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Renal function in male rats concurrently exposed to nicotine & ethanol.


Concurrent alcohol and nicotine consumption commonly occur together (1). Long-term alcohol intake produces serious harmful effects on renal function (2). Nicotine, being vasoconstrictive, increases blood pressure, potentially altering renal function (3).

The incidence of smoking among individuals who abuse alcohol and opiates, is about 90 per cent, although alcoholic individuals smoke more cigarettes than those who abuse other substances (4). The interactions between components of tobacco smoke and drugs have been of much concern and the subject of many investigations (5). Although some workers investigated the influence of ethanol on renal function (6) and nicotine on renal parameters (5), very little information is available on the concurrent intake of nicotine and ethanol on renal function. Therefore, the current experimental study in rats was performed to determine whether nicotine interacts with ethanol to compromise renal function in chronic substance users.

Sprague-Dawley rats (300-345 g) (7 wk) (n = 8) were housed in metabolic cages and maintained on a 12 h light/12 h dark cycle, in Department of Physiology, University of Zimbabwe, Zimbabwe. Food and water were provided ad libitum. Licensing was obtained from the Director of Veterinary Services Zimbabwe (as stipulated in the Scientific Animal Experiments Act, 1963) for animal experiments performed within the precincts of the University of Zimbabwe. Chronically separate groups of 8 rats were administered 1.6 g/kg body weight (bwt) ethanol daily by gavage, nicotine at 0.1 mg/kg bwt, and concurrently for 4 wk. Control rats (n=8) were administered volumes of de-mineralized water equivalent to those for ethanol and/or nicotine. Urine volume and [Na.sup.+]/[K.sup.+] excretion were determined in 24 h urine samples.

At the end of the 4 wk, all chronically treated animals were anaesthetized with intra-peritoneal injection of sodium 5-ethyl-5'-(1 -methyl-butyl)-2-thio-barbiturate at 0.11 g/kg, 1 bwt and challenged with intravenous hypotonic saline (0.077M NaCl) infusion via the right jugular vein. Following tracheotomy, cannulation, and urinary bladder incision, rats were placed on a warming tray at 37[degrees]C and equilibrated for 3 h. Thereafter, consecutive 20 min urine collections were made divided consecutively into 1 h control, 1 h 20 min treatment (nicotine and/or ethanol) and 1 h 40 m post-equilibration periods for determination of urine flow and [Na.sup.+] and [K.sup.+] excretion rates. Ethanol and/or nicotine were administered at 2.4 and 0.02 [micro]g/min, respectively. Urine volume was determined gravimetrically. [Na.sup.+] and [K.sup.+] excretion rates were analysed using flame photometry. A control or vehicle infused group was set up to check the stability of renal function over the 4 h period.

Trunk blood was collected in pre-cooled vials directly after the 1 h 20 min treatment period and centrifuged at 2500 g/min. Arginine vasopressin (AVP) was extracted using previous methods (7) using an AVP Radioimmunoassay kit supplied from Diagnostic Systems Laboratories, Texas, USA. AVP was extracted from plasma using Sep Pak C18 cartridges, the lower limit of detection being set at 0.5 fmol/l and intra- and inter-assay variations of 7.86 (n=15) and 12.32 per cent (n=15), respectively. Plasma aldosterone concentration was determined using Coat-A-Count by a Diagnostic Products kit, Los Angeles, USA. The test employed a solid-phase radioimmunoassay with an aldosterone-specific antibody immobilized to the wall of a polypropylene tube. The lower limit of detection was 44 fmol/l. Intra- and inter-assay coefficients of variation were 7.51 (n=15) and 7.93 per cent (n=15), respectively.

Data were statistically analysed using ANOVA-1 in MS-Excel (Analyse-IT Software, Ltd., Leeds). Scheffe's multiple comparison test was used to resolve any probable differences (CI = 95%).

Chronic nicotine administration did not significantly alter urine output, although there was a significant (P<0.05) reduction of [Na.sup.+] excretion by wk 4 compared with control animals (5.64 [+ or -] 1.02. vs. 7.10 [+ or -] 1.11 ml/ day, respectively). Chronic ethanol administration initially reduced urine volume in wk 1 (4.83 [+ or -] 0.68 vs. 6.03 [+ or -] 0.86 ml/day, respectively), but subsequently elevated in wk 4 (9.81 [+ or -] 1.02 vs. 6.11 [+ or -] 0.96 ml/day, respectively) compared to control. The mean weekly urinary [Na.sup.+] outputs were lower than control animals throughout the 4 wk treatment period. By wk 4, [Na.sup.+] excretion was 8.99 [+ or -] 0.5 mmol/day compared to 11.98 [+ or -] 0.9 mmol/day, in control rats. Concurrent ethanol and nicotine administration reduced weekly urine volume and [Na.sup.+] output throughout the 4 wk period. At wk 4, urine volume and [Na.sup.+] output in treated and control groups were 4.63 [+ or -] 1 vs. 5.63 [+ or -] 1 ml/day and 7.14 [+ or -] 0.65 vs. 9.01 [+ or -] 1 mmol/day, respectively. Urinary [K.sup.+] outputs did not differ significantly from control rats throughout the 4 wk period. Plasma aldosterone levels at wk 4 were significantly (P<0.05) elevated by chronic nicotine (3.65 [+ or -] 0.12 nmol/l), ethanol (3.98 [+ or -] 0.32 nmol/ 1), or in combination (4.01 [+ or -] 0.22 nmol/l) vs. controls (1.82 [+ or -] 0.11 nmol/l). Plasma AVP concentrations by wk 4 were not significantly altered in nicotine exposed rats (8.43 [+ or -] 1.32 fmol/l), reduced (P<0.05) in ethanol treated animals (7.01 [+ or -] 1.15 fmol/l) and elevated (P<0.05) with combined treatments (9.54 [+ or -] 1.08 fmol/l) compared to control rats (8.15 [+ or -] 1.24 fmol/l).

The urine flow rate in control animals did not differ significantly from the vehicle infusion rate of 150 [micro]l/ min. Nicotine treated rats had unaltered urine flow and [Na.sup.+] and [K.sup.+] excretion rates during the treatment period, followed thereafter by a significant (P<0.05) excretion of electrolytes at the end of the post-equilibration period compared with controls ([Na.sup.+]: 10.23 [+ or -] 1.56 [micro]mol/min vs. 8.97 [+ or -] 1.26 [micro]mol/min, [K.sup.+]: 6.41 [+ or -] 1.64 [micro]mol/min vs. 4.82 [+ or -] 1.33 [micro]mol/min, respectively). At the end of the post-equilibration period ethanol treatment significantly (P<0.05) elevated [Na.sup.+] output compared with controls (14.67 [+ or -] 1.18 [micro]mol/minvs. 8.86 [+ or -] 1.32 [micro]mol/min, respectively). There were no noticeable changes in urine flow and [K.sup.+] excretion rates. Co-administration, whilst having no effect on [K.sup.+] excretion rate, significantly (P<0.05) increased [Na.sup.+] excretion (12.23 [+ or -] 1.12 [micro]mol/min vs. 8.86 [+ or -] 1.32 [micro]mol/min, respectively) and urine flow rate (151.21 [+ or -] 15 [micro]l/min vs. 142.25 [+ or -] 10 [micro]l/min, respectively). Plasma aldosterone concentrations at the end of the postequilibration period were significantly (P<0.05) reduced for acute treatment of nicotine (1.32 [+ or -] 0.29 nmol/l), ethanol (1.88 [+ or -] 0.25 nmol/l), or in combination (1.56 [+ or -] 0.31 nmol/l) vs. controls (1.79 [+ or -] 0.13 nmol/l). Plasma AVP concentrations at the end of the post-equilibration period were not significantly altered in nicotine or ethanol treated rats (8.43 [+ or -] 1.32 fmol/l), but significantly reduced (P<0.05) in concurrent administration compared with controls (7.68 [+ or -] 1.32 fmol/l vs. 8.15 [+ or -] 1.24 fmol/l, respectively).

Findings in the current study suggest that the in-take of acute loads of nicotine and/or ethanol in chronic smokers and/or drinkers interferes with renal function by promoting [Na.sup.+] loss. Chronic administration induced renal [Na.sup.+] retention suggestive of increase in [Na.sup.+]/[K.sup.+]-ATPase activity in the cortex and outer medulla of the kidney (8). Retention of [Na.sup.+] in ethanol treated rats has been previously reported (6). Acutely, [Na.sup.+] excretion rate was elevated but was interestingly not associated with alterations in AVP in nicotine and ethanol treated groups. This was in contrast to a previous study which showed that low doses of ethanol increased the total urinary [Na.sup.+] loss and elevated plasma AVP concentrations (9). Discrepancies can be explained by differences in experimental design in the present study wherein chronically treated rats were acutely exposed to ethanol. The discrepancy between renal [Na.sup.+] handling in chronic and acute exposures in the current study, suggests compromised tubular function that may be associated with a rise in blood pressure in chronic smokers. Chronic administration of nicotine and ethanol decreased urine flow and [Na.sup.+] excretion rate in the present study. The effect is more marked when nicotine and ethanol were administered in combination, presumably lowering blood pressure through reduction in stroke volume via loss of [Na.sup.+] and water. Nicotine acts in combination with ethanol to stimulate water and salt retention. This may have adverse consequences on renal function by elevating stroke volume and retaining metabolic waste. It would be interesting to investigate a timed chronic consumption of nicotine and/or ethanol and possible histological effects on renal structure.

Ross Gordon Cooper

Department of Physiology

College of Health Sciences

University of Zimbabwe

Mount Pleasant, Harare, Zimbabwe

Present address: Division of Physiology

Faculty of Health, UCE Birmingham

Baker Building, Room 701

Franchise Street, Perry Barr

Birmingham B42 2SU, UK



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Title Annotation:Correspondence
Author:Cooper, Ross Gordon
Publication:Indian Journal of Medical Research
Article Type:Letter to the editor
Date:Jun 1, 2007
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