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Experimental nephropathy by chronic administration of cocaine in rats
ELSEVIER
Toxicology 98 (1995) 41-46
Experimental nephropathy
by chronic administration in rats
Rosario Barroso-Moguel *, Marisela Mendez-Armenta,
of cocaine
Juana Villeda-Hernandez
Luboratorio de Neuromorjologia Celular, Institute National de Neurologia y Neurocirugia ‘Manuel Velasco Sucirez’, S.S. Insurgentes Sur No. 3877. MPxico 14269, Mexico
Received 23 July 1994; accepted 8 September 1994
Abstract The recent and significant increase of cocaine abuse has emerged as a major public health problems. Cocaine abuse is frequently associated with multiorganic lesions, including renal failure. We report the light-microscopic features of the progression of renal lesions produced by chronic cocaine administration in rats. Male Wistar rats weighing 225-250 g were used. Twenty eight rats received an aqueous solution of cocaine hydrochloride (30 mgIkg/day i.p.) daily, while 28 control rats were injected i.p. daily with a saline solution. Rats from both groups were sacrificed after 7, 15, 30, 45, 60, 75 and 90 days of treatment. The histopathological study showed early changes on day 15, with damage to glomerular capillary walls and swelling of tubular epithelium, and lesions progressed to 90 days with development of glomerular atrophy and sclerosis. The tubular epithelial cells were necrotic and sloughed, and the lumen of papillary ducts contained destroyed red blood cell (RBC) casts. The interstitium had numerous foci of necrosis and haemorrhage. The results show that chronic treatment with cocaine in rats produce severe lesions both to glomerular, interstitium and tubular cells. Keyword: Cocaine; Kidney; Glomeruli; Atrophy; Tubules; Haemorrhage; Necrosis
1. Introduction The widespread systemic pathophysiological effects of cocaine have been described (Loper, 1989; Barroso-Moguel et al., 1991). Recent extensive abuse of cocaine has resulted in an alarming increase in hospital emergency-room admissions for treatment of acute cocaine toxicity. The adverse effects of chronic administration of cocaine, l
Corresponding author.
include, cerebrovascular accidents, myocardial infarctions, and rhabdomyolysis with myoglobinuria and renal failure, which may progress rapidly to sudden death (Loper, 1989; Flaque-Coma, 1990; Nolte, 1991). Some authors have reported human cases of acute myocardial infarction as well as intracranial haemorrhage after acute or chronic cocaine abuse. Cocaine and its metabolites, benzoylecgonine and ecgonine, were present in large amounts in the urine of those patients with renal failure (Finkle
0300-483XI95/W9.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0300-483X(94)02954-S
42
R. Borroso-Moguelet al. / Toxicology98 (1995) 41-46
and Closky, 1978; Russell et al. 1985; Tuchman et al. 1987). Although cocaine is a commonly abused drug, light-microscopic (LM) progression of renal lesions have not been studied, and, to the best of our knowledge, there is no reported work on the experimental pathogenesis of renal failure in cocaine abusers. In the present work, we studied the development of cocaine-induced nephrotoxicity in adult Wistar rats, at the LM level.
10% form01 solution for 15 days. Tissue samples were embedded in paraffin, and serial sectioned at 3 pm. Sections were stained with hematoxylin and eosin, Masson’s trichrome and Rio-Horteg6.s silver stain (Luna, 1960; Barroso-Moguel and Costero, 1962). Sections were then examined with a Zeiss light photomicroscope.
2. Materials and methods
No renal lesions were observed in control rats (Fig. 1). Treated rats demonstrated progressive renal lesions in the glomerular capillary endothelial cells and Bowman’s capsule epithelial cells, as well as lesions of wall cells in the tubuli and interstitium.
2. I. Reagents Cocaine hydrochloride (C17H22C1N04) was obtained from the Direcci6n General de Insumos para la Salud, Departamento Mtdico de Estupefacientes y Psicotr6picos de la Secretaria de Salud de M6xico. All other reagents were purchased from Merck (Mexico). 2.2. Animals Fifty-six adult male NIH Wistar rats (225-250 g) were obtained locally. They were fed ad libitum a standard rodent chow (Purina Chow) and had free access to water. A diurnal lighting cycle was maintained between 1900 h and 0700 h, at a room temperature of 2YC and a relative humidity of 40%. Twenty eight control rats were given 1 ml of saline solution i.p. daily, while another 28 rats received cocaine hydrochloride in aqueous solution i.p. daily, at variable times, 5 days per week at a dosage of 30 mgJkg/day, equivalent to 26 mg/kg/day of free base cocaine. Similar doses have been used study the long-term effects of cocaine in rats (Gordon et al., 1980; Church et al., 1987; Dow-Edwards, 1989; Barroso-Moguel et al., 1994). This dose of cocaine did not produce mortality in any of the treatment groups. Four rats from each treatment group were sacrificed on days 7, 15,30,45,60,75 and 90. Animals were deeply anesthetized with 0.3 ml of 3.5% chloral hydrate i.p. and then perfusion, fixed through the heart, using saline solution, for 15 min, followed by 10% (w/v) aqueous formaldehyde solution at 4°C for 20 min. The right kidney was stripped of its capsule, sliced in half and fixed in
3. Results
3.1. Glomerular lesions A variety of glomerular changes were found. In 15-day treated rats, the glomeruli showed an increase of mesangial matrix and epithelial cells decreased in number or were shrunken (Fig. 2, arrows). Some capillary loops were occluded by thrombi (Fig. 2, stars). By day 30, the capillary walls were thinner and may have ruptured or were destroyed. Some areas showed adhesions to Bowman’s capsule (Fig. 3, arrows), and the basal membrane of Bowman’s capsule was thickened in many places. A more advanced stage of glomerular deformity was seen from 60-90 days of cocaine administration. The glomeruli showed almost complete loss of their original architecture. By day 60, glomeruli showed moderate mesangial cell proliferation and diffuse thickening of the capillary basement membrane. In addition, glomerular tufts had numerous adhesions to Bowman’s capsule (Fig. 4 arrows). At day 90, glomeruli were smaller, showed deformities, altered capillaries and were adhered in part to the Bowman’s capsule (Fig. 5). Furthermore, there were some active fibroblasts and fibrin in the capsular space. 3.2. Tubular and interstitial lesions Chronic cocaine administration also produced progressive changes in the uriniferous tubules. Tubular lumina increased and flattened epithelial cells were observed (Fig. 6). After 30 days, necrosis
R. Barroso-Moguel ef al. / Toxicology 98 (1995) 41-46
43
Fig. 1. Renal cortex of control rat without lesions in glomeruli with afferent artery (arrow) and tubules. (Silver stain, Rio-Hortega’s method, 100x ).
(arrows) of some of the tubular cells in distal collecting tubules (DCT) and proximal collecting tubules (PCT) was observed. This was accompanied by nuclear karyorrhexis or pyknosis, cytoplasmic eosinophilia and vacuolization. Some tubules contained sloughed epithelial cells and destroyed RBC casts with marked tubular dilation (Fig. 6). At 60 days, the majority of the epithelial cells of the pars recta of the DCT had vacuoles or were necrotic and sloughed and mixed with destroyed RBC. There were many ruptures in the basement membrane, the lumen contained casts and some interstitial capillaries had thrombi (Fig. 7). After 75 days of cocaine administration, several large focal areas of haemorrhagic necrosis between the pars recta of the DCT and the interstitium were seen (Fig. 8). At 90 days, some of the collecting and terminal uriniferous ducts of the pyramids had blood casts. In the interstitium there were small areas of necrosis (Fig. 9, arrows).
4. Discussion Various drugs and toxins such as cocaine, lead, cadmium, mercury, ethanol, thinner, even ultrasound, produce similar nephropathy (Jones, 1968; Elbadawi et al., 1974; Gyorkey et al., 1974; Richey et al., 1974; Rosen et al., 1974; Ware et al., 1974; Barroso-Moguel et al., 1988; Barroso-Moguel et al., 1991). All produce renal failure with albuminuria, hematuria, cylindruria, cellular or hyaline casts, and lesions throughout the kidney. The renal morphological changes produced experimentally by chronic cocaine administration i.p. to Wistar rats are not specific, but the combination of glomerulo-tubular lesions are characteristic for this model. The present study indicates that lesions after cocaine administration to rats are similar to those observed in human narcotic addicts after chronic cocaine abuse, whereby they develop glomerulosclerosis and renal failure (Gyorkey et al., 1974). It is suggested that the epithelial proliferation in
Fig. 5. By day 90 the glomerulus is smaller, shrunken and most of the capillary capsule (arrows). (Silver stain, Rio-Hortega’s method, 100 x ).
cells are destroyed.
area and adhesions
to the Bowman’s
cell. Some of the capillary lumina are reduced, There is fibrin in the capsular
Fig. 4. The glomerular lesions were advanced at 60 day. The glomerular tufts are distended and have few mesangial and there are numerous adhesions to the Bowman’s capsule (arrows). (Silver stain, Rio-Hortega’s method, loox ).
Fig. 2. Glomerulus of rat after I5 days of i.p. cocaine administration. There is an increase of mesangial matrix and some capillary loops are occluded by thrombi (arrows). (Silver stain, Rio-Hortega’s method, 100x ). Fig. 3. At day 30 the glomerular capillary walls were thinner and some had ruptured, resulting in adhesions to the Bowman’s capsule (arrows). Epithelium of some proximal convoluted tubules were stained intensively. (Silver stain, Rio-Hortega’s method, 100 x ).
‘(XOZ ‘pOqlXU
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@els)
qi!M
waaeld atuos II!luapjaaSW, uo!lel!plE[nqnl ‘@) dk?pl(g 'L '%!d
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s!soJz~~pue a%sq~Jot~a~~qjo!3ojaJaM aJaqi ‘5~ Lep kg '8 ?i!d
'(SMOJJB)S]SlZa poolq peq Slanp SnOJaJgJn ll+UL~alpue h!laa[[O3 aLUOS ‘Sbep 06 IV '6 '%!d
'poylaurs,e%atlog-og ‘uiels.taqS)
'(XOL ‘poqiam s.uosse~) 'sa[nqnllewp 8uy1o~y ,(xwf ‘(SMOJJe)UaqoJq Jo Jauwql aJaM SaueJquIaw leseq ‘(a3)S!SOJWI lepqla3 paMoqs sap'iqnl aqlJ0 awes
'(x001 ‘poqlam s,t@alJoH-o!x ‘yeis Jaq!s) .ewapao legpualu! s! aJau we3 %u! -wOJ W3 POW PJ P~oJlsap ql!M pax!uIpue paqSnols aJaM sllaaauros!(SMOJJE)S!SOJXIU leyaql!daq]!m paualleU aramsa[nqnl pa~n~ohuoa~etu!xoJd'o~,kp 6~ ‘9 ‘By
46
R. Barroso-Moguel et al. / Toxicology 98 (1995) 41-46
Bowman’s space is also related to glomerular injuries, in that the leakage of the blood fibrin or other plasma constituents, results in focal adhesions to Bowman’s capsule. There is a progression of glomerular changes that appear simultaneously in the glomeruli, tubular and interstitial degeneration space, with foamy, necrotic and sloughed cells. Lesions observed in the present study could be produced by the action of a cocaine-enhanced catecholamine effect, which in turn may increase vasoconstriction (Ritchie and Greene, 1985), and also due to the action of cocaine catabolites in the urine (Ishizuka et al., 1989; Malandri et al., 1993). In addition, a direct vasoconstrictive effect of cocaine (Hogestatt et al., 1988) may induce abasement and endothelial membrane lesions of renal vessels and tubules followed by tubular necrosis and interstitial oedema. Acknowledgements
The authors thank Dr. Camilo Rios for his help in preparing the manuscript. References Barroso-Moguel, R. and Costero, I. (1962) Argentafin ceils of the carotid body tumor. Am. J. Pathol. 41, 389-403. Barroso-Moguel, R. and Romero, D.V. (1988) Thinner: Inhalacion y Consccuencias. Instituto National de Neurologia y Neurocirugia, Fundacion de Investigaciones, A.C. FISAC. Mexico, D.F. Barroso-Moguel, R., Villeda-Hemandez, J. and MendezArmenta, M. (1991) Medical causes and effects of cocaine abuse. Arch. Invest. M&l. 22, 3-8. Barroso-Moguel, R., Mindez-Armenta, M. and VilledaHemandez, J. (1994) Testicular lesions by chronic administration of cocaine in rats. J. Appl. Toxicol. 13, 37-41. Church, W.M., Dintcheff, A.B. and Gessner, K.P. (1987) Dosedependent consequences of cocaine on pregnancy outcome in the Long-Evans rat. Neurotoxicol. Teratol. 10, 51-58. Dow-Edwards, L.D. (1989) Long-term neurochemical and neurobchavioral consequences of cocaine-use during pregnancy. Ann. N.Y. Acad. Sci. 562, 280-289. Elbadawi, CA., Linke, C.A. and Schenk, E.A. (1974) Histopathologic characteristic of ultrasound-induced renal injury. Sci. Proc. Am. J. Pathol. 74, 20a.
Finkle, B.S. and Closky, M.E. (1978) The forensic toxicology of cocaine. J. Forensic Sci. 23, 173-188. Flaque-Coma, J. (1990) Cocaine and rhabdomyolysis: report of a case and review of the literature. Bol. Assoc. Med. P.R. 82, 423-424. Hogestatt, E.D., Johanson, O., Andersson, K.E. and Kullendot% CM. (1988) Influence of renal denervation on vascular responsiveness of isolated rat intrarenal arteries. Acta Physiol. &and. 132, 59-66. Gordon, L.A., Mostosky, D.I. and Gordon, G.G. (1980) Changes in testosterone levels in the rat following intraperitoneal cocaine HCL. Int. J. Neurosci. 11, 139-141. Gyorkey, K.W., Mitt, I., Krisko, P., Gyorkey, P. and Eknoyan, G. (1974) The nephropathy of drug addiction and its clinical evolution correlation. Sci. Proc. Am. J. Pathol. 74, 22a. Ishizuka, Y., Rockhold, R.W., Kirchner, K. and Ho, I.K. (1989) Differential sensitivity to cocaine in spontaneously hypertensive and Wistar-Kyoto rats. Life Sci. 45, 223-232. Jones, D.B. (1968) Formation and healing of glomerular epithelial crescents. Lab. invest. 18, 326-327. Loper, K.A. (1989) Clinical toxicology of cocaine. Med. Toxicol. Adverse Drug Exp. 4, 174-185. Luna, G. (1960) Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology. American Registry of Pathology, Washington, DC, pp. 258-259. Malandri, R., Santaro, A., Zele, J., Tomba, N., Pezzilli, R., Re, G. and Miglioli, M. (1993) Cocaine poisoning in acute renal insufficiency. Recenti Prog. Med. (Italy) 84, 188-19 1. Nolte, K.B. (199 1) Rhabdomyolysis associated with cocaine abuse. Hum. Pathol. 22, 1141-I 145. Richey, W.A., Krigman, M.R. and Goyer, R.A. (1974) A morphometric analysis of lead. Nephropathy in the rat. Sci. Proc. Am. J. Pathot. 74, 22a. Ritchie. M.J. and Greene, M.N. (1990) Local Anesthetics. In: A.G. Gilman, A.F. Goodman, W.T. Rall, A.S. Nies and P. Taylor (Eds), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, MacMillan, New York, pp. 31 I-320. Rosen, J., Gonick, H.C., Neustein, H. and Van de Velde, R. (1974) Cadmium-induced Fanconi Syndrome: an ultrastructural study. Sci. Proc. Am. J. Pathol. 74, 21a. Russell, E., Howard, D., Hueter, C. and Gary, J.D. (1985) Acute myocardial infarction following cocaine abuse in a young woman with normal coronary arteries. J. Am. Med. Assoc. 254, 96-98. Tuchman, A.J., Doras, M., Zalzal, P. and Mangiardi, J. (1987) Intracranial hemorrhage after cocaine abuse. J. Am. Med. Assoc. 257, 1175. Ware, W.A., Bukholder, P.M. and Chang, L.W. (1974) Pathologic effects of experimental mercury intoxication on renal function. Sci. Proc. Am. J. Pathol. 74, 21a.
Toxicology 98 (1995) 41-46
Experimental nephropathy
by chronic administration in rats
Rosario Barroso-Moguel *, Marisela Mendez-Armenta,
of cocaine
Juana Villeda-Hernandez
Luboratorio de Neuromorjologia Celular, Institute National de Neurologia y Neurocirugia ‘Manuel Velasco Sucirez’, S.S. Insurgentes Sur No. 3877. MPxico 14269, Mexico
Received 23 July 1994; accepted 8 September 1994
Abstract The recent and significant increase of cocaine abuse has emerged as a major public health problems. Cocaine abuse is frequently associated with multiorganic lesions, including renal failure. We report the light-microscopic features of the progression of renal lesions produced by chronic cocaine administration in rats. Male Wistar rats weighing 225-250 g were used. Twenty eight rats received an aqueous solution of cocaine hydrochloride (30 mgIkg/day i.p.) daily, while 28 control rats were injected i.p. daily with a saline solution. Rats from both groups were sacrificed after 7, 15, 30, 45, 60, 75 and 90 days of treatment. The histopathological study showed early changes on day 15, with damage to glomerular capillary walls and swelling of tubular epithelium, and lesions progressed to 90 days with development of glomerular atrophy and sclerosis. The tubular epithelial cells were necrotic and sloughed, and the lumen of papillary ducts contained destroyed red blood cell (RBC) casts. The interstitium had numerous foci of necrosis and haemorrhage. The results show that chronic treatment with cocaine in rats produce severe lesions both to glomerular, interstitium and tubular cells. Keyword: Cocaine; Kidney; Glomeruli; Atrophy; Tubules; Haemorrhage; Necrosis
1. Introduction The widespread systemic pathophysiological effects of cocaine have been described (Loper, 1989; Barroso-Moguel et al., 1991). Recent extensive abuse of cocaine has resulted in an alarming increase in hospital emergency-room admissions for treatment of acute cocaine toxicity. The adverse effects of chronic administration of cocaine, l
Corresponding author.
include, cerebrovascular accidents, myocardial infarctions, and rhabdomyolysis with myoglobinuria and renal failure, which may progress rapidly to sudden death (Loper, 1989; Flaque-Coma, 1990; Nolte, 1991). Some authors have reported human cases of acute myocardial infarction as well as intracranial haemorrhage after acute or chronic cocaine abuse. Cocaine and its metabolites, benzoylecgonine and ecgonine, were present in large amounts in the urine of those patients with renal failure (Finkle
0300-483XI95/W9.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0300-483X(94)02954-S
42
R. Borroso-Moguelet al. / Toxicology98 (1995) 41-46
and Closky, 1978; Russell et al. 1985; Tuchman et al. 1987). Although cocaine is a commonly abused drug, light-microscopic (LM) progression of renal lesions have not been studied, and, to the best of our knowledge, there is no reported work on the experimental pathogenesis of renal failure in cocaine abusers. In the present work, we studied the development of cocaine-induced nephrotoxicity in adult Wistar rats, at the LM level.
10% form01 solution for 15 days. Tissue samples were embedded in paraffin, and serial sectioned at 3 pm. Sections were stained with hematoxylin and eosin, Masson’s trichrome and Rio-Horteg6.s silver stain (Luna, 1960; Barroso-Moguel and Costero, 1962). Sections were then examined with a Zeiss light photomicroscope.
2. Materials and methods
No renal lesions were observed in control rats (Fig. 1). Treated rats demonstrated progressive renal lesions in the glomerular capillary endothelial cells and Bowman’s capsule epithelial cells, as well as lesions of wall cells in the tubuli and interstitium.
2. I. Reagents Cocaine hydrochloride (C17H22C1N04) was obtained from the Direcci6n General de Insumos para la Salud, Departamento Mtdico de Estupefacientes y Psicotr6picos de la Secretaria de Salud de M6xico. All other reagents were purchased from Merck (Mexico). 2.2. Animals Fifty-six adult male NIH Wistar rats (225-250 g) were obtained locally. They were fed ad libitum a standard rodent chow (Purina Chow) and had free access to water. A diurnal lighting cycle was maintained between 1900 h and 0700 h, at a room temperature of 2YC and a relative humidity of 40%. Twenty eight control rats were given 1 ml of saline solution i.p. daily, while another 28 rats received cocaine hydrochloride in aqueous solution i.p. daily, at variable times, 5 days per week at a dosage of 30 mgJkg/day, equivalent to 26 mg/kg/day of free base cocaine. Similar doses have been used study the long-term effects of cocaine in rats (Gordon et al., 1980; Church et al., 1987; Dow-Edwards, 1989; Barroso-Moguel et al., 1994). This dose of cocaine did not produce mortality in any of the treatment groups. Four rats from each treatment group were sacrificed on days 7, 15,30,45,60,75 and 90. Animals were deeply anesthetized with 0.3 ml of 3.5% chloral hydrate i.p. and then perfusion, fixed through the heart, using saline solution, for 15 min, followed by 10% (w/v) aqueous formaldehyde solution at 4°C for 20 min. The right kidney was stripped of its capsule, sliced in half and fixed in
3. Results
3.1. Glomerular lesions A variety of glomerular changes were found. In 15-day treated rats, the glomeruli showed an increase of mesangial matrix and epithelial cells decreased in number or were shrunken (Fig. 2, arrows). Some capillary loops were occluded by thrombi (Fig. 2, stars). By day 30, the capillary walls were thinner and may have ruptured or were destroyed. Some areas showed adhesions to Bowman’s capsule (Fig. 3, arrows), and the basal membrane of Bowman’s capsule was thickened in many places. A more advanced stage of glomerular deformity was seen from 60-90 days of cocaine administration. The glomeruli showed almost complete loss of their original architecture. By day 60, glomeruli showed moderate mesangial cell proliferation and diffuse thickening of the capillary basement membrane. In addition, glomerular tufts had numerous adhesions to Bowman’s capsule (Fig. 4 arrows). At day 90, glomeruli were smaller, showed deformities, altered capillaries and were adhered in part to the Bowman’s capsule (Fig. 5). Furthermore, there were some active fibroblasts and fibrin in the capsular space. 3.2. Tubular and interstitial lesions Chronic cocaine administration also produced progressive changes in the uriniferous tubules. Tubular lumina increased and flattened epithelial cells were observed (Fig. 6). After 30 days, necrosis
R. Barroso-Moguel ef al. / Toxicology 98 (1995) 41-46
43
Fig. 1. Renal cortex of control rat without lesions in glomeruli with afferent artery (arrow) and tubules. (Silver stain, Rio-Hortega’s method, 100x ).
(arrows) of some of the tubular cells in distal collecting tubules (DCT) and proximal collecting tubules (PCT) was observed. This was accompanied by nuclear karyorrhexis or pyknosis, cytoplasmic eosinophilia and vacuolization. Some tubules contained sloughed epithelial cells and destroyed RBC casts with marked tubular dilation (Fig. 6). At 60 days, the majority of the epithelial cells of the pars recta of the DCT had vacuoles or were necrotic and sloughed and mixed with destroyed RBC. There were many ruptures in the basement membrane, the lumen contained casts and some interstitial capillaries had thrombi (Fig. 7). After 75 days of cocaine administration, several large focal areas of haemorrhagic necrosis between the pars recta of the DCT and the interstitium were seen (Fig. 8). At 90 days, some of the collecting and terminal uriniferous ducts of the pyramids had blood casts. In the interstitium there were small areas of necrosis (Fig. 9, arrows).
4. Discussion Various drugs and toxins such as cocaine, lead, cadmium, mercury, ethanol, thinner, even ultrasound, produce similar nephropathy (Jones, 1968; Elbadawi et al., 1974; Gyorkey et al., 1974; Richey et al., 1974; Rosen et al., 1974; Ware et al., 1974; Barroso-Moguel et al., 1988; Barroso-Moguel et al., 1991). All produce renal failure with albuminuria, hematuria, cylindruria, cellular or hyaline casts, and lesions throughout the kidney. The renal morphological changes produced experimentally by chronic cocaine administration i.p. to Wistar rats are not specific, but the combination of glomerulo-tubular lesions are characteristic for this model. The present study indicates that lesions after cocaine administration to rats are similar to those observed in human narcotic addicts after chronic cocaine abuse, whereby they develop glomerulosclerosis and renal failure (Gyorkey et al., 1974). It is suggested that the epithelial proliferation in
Fig. 5. By day 90 the glomerulus is smaller, shrunken and most of the capillary capsule (arrows). (Silver stain, Rio-Hortega’s method, 100 x ).
cells are destroyed.
area and adhesions
to the Bowman’s
cell. Some of the capillary lumina are reduced, There is fibrin in the capsular
Fig. 4. The glomerular lesions were advanced at 60 day. The glomerular tufts are distended and have few mesangial and there are numerous adhesions to the Bowman’s capsule (arrows). (Silver stain, Rio-Hortega’s method, loox ).
Fig. 2. Glomerulus of rat after I5 days of i.p. cocaine administration. There is an increase of mesangial matrix and some capillary loops are occluded by thrombi (arrows). (Silver stain, Rio-Hortega’s method, 100x ). Fig. 3. At day 30 the glomerular capillary walls were thinner and some had ruptured, resulting in adhesions to the Bowman’s capsule (arrows). Epithelium of some proximal convoluted tubules were stained intensively. (Silver stain, Rio-Hortega’s method, 100 x ).
‘(XOZ ‘pOqlXU
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@els)
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s!soJz~~pue a%sq~Jot~a~~qjo!3ojaJaM aJaqi ‘5~ Lep kg '8 ?i!d
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'(x001 ‘poqlam s,t@alJoH-o!x ‘yeis Jaq!s) .ewapao legpualu! s! aJau we3 %u! -wOJ W3 POW PJ P~oJlsap ql!M pax!uIpue paqSnols aJaM sllaaauros!(SMOJJE)S!SOJXIU leyaql!daq]!m paualleU aramsa[nqnl pa~n~ohuoa~etu!xoJd'o~,kp 6~ ‘9 ‘By
46
R. Barroso-Moguel et al. / Toxicology 98 (1995) 41-46
Bowman’s space is also related to glomerular injuries, in that the leakage of the blood fibrin or other plasma constituents, results in focal adhesions to Bowman’s capsule. There is a progression of glomerular changes that appear simultaneously in the glomeruli, tubular and interstitial degeneration space, with foamy, necrotic and sloughed cells. Lesions observed in the present study could be produced by the action of a cocaine-enhanced catecholamine effect, which in turn may increase vasoconstriction (Ritchie and Greene, 1985), and also due to the action of cocaine catabolites in the urine (Ishizuka et al., 1989; Malandri et al., 1993). In addition, a direct vasoconstrictive effect of cocaine (Hogestatt et al., 1988) may induce abasement and endothelial membrane lesions of renal vessels and tubules followed by tubular necrosis and interstitial oedema. Acknowledgements
The authors thank Dr. Camilo Rios for his help in preparing the manuscript. References Barroso-Moguel, R. and Costero, I. (1962) Argentafin ceils of the carotid body tumor. Am. J. Pathol. 41, 389-403. Barroso-Moguel, R. and Romero, D.V. (1988) Thinner: Inhalacion y Consccuencias. Instituto National de Neurologia y Neurocirugia, Fundacion de Investigaciones, A.C. FISAC. Mexico, D.F. Barroso-Moguel, R., Villeda-Hemandez, J. and MendezArmenta, M. (1991) Medical causes and effects of cocaine abuse. Arch. Invest. M&l. 22, 3-8. Barroso-Moguel, R., Mindez-Armenta, M. and VilledaHemandez, J. (1994) Testicular lesions by chronic administration of cocaine in rats. J. Appl. Toxicol. 13, 37-41. Church, W.M., Dintcheff, A.B. and Gessner, K.P. (1987) Dosedependent consequences of cocaine on pregnancy outcome in the Long-Evans rat. Neurotoxicol. Teratol. 10, 51-58. Dow-Edwards, L.D. (1989) Long-term neurochemical and neurobchavioral consequences of cocaine-use during pregnancy. Ann. N.Y. Acad. Sci. 562, 280-289. Elbadawi, CA., Linke, C.A. and Schenk, E.A. (1974) Histopathologic characteristic of ultrasound-induced renal injury. Sci. Proc. Am. J. Pathol. 74, 20a.
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