor necrosis factor-a-induced apoptosis in cardiac myocytes: involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 98:2854–2865.
Shen HM, Kennedy JL, Ou DW. 1994. Inhibition of cytokine release by cocaine. Int J Immunpharmac 16:295–300.
Wang YJ, Huang DS, Watson RR. 1994. In vivo and in vitro cocaine modulation on production of cytokines in C57BL/6 mice. Life Sci 54:401–411.
Kawai C. 1999. From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death-learning from the past for the future. Circulation 99:1091–1100.
Feldman AM, McNamara D. 2000. Myocarditis. New Engl J Med 343:1388–1398.
Reichenbach DD, Benditt EP. 1970. Catecholamines and cardiomyopathy: the pathogenesis and potential importance of myofibrillar degeneration. Hum Pathol 1:125–129.
Hoekstra JW, Griffith R, Kelly R, Cody RJ, et al. 1993. Effect of standard-dose versus high-dose epinephrine on myocardial high-energy phosphates during ventricular fibrillation and closed-chest CPR. Ann Emerg Med 22:1385–1391.
Isner JM, Chokshi SK. 1991. Cardiac complications of cocaine abuse. Annu Rev Med 42:133–138.
Rezkalla SH, Hale S, Kloner RA. 1990. Cocaine-induced heart diseases. Am Heart J 20:1403–1408.
Sepulveda RT, Jiang S, Beischel J, Bellamy WT, Watson RR. 2001. Cocaine injection and coxsackievirus B3 infection increase heart disease during murine AIDS. JAIDS 25:S19–S26.
Chidsey CA, Kaiser GA, Sonnenblick EH, Spann JF, Jr, Braunwald E. 1964. Cardiac norepinephrine stores in experimental heart failure in dogs. J Clin Invest 43:2386–2389.
Chidsey CA, Sonnenblick EH, Braunwald E. 1966. Norepinephrine stores and contractile force of papillary muscle from the failing human heart. Circulation 33:43–46.
Noda M, Kavano O, Uchida O, Sawabe T, Saito G. 1970. Myocarditis induced by sympathomimetic amines. Jpn Circ J 34:7–12.
Van Vliet PD, Burchell HB, Titus JL. 1966. Focal myocarditis associated with pheochromocytoma. N Eng J Med 274:1102–1108.
Rezkalla S, Kloner RA, Khatib G, Smith F, Khatib R. 1988. Effect of metoprolol in acute Coxsackievirus B3 murine myocarditis. J Am Coll Cardiol 12:412–414.
Tominaga M, Matsumori A, Okada I, Yamada T, Kawai C. 1991. β-blocker treatment of dilated cardiomyopathy: Beneficial effect of Carteolol in mice. Circulation 83:2021–2028.
Goodkin K, Shapshak P, Metsch LR. 1998. Cocaine abuse and HIV-1 infection: epidemiology and neuropathogenesis. J Neuroimmunol 83:88–101.
Larrat EP, Zierler S. 1993. Entangled epidemics: cocaine use and HIV disease. J Psychoactive Drugs 25:207–221.
Shannon RP, Simon MA, Mathier MA, Geng Y-J, Mankad S, Lackner AA. 2000. Dilated cardiomyopathy associated with Simian AIDS in nonhuman primates. Circulation 101:185–193.
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Wang, JF., Sullivan, M.E., Min, J., Morgan, J.P. (2003). Cardiac Toxicity of Cocaine: from Myocardial Depression to Cardiomyopathy. In: Singal, P.K., Dixon, I.M.C., Kirshenbaum, L.A., Dhalla, N.S. (eds) Cardiac Remodeling and Failure. Progress in Experimental Cardiology, vol 5. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-9262-8_35
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