Comparative Study BetweenNebivolol And Lisinopril In
Experimentally Induced Diabetic NephropathyIn Rats
Mohamed El. Mansour,Mahmoud M. Elfouly,Omaima M. Abd Allah and Abeer
A.EldeebDepartment of Pharmacology & Therapeutics , Benha Faculty of Medicine, Benha
University.
Abstract
The present study was designed to compare the benificial prophylactic effects of
nebivolol and lisinoprilon the progression of diabetic nephropathy in a rat model of
streptozotocin induced diabetes. Animals were classified intoNormal Control group (received
no medication), Utreated diabetic group induced by administrated of single I.P injection
65mg/kg of streptozotocin "STZ", Nebivolol treated diabetic group (2mg/kg p.o) for 7
weeks,Lisinopril treated diabetic group (1mg/kg p.o) for 7 weeks. The obtained results in the
current work revealed that induction of diabetes by streptozotocin resulted in significant
increase of fasting blood glucose level (FBG), serum urea level, serum creatinine level, 24hrs
urinary albumin excretion (UAE) and significantly decrease renal blood flow (RBF), shows
significant changes in histological findings in the kidney as compared to control group. While
nebivolol treated group resulted in decrease FBG, serum urea, serum creatinine levels,
decrease UAE and significantly increased RBF. It shows improvement in the histological
findings as compared to untreated streptozotocin (STZ) induced diabetic nephropathy.
Lisinopril treated group resulted in no changes in FBG level, significantly decreased serum
urea level, serum creatinine level, decreased 24hrs UAE level and increased RBF. It also
shows improvement in the histological findings as compared to untreated streptozotocin (STZ)
induced diabetic nephropathy. Conclusively: Nebivolol may replace ACE inhibitor as the first
choice drug in diabetics for prevention of end organ damage. Lisinopril have the superiority in
improvement the parameters of kidney function but nebivolol show marked improvement of the
pathological changes occured in untreated diabetic nephropathy group and significantly
increase renal blood flow.
1
INTRODUCTION:
DN is one of the most serious complications of diabetes and the most common cause of
end-stage renal failure in the Western world. Diabetic kidney disease affects about 15 to 25%
of type 1 diabetic patients (Hovind et al., 2003) and 30 to 40% of patients with type 2 diabetes
(Yokoyama et al., 2000). Hyperglycemia is a significant risk factor for the development of
microalbuminuria, both in type 1 and in type 2 DM. A reduction of 1% in HbA1c is associated
with a 37% decrease in microvascular endpoints (Stratton et al., 2000). Arterial hypertension
is a main risk factor for the development of DN and probably the best known relevant factor
related to its progression. Analysis of United kingdom Prospective Diabetes Study (UKPDS)
showed that every 10 mmHg reduction in systolic BP is associated with a 13% reduction in the
risk of microvascular complications, with the smallest risk among those patients with systolic
BP <120 mm Hg (Adler et al., 2000).Proteinuria >2 g/24 h is associated with a greater risk of
end stage renal disease (ESRD). Diabetic nephropathy occurs as a result of an interaction
between hemodynamic and metabolic factors (Cooper, 2001). Hemodynamic factors include
increased systemic and intraglomerular pressure, as well as activation of vasoactive hormone
pathways including the renin angiotensin system and endothelin(Hargrove et al., 2000).
Hyperglycemia and advanced products of non-enzymatic glycosilation causes proliferation of
mesangial cells and their matrix, as well as the thickening of the basement membrane.The final
products of non-enzymatic glycosilation are bound to collagen and proteins that constitute the
glomerular basement membrane and make the glomerular barrier more permeable to the
passage of proteins, resulting in increased urinary albumin excretion (UAE) (Dronavalli et al.,
2008). Nebivolol a highly selective beta-1 adrenoceptor blocker possessing vasodilator
properties, delayed the progression of renalfibrosis and protected against endothelial
dysfunction through their ability to increase nitric oxide (NO) bioavailability and reduce
NADPH oxidase activity which exerts a fundamentalrole in the regulation of
renalfunction,glomerular filtration, renalblood flow and inducesnatriuresis (Whaley-Connell
et al., 2009). Renoprotective effects of lisinopril as it decrease in systemic blood pressure,
decrease in intraglomerular pressure, increased renal blood flow (counters ischemia
secondary to intrarenal vasoconstriction), decreases proteinuria, natriuretic secondary to
inhibition of angiotensin II, induce solute transport across proximal convoluted tubule,
decrease in aldosterone production, decrease in tubule-glomerular feed back sensitivity, fall in
filteration fraction, and decrease in peritubular osmotic pressure, inhibit non hemodynamic
effects of angiotensin II in turn leads to less proliferation, hypertrophy, matrix expansion, and
cytokine and growth factor synthesis (Piero et al. 2004, and Kobayashi et al., 2006)and
itinhibits the formation of TGF-ß and tubulointerstitial fibrosis in diabetic nephropathy patient
(Amann et al., 2003).
MATERIALS AND METHODS:
Diabetes was induced in rats by a single intraperitoneal (i.p.) injection of
Streptozotocin (65 mg/kg STZ) in overnight fasting rats. After 7 days followingSTZ blood was
collected from retro-orbital puncture and serum samples were analyzed for blood glucose.
Animals showing fasting blood glucose higher than 250 mg/dl were considered as diabetic and
used for the study (Masiello et al., 1998).
Animal groups: each group contained 6 rats.
Group (I): Normal Control group: Rats of this group received no medication.Group
(II): Non- treated diabetic group: Diabetes will be induced by administrated of single
intaperitoneal injection 65mg/kg of streptozotocin "STZ" (Masiello et al., 1998). Group
(III):Nebivolol treated diabetic group: Diabetic rats after 1 week of STZ administration were
treated with nebivolol (2mg/kg p.o) for 7 weeks (Kakadiya et al., 2010).Group (IV):Lisinopril
treated diabetic group: Diabetic rats after 1 week of STZ administration were treated with
lisinopril (1mg/kg p.o) for 7 weeks (Khurana et al., 2011).
STATISTICAL ANALYSIS:
All values were expressed as mean ± S.D. Data were statistically analyzed using one
2
way ANOVA followed by Tukey's multiple comparison tests. The p value of less than 0.05 was
considered to be statistically significant.
RESULTS:
Effect of nebivolol versus lisinopril on diabetic nephropathy parameters in rats after 8
weeks.
Data in table (1) show that untreated diabetic group resulted in significant increase in
FBS(457.66± 21.1), serum urea level (94.9± 2.4) and serum creatinine level (1.56± 0.11) in
comparison to control group while nebivolol show significant decrease in FBS level
(366.66±10.9), serum urea level (41.16± 1.9) and serum creatinine level (1.15± 0.08).
Lisinopril treated group resulted in no change in FBS (429.33± 18), significant decrease in
serum urea level (26.25± 1.3) and serum creatinine level (0.8± 0.07) in comparison to
untreated diabetic group.
Table (1): Effects of nebivolol and lisinopril at 8 weeks treatments on fasting blood
glucose (FBS), serum urea and serum creatinine levels in STZ-induced diabetic nephropathy
in rats.
Parameter
Groups
Control
Untreated diabetic
Nebivolol treated group
Lisinopril treated group
FBS
(mg/dl)
(mean±SEM)
100.5± 5.8
457.66± 21.1a
366.66±10.9a,b
429.33± 18a,c
Serum urea Serum creatinine (mg/dl)
(mg/dl)
(mean±SEM)
(mean±SEM)
18.6± 1.3
0.77±0.02
94.9± 2.4a
1.56± 0.11a
41.16± 1.9a,b
1.15± 0.08a,b
a,b,c
26.25± 1.3
0.8±0.07b,c
Data represented as Mean ± SEM (n = 6)
a: Significant difference from control group at p<0.05.
b: Significant difference from diabetic group at p<0.05.
c: Significant difference from nebivolol-treated group at p<0.05.
Data in table (2) show that untreated diabetic group resulted in significant increase in
24h UAE (14.42± o.68) and significant decrease of RBF (2.25± 2.4) in comparison to control
group while nebivololand lisinoprilshow significant decrease in 24h UAE (9.27±0.23and 6.9±
o.41) and significant increase of RBF (8.97± 0.23and 6.29± 0.31)respectively in comparison
to untreated diabetic group.
Table (2):Effects of nebivolol and lisinopril at 8 weeks treatments on 24 hours
urinary albumin excretion (UAE) and renal blood flow (R.B.F) in STZ-induced diabetic
nephropathy in rats.
parameter
24 hours UAE
R.B.F (ml/min)
(mean±SEM)
(mean±SEM)
groups
3.4± 0.12
11.45± 0.35
Control
Untreated diabetic
Nebivolol treated group
Lisinopril treated group
14.42± o.68a
9.27±0.23,a,b
6.9± o.41a,b,c
2.25± 2.4a
8.97± 0.23a,b
6.29± 0.31a,b,c
Data represented as Mean ± SEM (n = 6)
a: Significant difference from control group at p<0.05.
b: Significant difference from diabetic group at p<0.05.
c: Significant difference from nebivolol-treated group at p<0.05.
Histopthological Examination: Cut section of the kidney into 6mm-thick stained with
hematoxylin and eosin (H&E). Control group showed regular morphology of renal
3
parenchyma with well designated glomeruli and tubuli, no congestion of blood vessels or
infiltration of inflammatory cells (Figure 1). Untreated diabetic group showed tubular cell
swelling and dilatation, glomerular sclerosis and atrophy, congested blood vessels and
inflammatory cells infiltration (Figure 2).Nebivolol treated group showed marked reduction of
tubular cell swelling and dilatation, glomerular atrophy and sclerosis, congested blood vessels
and inflammatory cells infiltration (Figure3). Lisinopril treated group showed moderate
improvement of the pathological changes in the form of mild decrease tubular swelling and
dilatation, glomerular atrophy and sclerosis and inflammatory cells infiltration (Figure 4).
Figure (1): A photomicrograph of a cut section in the kidney of a control rat (group I)Showing
(A) Well designated glomeruli (B) Normal tubuli. (H&Ex40).
Figure (2): Photomicrograph of a cut section in the kidney of untreated diabetic rat (group
II)Showing (A) Glomerular sclerosis. (/A) Glomerular atrophy. (B) Tubular cell swelling and
tubular dilatation. (C) Congested blood vessels (H&Ex40).
Figure: (3): Photomicrographs of a cut section in the kidney of nebivolol treated diabetic rat
(group III)Showing (A) Marked reduction of glomerular atrophy and sclerosis. (B) Marked
reduction of tubular cell swelling and tubular dilatation. (C) Reduction Congested blood
vessels. (D) Reduction Inflammatory cells infilteration. (H&Ex40).
4
Figure (4): A photomicrograph of a cut section in the kidney of lisinopril treated diabetic rat
(group III)Showing (A) Moderate reduction of glomerular atrophy and sclerosis. (B) Moderate
reduction of tubular cell swelling and tubular dilatation. (C) Congested blood vessels. (D)
Reduction of Inflammatory cells infiltration. (H&Ex40).
DISCUSSION:
Diabetic nephropathy (DN) is typically defined by macroalbuminuria that is a urinary
albumin excretion of more than 300 mg in a 24-hour collection or macroalbuminuria and
abnormal renal function. Recent studies have suggested the emerging role of inflammatory
processes in the pathogenesis of diabetic nephropathy (Shlipak, 2009).
The present study was designed to explore the benificial prophylactic effect of nebivolol
and lisinopril on the progression of diabetic nephropathy in rats models of streptozotocin
induced diabetes regarding to their effect on Fasting blood glucose level (FBG), 24h urinary
albumin excretion (24h UAE), Serum urea level, serum creatinine level, Renal blood flow
(RBF) and histopathological changes in the kidney.
The obtained results in the current work revealed that induction of diabetes mellitus by
streptozotocin showed significant increase in Fasting blood glucose level (FBG), 24hs urinary
albumin excreation (24h UAE ), Serum urea level, Serum creatinine level and decrease of
renal blood flow. These results are in agreement with Khurana et al., 2011.
In the present study as regard FBG it is found that nebivolol administration to diabetic
rats for 7weeks study resulted in significant reduction in FBG level compared to diabetic
untreated rats however administration of lisinopril has no significant effect on FBG level as
compared to diabetic untreated rats.
These results are in agreement with Kakadiya et al., (2010) who observed significant
decrease in the glucose and HbA1c level in diabetic rats after treatment with nebivolol when
compared with untreated diabetic rats. Van Bortel, (2010) who observed that nebivolol
improved blood glucose levels and was well tolerated in hypertensive patients with concomitant
DM.
These results can be explained by Cockcroft et al., (1995) and Broeders et al., (2000),
who observed that nebivolol increases the bioavailability of endogenous nitric oxide (NO). NO
decreases the expression of plasminogen activator inhibitor (PAI-1) and improves insulin
sensitivity and muscle glucose uptake.
In contrast Schmidt et al., (2007) and Badar et al, (2011) noticed that nebivolol had
neutral effect on blood glucose level. Sawicki and Siebenhofer (2001), observed that selective
β1 blocker do not significantly affect glucose metabolism nor prolong hypoglycemia or mask
hypoglycemic symptoms.
Khurana et al., (2011), showed Treatment of diabetic rats with lisinopril for 7 weeks
did not produce any marked effect on serum glucose level, and these results are in line with
Wolfgange Wienen et al., (2001) who observed that Long-term treatment with either
telmisartan or lisinopril did not modify body weight and plasma and urine glucose level in
5
STZ-induced diabetic nephropathy. This is also in agreement with reports in the literature
using either the ACE-I perindopril or the Ang II AT1-receptor antagonist losartan (Cooper,
1988).
In contrast Agrawal et al., (1996), observed that lisinopril did not exhibit significant
reduction in blood glucose levels in normoglycemic rats but it showed significant antihyperglycemic activity in diabetic rats. These findings suggest that lisinopril may have some
insulin sensitivity potentiating properties in type2 diabetes mellitus but not in normoglycemic
rats. Murad et al., (2009) showed a potential hypoglycemic effect of ACE inhibitor and a
majority of these are with the use of captopril. The mechanism for lisinopril-induced
hypoglycaemia is not well defined, it is proposed that the increase in bradykinins associated
with ACE inhibitor use may cause an increase in insulin sensitivity (Vuorinen-Markkola et al.,
1995).
In the present study, it was found that administration of nebivolol and lisinopril to
diabetic rats for 7weeks after induction of diabetes mellitus resulted in significant reduction in
24 h UAE compared to diabetic untreated rats.
Our results are in agreement with Whaley-Connell et al., (2009), who showed that
nebivolol improves proteinuria through reductions in renal RAAS-mediated increases in
NADPH oxidase/ROS and increases in bioavailable NO. Bakris et al., (2005), have
demonstrated that treatment with nebivolol reduced albuminuria in patients with insulin
resistance and the metabolic syndrome. Several trials have demonstrated a beneficial effect of
nebivolol on kidney function including an increase in renal blood flow and a reduction in
microalbuminuria (Agrawal et al., 1996). In contrast Maria et al., (2010), observed that rats
with chronic renal failure treated with nebivolol show higher level of proteinuria like untreated
rats. Anderson et al., (1985) is in line with this result.
Perico et al., (2009), showed that ACE inhibitors given early after the induction of the
MI significantly reduced systemic BP and normalized urinary protein excretion. By contrast,
late administration of the drug was unable to affect proteinuria, despite effective control of BP.
Abbate et al., (1999), showed that lisinopril and mycophenolate significantly reduced
proteinuria induced inflammatory injury as well as the rate of disease progression in normal
rats with 1-5/6 nephrectomy (a procedure that reduces functioning kidney tissue to < 25% of
normal). This information implies that any therapy, such as treatment with an ACE inhibitor or
ARB reduces proteinuria may have a benefit that brought about by reduction in blood pressure
or alteration of glomerular hemodynamics. Schjoedt et al., (2009), evaluated the optimal
renoprotective effect of ultrahigh doses of lisinopril, as reflected by short-term changes in
urinary albumin excretion rate (UAER) in diabetic patients with diabetic nephropathy. Ariela
et al., (2003), found that the addition of lisinopril to TGF-B normalized proteinuria and
attenuated renal injury of diabetic nephropathy with limitation lymphocytes/macrophages
infiltration and decrease type III collagen in the renal interstitium.
As regard to serum urea and creatinine levels it is found that administration of
nebivolol and lisinopril to diabetic rats for 8 weeks study resulted in significant reduction in
their levels compared to diabetic untreated rats.
Kakadiya and Shah, (2011), observed that using nebivolol at 2 mg/kg may show more
reduced Creatinine same as sham control, and reduced renal complication in
Ischemia/Reperfusion induced renal damage in type 2 diabetic rats. Kakadiya et al., (2010),
showed decrease in serum urea level in Ischemia/reperfusion induced renal damage in diabetic
rats with treatment by nebivolol. In the hypertensive diabetic rats, Nebivolol showed a
significant reduction in blood urea level but not statistically significant reduction in serum
creatinine level (Vidhiyasagaran et al., 2013). In contrast Maria et al., (2010), who reported
that nebivolol administration to rats of chronic failure resulted in no changes in plasma
6
creatinine and urea concentrations, glomerular filtration rate, determined as creatinine
clearance, and urinary protein excretion.
Khurana et al., (2011), who found that lisinopril administration to diabetic rats
resulted in significant reduction in serum urea and creatinine levels. On the other hand, Jalal
et al., (2010), observed that lisinopril administration has no effect on serum creatinine or
creatinine clearance levels. Raineri et al., (1994), showed the same results. Onozato et al.,
(2002), found that administration of lisinopril to STZ-diabetic rats showed no significant effect
on serum creatinine level. In contrast with our results Olaiya et al., (2013), observed that
lisinopril may be associated with a rise in serum creatinine and BUN, GFR has been shown to
remain unchanged or improve in most diabetic patients.
As regard to RBF in the present study, it was found that administration of nebivolol and
lisinopril to diabetic rats for 7weeks study resulted in significant increase in RBF compared to
diabetic untreated rats.
These results are in agreement with Greven and Gabriëls, (2000), who observed that
nebivolol exerts significant renal vasodilating effects and increases urinary excretion of fluid
and solutes. The actions of nebivolol on renal hemodynamics are assumed to be mediated by a
stimulation of the NO-synthase. These findings are consistent with evidence obtained from
whole kidney studies showing that nebivolol increased renal plasma flow, reduced renal
perfusion pressure and dilated renal arteries (Georgescu et al., 2008). On ther hand
Mangrella et al., (1998), Showed that nebivolol does not significantly modify glomerular
filtration rate or renal plasma flow.
August et al., (1993), observed that patients who had a significant lower blood pressure
in response to lisinopril and verapamil had favorable renal hemodynamic responses as well
GFR remained stable, RBF was stable or increased, and filtration fraction, renal vascular
resistance, and proteinuria tended to decrease.
Histological examination of the kidney at the end of the study showed that lisinopril and
nebivolol caused improvement of histological findings in comparison to untreated diabetic
group.
These results are in agreement with Kakadiya et al., (2010), who found that administration
of nebivolol to STZ induced diabetic rats reduce tubular dilation, loss of interstitial
hemorrhage, and glomerular atrophy. Omer et al., (2008), who found that pre and post
treatment with nebivolol in contrast media induced nephropathy in rats attenuated tubular
necrosis (outer zone of medulla), proteinaceous casts (inner zone of the medulla), and
medullary congestion (outer zone of medulla). Maria et al., (2010), found that treatment with
nebivolol reduced tubular dilatation and atrophy, as well as tubulointerstitial infiltration and
fibrosis in chronic renal failure rats. These effects occurred as nebivolol induces vasodilation
through NO production, stimulated NO release, enhanced NO bioavailability and prevented
NO deactivation (Kakoki et al., 1999).
Khurana et al., (2011) observed that administration of lisinopril to diabetic rats for 7
weeks markedly protected the kidney from renal pathological changes. Ariela et al., (2003)
showed that treatment of diabetic rats with lisinopril produced reduction in the percentage of
glomeruli with sclerotic changes reduced tubular damage scores to values similar to controls.
In contrast Wolfgang Wienen et al., (2001), found that treatment of hypertensive diabetic rats
with lisinopril produced no changes in the pathological condition which present in the
untreated group.
CONCLUSION:
From the data obtained in the present work it could be concluded that: diabetes
induced by streptozotocin could induce diabetic nephropathy as indicated by increased
7
FBS, serum urea level, serum ceatinine level, 24hrs UAE and decrease RBF as well as
histopathological changes in kidney tissue. Treatment with nebivolol and lisinopril
resulted in prophylaxis against diabetic nephropathy as showed by marked reductions in
FBS with nebivolol treatment and reduction of serum urea level, serum creatinine level
and 24h UAE as well as significant increase in RBF and also improvement of
histopathological features with nebivolol and lisinopril treatment.
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10
‫دراسة مقارنة بين كال من النبيفولول والليسينوبريل فى اعتالل الكلى السكرى المحدث تجريبيا فى فئ ارن‬
‫التجارب‬
‫محمد المتولى منصور ومحمود محمد الفولى وأميمة محمد عبدهللا وعبير على الديب‬
‫قسم األدوية والعالج كلية طب بنها‪ -‬جامعة بنها‬
‫اعتالل الكلى السكري عبارة عن زيادة إفراز الزالل البولى أكثر من ‪300‬مجم في البول المجمع على مدار ‪24‬‬
‫ساعة وتكون وظيفة الكلى غير طبيعية‪ .‬وأشارت الدراسات الحديثة اهمية الدور الناشئ من عمليات االلتاابات‬
‫في التسبب في اعتالل الكلى السكري‪ .‬وقد تم تصميم هذه الدراسة للمقارنة بين كال من عقار النيبفولول‬
‫والليسينوبريل على تطور اعتالل الكلية السكري في الفئران المحدث باا مرض البول السكري بالستربتوزوتوسين‬
‫معمليا‪ .‬وقد تم تقسيم الفئران الى مجموعات‪ .‬المجموعة األولى "الضابطة" لم تاخذ عالج‪ .‬المجموعة الثانية‬
‫"المصابة بالبول السكرى" تم حقن الفئران باألستربتوزيتوسين "‪65‬مجم‪/‬كجم" مرة واحدة بالغشاء البروتونى‬
‫المبطن للجدار األمامى بالبطن‪ .‬والمجموعة الثالثة اخذت النبيفلول "‪2‬مجم‪/‬كجم" مرة واحدة يوميا بالفم لمدة ‪7‬‬
‫اسابيع بعد إحداث مرض البول السكرى‪ .‬المجموعة الرابعة اخذت الليسينوبريل "‪1‬مجم‪/‬كجم" مرة واحدة يوميا‬
‫لمدة ‪ 7‬أسابيع بعد احداث مرض البول السكرى‪ .‬وكشفت النتائج التي تم الحصول عليااان حقن‬
‫االستربتوزوتوسين أدى الى زيادة ملحوظة فى نسبة السكر الصائم بالدم ونسبة اليوريا والكرياتنين بالبالزما‬
‫وزيادة افراز الزالل البولى المجمع خالل ‪ 24‬ساعة وانخفاض ملحوظ بتدفق الدم الكلوى وتغيرات نسيجية‬
‫بالكلى بالمقارنة مع المجموعة الضابطة‪ .‬وأدى إعطاء النبيفلول إلى انخفاض مستوى السكر الصائم بالدم‬
‫ونسبة اليوريا والكرياتنين بالبالزما وانخفاض افراز الزالل البولى المجمع خالل ‪ 24‬ساعة وزيادة تدفق الدم‬
‫الكلوى وتحسين التغييرات النسيجية بشكل ملحوظ بالمقارنة مع المجموعة المريضة التى اخذت استربتوزتوسين‬
‫بدون عالج‪ .‬أما إعطاء الليسينوبريل فأدى الى عدم تغير فى نسبة السكر الصائم بالدم وانخفاض افراز الزالل‬
‫البولى المجمع خالل ‪ 24‬ساعة وزيادة تدفق الدم الكلوى وايضا تحسين التغيرات النسيجية بالمقارنة مع‬
‫المجموعة المريضة التى اخذت استربتوزوتوسين بدون عالج‪.‬‬
‫‪11‬‬