Renoprotective evaluations of different angiotensin inhibitors on Dia- betic Nephropathy in Rats Cutaneous Leishmania in Wadi Hadramout, Yemen

nternal edicine Middle East Journal of Internal Medicine ISSN 1837 9052 November 2016 - Volume 9, Issue 3 Chief Editor: Ahmad Husari Ethics Editor and Publisher: Ms Lesley Pocock medi+WORLD International Email: lesleypocock@mediworld.com.au Editorial enquiries: editor@me-jim.com Advertising enquiries: lesleypocock@mediworld.com.au While all efforts have been made to ensure the accuracy of the information in this journal, opinions expressed are those of the authors and do not necessarily reflect the views of The Publishers, Editor or the Editorial Board. The publishers, Editor and Editorial Board cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; or the views and opinions expressed.Publication of any advertisements does not constitute any endorsement by the Publishers and Editors of the product advertised. 2 Editorial Ahmad Husari Original Contribution / Clinical Investigation 3 Renoprotective evaluations of different angiotensin inhibitors on Diabetic Nephropathy in Rats Kawa F. Dizaye, Asmaa A. Ahmed 12 Digital clubbing may be a pioneer sign of cirrhosis in sickle cell patients Mehmet Rami Helvaci, Orhan Ayyildiz, Orhan Ekrem Muftuoglu, Lesley Pocock Community Care 18 Cutaneous Leishmania in Wadi Hadramout, Yemen S Amer Omer Bin Al-Zou Ofice Based Medicine 26 Obesity Management in Primary Health Care Abdulrazak Abyad The contents of this journal are copyright. Apart from any fair dealing for purposes of private study, research, criticism or review, as permitted under the Australian Copyright Act, no part of this program may be reproduced without the permission of the publisher.  FROM THE EDITOR From the Editor A paper from Turkey investigated the possibility that t Digital clubbing may be a pioneer sign of cirrhosis in sickle cell patients. All patients with SCDs were taken into the study. The study included 397 patients (193 females and 204 males). There were 36 patients (9.0%) with digital clubbing. The male ratio was signiicantly higher in the digital clubbing group (66.6% versus 49.8%, p<0.05). The author concluded that SCDs are chronic catastrophic processes on endothelium particularly at the capillary level, and terminate with accelerated atherosclerosis induced end-organ failures in early years of life. Digital clubbing may show an advanced disease and be a pioneer sign of cirrhosis in such patients. Ahmad Husari (Chief Editor) Email: editor@me-jim.com This is the last issue this year of the journal. The issue has papers from various countries in the region dealing with various topics. In addition with this issue we are Introducing the Middle East Primary Care Quality Improvement program (MEQUIP). See www.mejfm/MEQUIP/index.htm A paper from Yemen attempt to describe epidemiological and clinical features of cutaneous leishmana cases. It was a retrospective descriptive records review of all patients with cutaneous leishmaniasis diagnosed at the Seiyun general hospital from January to December 2013. A total of 122 patients were diagnosed with cutaneous leishmaniasis. The age of patients ranged between 1 to 62 years and the mean age is 26.5 ± 18.1 years. Most of the patients 56(45.9%) were of age group less than 20 years. The most common type of lesions were nodulo-ulcerated 52(42.7%) followed by nodular 45(36.9%). The distribution of sex, in which males and females of age group less than 20 years, were predominant 38 (31.1%) and 18 (14.8%) respectively. The authors concluded that that Wadi Hadramout is an endemic region of leishmaniasis and our indings will be of great interest to the public health authorities in Hadramout. A paper from Iraq was designed to compare the effectiveness of different angiotensin inhibitors; direct rennin inhibitor (Aliskiren), angiotensin-converting enzyme inhibitors (Ramipril) and angiotensin II receptor blocker (Irbesartan) in prevention and treatment of nephropathy in a group of rat diabetic nephropathy in rats. Diabetic nephropathic rats showed a signiicant increase in blood glucose level, blood pressure, heart rate, serum urea, serum creatinine, in addition to deteriorating renal functions including (urine low, glomerular iltration rate, Na+ and K+ excretion rate, albumin and creatinine in the urine). The administration of (Ramipril, Irbesartan, and Aliskiren) caused a signiicant reduction in blood pressure, blood glucose, serum urea, Na+ and K+ excretion rate, with a signiicant improvement in urine low and glomerular iltration rate. All three drugs induced a signiicant elevation in serum K+ concentration. The authors concluded that administration of different angiotensin inhibitors (ramipril, irbesartan, & aliskiren) could slow the progression of nephropathy in alloxan induced diabetic rats. Both ramipril and irbesartan have the same renoprotective effects for most parameters. A review paper form Lebanon looked at obesity Management in Primary Health Care. The author stressed that Obesity is a key public health problem across the world. Easy solutions are unlikely, given the complex interaction between the abundant availability of energy dense food, the ever decreasing demand for energy expenditure in the modern world. This review paper address the issues of overweight and obesity in primary health care. MIDDLE EAST JOURNAL OF INTERNAL MEDICINE VOLUME 9 ISSUE 3 NOVEMBER 2016 2 M I D D L E E A S T J O U R N A L O F I N T E R N A L M E D I C I N E • VO LU M E 2 , I S S U E 3 O R I G I N A L CO N T R I B U T I O N / C L I N I C A L I N V E S T I G AT I O N Renoprotective evaluations of different angiotensin inhibitors on Diabetic Nephropathy in Rats Kawa F. Dizaye (1) Asmaa A. Ahmed (2) (1) PhD. Head of Department of Pharmacology, College of Medicine. Hawler Medical University, Erbil, Iraq (2) MSc. Rizgary Teaching Hospital, Ministry of Health, Erbil, Iraq Correspondence: Prof. Dr. Kawa Dizaye Professor of Pharmacology Hawler Medical University, Erbil, Iraq Tel: 009647504452392 Web: hmu.edu.iq Email: kawa.dizaye@hmu.edu.iq ABSTRACT Background: This study was designed to compare the effectiveness of different angiotensin inhibitors; direct renin inhibitor (Aliskiren), angiotensin-converting enzyme inhibitors (Ramipril) and angiotensin II receptor blocker (Irbesartan) in prevention and treatment of nephropathy in a group of rat diabetic nephropathy in rats. Methods: Thirty rats were divided into two groups. The first group consisted of 6 rats which were considered as the normal control group. The second group included 24 induced diabetic rats. The diabetic model rats were subdivided into four subgroups of six rats each. The first subgroup served as a positive control. The second, third and fourth subgroup received Ramipril, Irbesartan and Aliskiren respectively. Results: Diabetic nephropathic rats showed a significant increase in blood glucose level, blood pressure, heart rate, serum urea, serum creatinine, in addition to deteriorating renal functions including (urine flow, glomerular filtration rate, Na+ and K+ excretion rate, albumin and creatinine in the urine). The administration of (Ramipril, Irbesartan, and Aliskiren) caused a significant reduction in blood pressure, blood glucose, serum urea, Na+ and K+ excretion rate, with a significant improvement in urine flow and glomerular filtration rate. All three drugs induced a significant elevation in serum K+ concentration. Conclusion: Administration of different angiotensin inhibitors (ramipril, irbesartan, & aliskiren) could slow the progression of nephropathy in alloxan induced diabetic rats. Both ramipril and irbesartan have the same renoprotective effects for most parameters. Key words: Diabetic nephropathy, Aliskiren, Irbesartan, Ramipril M I D D L E E AOF S T JINTERNAL O U R N A L OMEDICINE F I N T E R N A L VOLUME M E D I C I N E9 ISSUE • VO LU3MNOVEMBER E 2 , I S S U E 3 2016 MIDDLE EAST JOURNAL 3 O R I G I N A L CO N T R I B U T I O N A N D C L I N I C A L I N V E S T I G AT I O N The animals were maintained on a balanced diet (bread, barley, carrots, lettuce, milk) and fresh-water supply. Introduction Diabetic nephropathy is a major microvascular complication of diabetes, representing the leading cause of end stage renal disease in the world. Diabetic nephropathy is characterized by a progressive increase in urinary albumin excretion (microalbuminuria) and a decline in glomerular iltration rate (GFR), which occurs in association with an increase in blood pressure, ultimately leading to end stage renal disease (1, 2). Basic and clinical research supports the use of renin angiotensin aldosterone system (RAAS) inhibitors in diabetic nephropathy (3, 4, 5). Several basic and clinical studies, mainly in diabetic patients, have provided evidence that some antihypertensive agents that inhibit the renin angiotensin aldosterone system (RAAS), like angiotensin II type 1 receptor blockers (ARB) and angiotensinconverting enzyme inhibitors (ACEI), are renoprotective (6, 7). The reno-protection provided by these drugs seems at least partly independent of BP lowering and related perhaps to the inhibition of the RAS (8, 9, 10). Induction of experimental diabetes Diabetes was induced by a single intraperitoneal injection of 120mg/kg body weight of alloxan dissolved in distilled water immediately before injection 16. Alloxan treated animals were allowed to drink 5% of glucose overnight to prevent the potentially fatal hypoglycemia occurring as a result of massive insulin release following alloxan injection (17). Rats showing blood glucose levels above 180 mg/dl were considered to be diabetic (18) and used for drug treatment. Experimental design Thirty rats were divided into ive groups each consisting of 6 rats in order to study the effect of different angiotensin inhibitors (Ramipril, Irbesartan, Aliskiren) during the 21 days study period: Group I: Normal control rats given D.W Group II: Control diabetic rats given D.W Several mechanisms participate in the renal protection afforded by angiotensin inhibitors. ACEIs increase the permeability selectivity of the iltering membrane, thereby diminishing exposure of the mesangium to proteinaceous factors that may stimulate mesangial cell proliferation and matrix production, two processes that contribute to expansion of the mesangium in diabetic nephropathy. Since angiotensin II is a growth factor, reductions in the intrarenal levels of angiotensin II may further attenuate mesangial cell growth and matrix production (11, 12, 13). Group III: Diabetic rats given Ramipril 10mg/kg. Group IV: Diabetic rats given Irbesartan 10mg/kg. Group V: Diabetic rats given Aliskiren 10 mg/kg. The solution of drugs was freshly prepared in normal saline before administration by an oral gavage every morning. Collection of samples 1-Urine Thus, there do not appear to be signiicant differences between ACEI and ARBs in type 2 diabetic patients with nephropathy based on a small number of comparison studies. Other studies in hypertensive type 2 diabetics with early nephropathy comparing ACEIs and ARBs have also failed to show signiicant differences in the effects of these two drug classes on BP and urinary albumin excretion (14, 15). Only a few studies have addressed the question of whether ACE inhibitors are better than ARBs or vice versa. This study is designed to compare the effectiveness of different angiotensin inhibitors, direct renin (DR) inhibitor (Aliskiren), ACEI (Ramipril) ARBs (Irbesartan) in prevention and treatment of nephropathy in rat induced diabetes. Materials and Methods After 3 days, and at the end of drug treatment, all of the animals were kept in metabolic cages. Animals were fasted but allowed free access to water. Urine sample were collected after 24 hours in urine collecting bottles from which the urine collected was tested for: Albumin, Creatinine, Na+ excretion rate and K+ excretion rate, glomerular iltration rate and others. 2-Blood At the end of drug treatment, all of the animals were fasted overnight but allowed free access to water. The next morning, blood samples were taken by cardiac puncture into a plastic syringe under a combination of ketamine in a dose of 75 mg/kg with xylazine in a dose of 10 mg/kg. At 10th day and at the end of experiment (after 21 days), a 24 hours urine collection was carried out by using the metabolic cage. The urine was checked for the albumin and total protein by using Cybow diagnostic kits (DFI co. Ltd, Gimhae- City, Gyung- Nam, Korea). Statistical Analysis Animals Healthy adult albino rats of both sexes were used in the present study. Their weight ranged from 250-300 grams. Rats were grouped and kept in separate animal cages at the animal house of the College of Medicine under prevailing atmospheric conditions (room temperature of about 25c). All data are expressed as the mean ± standard error means (M ± SEM). The results were evaluated by using the Statistical Package for the Social Sciences (SPSS Version 21) computer program and the differences in all parameters between diabetic and non-diabetic rats were analyzed by a MIDDLE EAST JOURNAL OF INTERNAL MEDICINE VOLUME 9 ISSUE 3 NOVEMBER 2016  M I D D L E E A S T J O U R N A L O F I N T E R N A L M E D I C I N E • VO LU M E 2 , I S S U E 3 O R I G I N A L CO N T R I B U T I O N / C L I N I C A L I N V E S T I G AT I O N one-way analysis of variables (ANOVA). The comparison between groups was done using Duncan test. A change was considered statistically signiicant when P<0.05. The experiments were carried out with the approval of the ethic committee of Hawler Medical University/college of Medicine. Results Effect of Ramipril, Irbesartan, and Aliskiren on the blood pressure and heart rate of diabetic rats. In alloxan-induced diabetic rats, a signiicant high elevation in blood pressure was seen when compared to the normal control group, Table 1. The heart rate of diabetic rats was moderately higher than that of the normal control. A signiicant reduction in blood pressure was observed following oral 10 mg/kg administration of all the angiotensin inhibitors (Ramipril, Irbesartan, and Aliskiren) when compared to the diabetic group. Table (1). Ramipril and aliskiren treated group had a signiicant reduction in their heart rate, while irbesartan caused non-signiicant changes when compared to the diabetic group. Effect of angiotensin inhibitors on the renal function of diabetic rats The urine low of the diabetic rats was signiicantly higher than the normal control group. Aliskiren caused a signiicant reduction in the urine low when compared to the diabetic rats, while ramipril, and irbesartan produced a non-signiicant reduction in the urine low when compared with both groups. While the glomerular iltration rate (GFR) of diabetic rats was found to be signiicantly lower than normal rats. Angiotensin inhibitors (Ramipril, Irbesartan, & Aliskiren) induced a signiicant improvement in the GFR when compared to the diabetic group Table (2) - next page. In alloxan-induced diabetic rats there was a marked elevation in albuminuria when compared to the control animals. Daily oral administration of angiotensin inhibitors for 21 days caused a signiicant reduction in albumin excreted through urine when compared to the diabetic group. The effect of different angiotensin inhibitors on Na+ concentration in the urine, were non-signiicantly reduced in comparison to the diabetic animals, although the urinary Na+ concentration did not return to the normal value. Table (3). The Irbesartan treated rats did not show a signiicant improvement in Na+ excretion rate, while Ramipril and Aliskiren treated rats induced a signiicant reduction in Na+ excretion rate. As shown in Table (3) there was a signiicant reduction in Na+ serum concentration level of angiotensin inhibitors treated rats when compared to the diabetic rats. In comparison to the diabetic rats, the percentage of Na+ reabsorption in the angiotensin inhibitors treatment groups were non-signiicantly reduced. Table (3) - next page. Effect of angiotensin inhibitors on the renal excretion of K+ of the diabetic rats Following the induction of diabetes by alloxan, there was a reduction in K+ urine concentration accompanied by an increase in the urinary potassium excretion rate. There was a signiicant elevation in K+ urine concentration in the groups which received different angiotensin inhibitors in comparison with diabetic group. The angiotensin inhibitor treated rats showed a signiicant decrease in the K+ excretion rate in comparison to the diabetic rats, albeit not reaching the normal range. The serum concentration of K+ was increased signiicantly in diabetic and treated rats with angiotensin inhibitors when compared to the control group. Table (4) - page 7. Table 1: The effects of 10 mg/kg of angiotensin inhibitors on the blood pressure & heart rate of the diabetic rats * Similar letters indicate no signiicant differences. * Different letters indicate signiicant differences at P < 0.05. M I D D L E E AOF S T JINTERNAL O U R N A L OMEDICINE F I N T E R N A L VOLUME M E D I C I N E9 ISSUE • VO LU3MNOVEMBER E 2 , I S S U E 3 2016 MIDDLE EAST JOURNAL  O R I G I N A L CO N T R I B U T I O N A N D C L I N I C A L I N V E S T I G AT I O N Table 2: The effects of 10 mg/kg of angiotensin inhibitors on the urine low, GFR, and albuminuria of the diabetic rats * Similar letters indicate no signiicant differences. * Different letters indicate signiicant differences at P < 0.05. Table 3: Effects of angiotensin inhibitors on the renal excretion of Na+ of the diabetic rats * Similar letters indicate no signiicant differences. * Different letters indicate signiicant differences at P < 0.05. MIDDLE EAST JOURNAL OF INTERNAL MEDICINE VOLUME 9 ISSUE 3 NOVEMBER 2016  M I D D L E E A S T J O U R N A L O F I N T E R N A L M E D I C I N E • VO LU M E 2 , I S S U E 3 O R I G I N A L CO N T R i B U T I O N / C L I N I C A L I N V E S T I G AT I O N Table 4: Effects of different angiotensin inhibitors on the renal excretion of K+ of the diabetic rats * Similar letters indicate no signiicant differences. * Different letters indicate signiicant differences at P < 0.05. Table 5: Effect of angiotensin inhibitors on the biochemical parameters of the diabetic rats * Different letters indicate signiicant differences at P < 0.05 Effect of angiotensin inhibitors on the biochemical parameters (blood glucose, serum urea, & serum creatinine) of the diabetic rats Following the treatment of diabetic animals with angiotensin inhibitors Ramipril, Irbesartan, and Aliskiren at a dose of 10 mg/kg for 21 days, a signiicant reduction in the blood glucose and serum urea were noticed when compared to the diabetic group. The ramipril, irbesartan, and aliskiren did not signiicantly change the serum creatinine in comparison to the diabetic rats. Table (5). Discussion Several randomized trials have shown that improved glycemic control in both type 1 and 2 diabetic patients decreases the risk of diabetic nephropathy and other complications. Although signiicant improvement in the treatment of diabetic nephropathy has occurred over the past 25 years, as a result, pharmacological inhibition of the RAS has been proposed as a key strategy in reducing kidney damage beyond the predicted effects as a result of blood pressure reduction. (19, 20, 21). In diabetic rats, a deinite and elevated blood pressure was seen when compared to the normal control group, while the heart rate of diabetic rats was moderately higher than that of the normal group. The result obtained from experiments on rats through detecting the effect of (Ramipril, Irbesartan, and Aliskiren) on blood pressure and heart rate, showed that there was a statistically signiicant decrease in blood pressure with a non-signiicant decrease in heart rate. Ramipril and irbesartan were better than aliskiren in decreasing Blood pressure. The hypotensive effect of different angiotensin inhibitors may be explained by the vasodilating effects of ACEI on the glomerular efferent arterioles, where it prevents the Ang-II formation (22). Inhibition of angiotensin lowers systemic vascular resistance and blood pressure; this is not surprising when the renal vessels are exceptionally sensitive to the vasoconstrictor actions of angiotensin II (23). Angiotensin inhibitor increases renal blood low without increasing GFR; thus reducing the iltration fraction. Both the afferent and efferent arterioles are dilated as well M I D D L E E AOF S T JINTERNAL O U R N A L OMEDICINE F I N T E R N A L VOLUME M E D I C I N E9 ISSUE • VO LU3MNOVEMBER E 2 , I S S U E 3 2016 MIDDLE EAST JOURNAL  O R I G I N A L CO N T R I B U T I O N A N D C L I N I C A L I N V E S T I G AT I O N as causing systemic arteriolar dilatation. ACEI increases the compliance of large arteries, which contributes to systolic pressure reduction (24). The urine low of the diabetic rats was signiicantly higher than the normal control group, while the glomerular iltration rate (GFR) of diabetic rats was found to be signiicantly lower than in the normal rats. In the present study, the result obtained from the experiment on rats for detecting the effect of different angiotensin inhibitors (Ramipril, Irbesartan, and Aliskiren) on urine low and glomerular iltration rate, showed a signiicant improvement in the urine low and GFR. Both ramipril and irbesartan had a superior renoprotective effect than that of aliskiren. The renal protection effect of different angiotensin inhibitors may be explained by ACEI probably attenuating the progression of renal insuficiency in patients with a variety of nondiabetic nephropathies, and may arrest the decline in GFR even in patients with severe renal disease (25, 26, 27). Normally, GFR is slightly reduced by angiotensin II; however, during renal artery hypotension, the effects of angiotensin II on the efferent arteriole predominate, leading to increased renal blood low, hence increasing GFR. Therefore, blockade of the renin-angiotensin system may cause acute renal failure in patients with bilateral renal artery stenosis and in patients with unilateral stenosis who have only a single kidney (7). Angiotensin II variably inluences GFR via several mechanisms such as constricting the afferent arterioles, which reduces intra-glomerular pressure and GFR, or by contracting the mesangial cells, which decreases the capillary surface area within the available glomerulus which subsequently leads to decrease GFR, and it could be due to constricting effect on the efferent arterioles, which increases intra-glomerular pressure which increases GFR (28, 29). The result of this experiment is in agreement with a study by Weidmann et al (1995) who concluded that GFR is better preserved in ACEI treated groups (30). Furthermore, Lebovitz et al (1996) (31) declared that enalapril prevented falling in GFR in hypertensive patients. However, the result of the present study does not agree with Kasiske et al (1993) who found that ACEI is more superior to B blockers in decreasing GFR among diabetic patients (32). Parving and Rossing (1994)) concluded that lisinopril has no signiicant effects in decreasing GFR in diabetic nephropathic patients 33 . Moreover, Barnett et al (2005) showed that the rate of GFR decrease was equivalent in both enalapril and telmisartan treated patients (34). In the present study a marked elevation in albuminuria was seen in diabetic rats. Increased glomerular pressure associated with diabetes can be enhanced by aII-mediated constriction of the glomerular arterioles, causing further elevation in microcirculatory pressure within the glomerulus, and leading to excretion of albumin, and thus to the development of microalbuminuria and proteinuria (35). While after the oral administration of (ramipril, irbesartan and aliskiren) a signiicant reduction in urinary albumin was noticed. In addition, both ramipril and irbesartan better reduced the albumin in the urine. This result is in agreement with studies conducted by Chan et al (2000), and Jerums et al (2001) who reported that treatment with ACEI & aliskiren decrease albumin excretion rate (36, 37). Studies in streptozotocin diabetic rats have demonstrated that both AIIB and ACEi blocked the development of hypertension and signiicantly decreased albuminuria 38. Whereas in the DETAIL (Diabetic exposed to telmisartam and enalapril) study there were no signiicant differences in albumin excretion rate in both enalapril and telmisartan treated patients (34). Several mechanisms have been suggested for antiproteinuric effects of RAS inhibition. First, it may be related to a reduction in intraglomerular blood pressure independently of systemic blood pressure by vasodilatation preferentially of the postglomerular arterioles (39). Second, RAS inhibition may improve the charge and size selectivity of the glomerular membrane (40), which may be related, in part, to reduced loss of glomerular nephrin, which has been suggested to play a central role in the function of the glomerular iltration barrier (41). The administration of both ramipril and aliskiren induced a signiicant change in Na+ excretion rate, while irbesartan did not show any signiicant improvement in diabetic rats. On the other hand the effect of ramipril, irbesartan, and aliskiren on the Na+ concentration in the urine was non-signiicant. There was a non - signiicant reduction in the level of serum Na+ concentration in all treated rats. The percentage of Na+ reabsorption in the angiotensin inhibitor treatment group was non - signiicantly reduced but still lower than the control group. However, it has been suggested that angiotensin II can act presynaptically to potentiate the release of norepinephrine from sympathetic nerve terminals and thus enhancing the renin release from the renal tubule (42, 43). The rise in sodium level in diabetic rats could be related to the fact that angiotensin II stimulates the zona glomerulosa of the adrenal cortex to increase the synthesis and secretion of aldosterone which acts on the distal and collecting tubules to cause retention of Na+ and excretion of K+ and H+. The stimulant effect of angiotensin II on aldosterone synthesis and release is enhanced under conditions of hyponatremia or hyperkalemia and reduced when concentrations of Na+ and K+ in plasma are altered in the opposite directions (44). Very low concentrations of angiotensin II stimulate Na+/H+ exchange in the proximal tubule; an effect that increases Na+, Cl-, and angiotensin II may reduce Na+ excretion in part by diminishing medullary blood low. In the present study, the signiicant decrease in the K+ excretion rate accompanied by a non-signiicant rise in the serum K+ level were detected following administration of ramipril, irbesartan, and aliskiren. These effects could be explained by suppression of endogenous aldosterone and worsening kidney function (45). Despite some reduction in the concentration of aldosterone, signiicant K+ retention is rarely encountered in patients with normal renal function who have not been taking other drugs that cause K+ retention (46). In this study, the level of blood glucose in diabetic rats was signiicantly increased when compared to the control group. This result in accordance with studies of Bilal et al (1998), Azuma MIDDLE EAST JOURNAL OF INTERNAL MEDICINE VOLUME 9 ISSUE 3 NOVEMBER 2016  M I D D L E E A S T J O U R N A L O F I N T E R N A L M E D I C I N E • VO LU M E 2 , I S S U E 3 O R I G I N A L CO N T R i B U T I O N / C L I N I C A L I N V E S T I G AT I O N et al (2007) who suggested that elevated blood glucose levels in diabetes are caused by a defect in production and or secretion of the hormone insulin (47, 48). In this study the elevation of blood glucose level indicate that this effect is caused by the direct inluence of alloxan on pancreatic beta cells. 3- Koike H. New pharmacologic aspects of CS-866, the newest angiotensin II receptor antagonist. The American journal of cardiology. 2001;87(8):33-6. Treatment with angiotensin inhibitors Ramipril, Irbesartan, and Aliskiren caused a signiicant reduction in the blood glucose level of diabetic rats. However, aliskiren was better in reducing blood glucose than the other two drugs. 4- Koike H, Sada T, Mizuno M. In vitro and in vivo pharmacology of olmesartan medoxomil, an angiotensin II type AT1 receptor antagonist. Journal of hypertension Supplement: oficial journal of the International Society of Hypertension. 2001;19(1):S3-14. In this study the hypoglycemic effect of angiotensin inhibitors may be due to increased rate of glucose uptake into the cell, and to improve glucose metabolism (49, 50). Clariication of the mechanism of this effect is in progress. In patients with essential hypertension, plasma insulin and blood glucose levels increase together, indicating reduced insulin sensitivity. Because of this, even without the onset of diabetes, a latent rise in blood glucose level may be seen. Angiotensin receptor blocker and ACEI can improve glucose metabolism via blocking the inhibitory effect of angiotensin II on insulin signal transmission (51, 52). On the other hand, the vasodilatory action of angiotensin inhibitor may increase the access of insulin and glucose to the skeletal muscle tissue, the main site of insulinmediated removal of glucose 53. The result of hypoglycemic effects of ramipril, irbesartan, and aliskiren in the diabetic rats is in agreement with other studies done by Jacobsen et al (2003), Lau et al (2004), Dizaye and Rashid (2009) (54, 55, 56). Subsequent studies indicated that telmisartan also suppressed the new onset of diabetes (53). In the present study ramiprl, irbesartan, and aliskiren did not signiicantly decrease serum creatinine, and this effect was compatible with the inding of Lewis et al (2001) who suggested that the level of serum creatinine was not signiicantly changed by irbesartan in nephropathic patients (21). Along the same lines, are the data from other studies which showed that serum creatinine levels did not signiicantly change in the ACEI group (57, 58). However, the result of this study was in disagreement with the study of Brenner et al (2001), who found that there was 25% reduction for doubling the serum creatinine level after using ACEi (20). Conclusion Administration of different angiotensin inhibitors (ramipril, irbesartan, and aliskiren) could slow the progression of nephropathy in alloxan induced diabetic rats. Both ramipril and irbesartan had the same renoprotective effects for most parameters. References 1. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. Major congenital malformations after irst-trimester exposure to ACE inhibitors. New England Journal of Medicine. 2006;354(23):2443-51. 2. Caramori ML, Mauer M. Diabetes and nephropathy. Current opinion in nephrology and hypertension. 2003;12(3):273-82. 5- Mizuno M, Sada T, Kato M, Koike H. 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