Histological assessment of the possible protective role of glimepiride against progression of experimentally induced diabetic nephropathy in rats

little is known about the potential effects induced by sulphonylureas independently of their anti-hyperglycemic action. The present study examined the effect of glimepiride treatment on the progression of renal histological changes in diabetic rats to determine whether therapeutic intervention with these agents would prevent the onset and progression of renal complications or not. forty-eight adult male albino rats were equally divided into four groups; control, normal rats receiving glimepiride, streptozotocin induced diabetic non-treated rats and glimepiride-treated diabetic rats. Blood glucose level measurement and histological evaluation of renal tissue elements using H and E, Masson trichrome, and PAS reaction techniques at four and eight weeks after treatment were performed. Stained sections were subjected to some morphometric measurements namely, glomerular tuft area [GTA], mesangial matrix index [MMI] and area per cent of connective tissue [CT]. Statistical analysis for significance of obtained data was performed using analysis of variance and student-T test. Glimepiride did not cause any histological renal impairment when used solely. Induction of diabetes had a significant negative impact on renal structure. In addition to significant elevation of blood glucose levels, increased kidney and kidney to body weight ratio was estimated. A variety of histological changes affecting the glomerular and tubular elements of renal tissue were detected and were more intense in the eighth week of the experiment. A significant increase in GTA, MMI and area per cent of C.T. were also found in diabetic rats. All the tested parameters showed a significant improvement in-the glimepiride-treated group. glimepiride could attenuate most of the histological changes produced in case of experimentally induced diabetic nephropathy in spite of persistent hyperglycemia. glimepiride could be used in Type I and type II diabetics to protect or slow down the progression of diabetic nephropathy

role of ATP-sensitive K[+] channels in the antinociceptive effect of gabapentin and lamotrigine in rats

Persistent pain syndromes are considered by some to be poorly responsive to analgesics such as opioids and non-steroidal antiinflammatory drugs. There has been growing interest in the potential utility of anticonvulsant drugs in the treatment of persistent pain, but systematic studies comparing the various clinically used drugs have not been conducted. Was to investigate the analgesic effects of anticonvulsant drugs [gabapentin and lamotrigine] in a persistent pain model, the formalin test which shows injury-induced hyperalgesia as well as acute pain and the spinal reflex test, paw-pressure test. Also, to determine the participation of the ATP-sensitive K[+] channels in the antinociceptive effect of both drugs. Seventy two adult male albino rats were divided into 2 main groups, the formalin test [group I] and the paw pressure test [group II]. Each group was divided into 6 subgroups [6 rats each]: Subgroup a: rats served as the untreated control, whereas, Subgroup a: rats were given intraperitoneal [i.p.] saline as a solvent of glibenclamide. Subgroups b and c: rats received a single oral dose of gabapentin [300 mg/kg] or lamotrigine [100mg/kg], respectively, by gastric gavage. One hour later, rats were subjected to formalin test or paw pressure test. Subgroups d and e: rats received glibenclamide in a dose of [0.5 mg/kg i.p], 15 minutes later, rats received either oral gabapentin or lamotrigine, respectively, in the same previously mentioned doses. One hour later, rats were subjected to formalin test or paw pressure test. A single oral dose of gabapentin [300 mg/kg] or lamotrigine [100 mg/kg] reduced the flinching behavior significantly in both the first and second phases of the formalin test. Moreover, gabapentin and lamotrigine significantly increased the paw withdrawal threshold. The selective blockers of ATP-sensitive K[+] channels glibenclamide [0.5 mg/kg i.p] partially antagonized the antinociception induced by gabapentin and lamotrigine both in formalin test and paw-pressure test. The results showed that a single oral dose of gabapentin or lamotrigine produced antinociceptive effects it both the formalin test and the paw pressure test. Intraperitoneal glibenclamide significantly attenuated the antinoceciptive effect of both drugs, suggesting that activation of ATP sensitive K[+] channels plays a role in the antinoceciptive effect of gabapentin or lamotrigine

Effect of candesartan on cardiac and renal fibrosis induced by high salt intake in albino rats

High salt diet is independent determinant of left ventricular hypertrophy in addition to cardiac and renal fibrosis. Angiotensin II has possible role in mediating these deleterious effects. This work was designed to evaluate the possible effect of AT1 receptors blocker, candesartan on pathological change in heart and kidney induced by high salt diet [8%]. Materials and methods: High salt diet [8%] was administered to 30 male albino rats for eight weeks to induce left ventricular and renal hypertrophy and fibrosis. Candesartan in therapeutic equipotent dose in human [0.02mg/kg/day orally] was started one week before [prophylactic group] or five weeks after [curative group] starting high salt intake. By the end of eighth week from starting high salt diet intake, blood pressure was recorded rats were sacrified heart and kidney were removed, weighed and perpared for pathological examination. Results and Candesartan caused significant improvement in all parameters studied although the improvement was more evident in prophylactic than curative group. High salt intake [8%] induced hypertension, cardiac and renal hypertrophy with fibrosis in albino rats. These histological changes can be avoided or cured to a great extent by oral administration of AT1 blocker, candesartan. Angiotensin II may play a role in these deleterious changes induced by high salt diet

postulated protective role of lacidipine and verapamil against cyclosporin A-induced nephrotoxicity and its relation to P-glycoprotein expression in rat kidney

Cyclosporin-A [CsA] has markedly improved the results of transplantation and its use is extended to include autoimmune and primary renal diseases. However, the major limitation of its use is its nephrotoxicity. P-glycoprotein [P-gp] is a transmembrane efflux pump for hydrophobic, potentially toxic compounds, including CsA. CsA has been shown to increase P-gp expression in tubular and endothelial cells. Aim of Work: The aim of the present study was to elucidate the protective effect of the calcium channel blockers lacidipine and verapamil against CsA-induced nephrotoxicity and the relation of this protective effect to P-gp expression in rat kidney. This study included 7 groups, each containing 7 rats: oral saline group. intraperitoneal [IP] saline group, CsA [25 mg/kg/] group: rats received CsA IP for 14 days, lacidipine [1 mg/kg/d] group: rats received lacidipine orally for 17 days, concomitant lacidipine and CsA group: rats received lacidipine for 3 days and concomitant with CsA for another 14 days, yerapamil [0.1 mg/kg/d] group: rats received erapamil i.p for 17 days and concomitant verapamil and CsA group: rats received verapamil for 3 days and concomitant with CsA for another 14 days Serum creatinine, histopathological and immunostaining for P-gp for rat kidneys were done for all rats. This study revealed that CsA significantly raised serum creatinine, produced vacuolization and necrosis in tubular cells and increased P-gp expression. Kidneys treated with lacidipine alone revealed no significant changes biochemically and histologically. When lacidipine was given with CsA, it significantly protected the kidneys against CsA-induced nephrotoxicity and increased expression of P-gp in kidneys. Verapamil alone caused mild nephrotoxicity in the form of vacuolization and increased serum creatinine level. It also inhibited P-gp expression in rat kidneys. Verapamil given with CsA significantly ameliorated CsA nephrotoxicity and decreased P-gp expression. lacidipine had protective effect against CsA nephrotoxicity more than verapamil. Hemodynamic effect is the main effect and moreover, lacidipine may protect via P-gp over- expression

Effect of heparin sodium and enoxaparin on spasmogen-induced contraction of isolated sensitized guinea pig tracheal strips and on sensitized rat peritoneal mast cells

Atopic asthma is a chronic inflammatory disorder of the airways associated with hyperresponsiveness to various bronchoconstrictor stimuli. Prompt search effort to identify alternate therapy that are effective in poorly controlled asthma while receiving standard therapy. Heparin possesses multiple non-anticoagulant properties, including anti-allergic and anti-inflammatory actions. The present study was directed to investigate the effects of unfractionated heparin [UF-heparin, heparin sodium] and low molecular weight heparin [LMWheparin, enoxaparin] on spasmogen, [histamine, acetyl choline [Ach], serotonin and potassium chloride [KCII] - induced contraction of isolated tracheal smooth muscles [TSM], and on antigen-induced histamine release from sensitized mast cells. Tracheal smooth muscle obtained from guinea pig sensitized with ovalbumin and was suspended in an organ bath containing oxygenated [95% 02, 5%C 02] Krebs-Henseleit buffer at 37°C. The influence of drugs on the in vitro reactivity of tracheal smooth muscle was evaluated. After an equilibration period, the tissues were treated with heparin sodium or enoxaparin dissolved in phosphate-buffered saline [PBS], at concentrations of 0.1, 1, or 10 U/ml. After 15 minutes incubation with either drugs, the response of the preparation to submaximal concentrations of histamine, ACh, serotonin and KC1 was tested. The percentage of change of height of contraction induced by each concentration of the tested drugs was measured against the height of contraction induced by submaximal dose of spasmogens on the same tracheal spiral strip. Also, the actively sensitized peritoneal mast cells of rats were pre-incubated with heparin sodium or enoxaparin in the same above concentrations prior to antigen challenge. UF-heparin caused a dose-dependent inhibition of histamine -induced contraction of [TSM] by 8 +/- 1.3% [0.lU/ml], 20 +/- 3.2% [lU/mi] and 44 +/- 6.0% [1OU/ml] [F=126, P<0.05]. The histamine-induced [TSM] contractions were inhibited by 30.7 +/- 5.0%, 46.1 +/- 7.8% and 61.5 +/- 6.5% with enoxaparin at doses of [0.1, 1 and 10 U/ml] respectively [F33.3, p<0.05]. UF-heparin attenuated KC1 -induced contraction of [TSM] in dose-dependent fashion. A dose of 0.1U/ml caused 14.2 +/- 3.3% inhibition, a dose of lU/ml caused 28.5 +/- 4.9% inhibition, whereas a dose of 10 U/ml caused 40 +/- 3.4% inhibition [F=64.7, p<0.05]. Pretreatment with enoxaparin attenuated KC1-induced contraction in dose-dependent fashion. Contraction was inhibited by 30 +/- 3.7% [0.1 U/ml], 45.4 +/- 5.9% [IU/ml] and 54.5 +/- 6.6% [10 U/ml] [F=29.9, p<0.05]. In vitro, preincubation with either heparin sodium or enoxaparin [0.1, 1 and 10 U/ml] inhibited the release of histamine from rat peritoneal mast cells in a dose dependent fashion [8.3 +/- 1.7%, 16.6 +/- 2.6% and 31.2 +/- 3.7 [F= 103.66, peO.O5] respectively for heparin sodium and 18.1 +/- 1.7%, 25 +/- 3.4% and 50 +/- 5.6% [F=l 10.6, p<0.05] respectively for enoxaparin. It is concluded that UF-heparin and LMW heparin reduced histamine and KCL- induced TSM contraction, but failed to inhibit ACh and serotonin-induced contraction. The bronchodilator effect of heparin is molecular-weight dependent. UF-heparin and LMW-heparin inhibited the release of histamine from sensitized rat peritoneal mast cells in a dose dependent fashion

possible protective role of lisinopril as a pro-apoptotic agent in cyclosporin A induced nephrotoxicity in rats

The study was carried out on 40 male albino rats, which were divided into five groups: Group 1, normal control group, group 2, saline treated group, group 3, cyclosporin A treated group [rats received saline 0.2 ml for one week orally daily, then received cyclosporin A [20 mg/kg/day] intraperitoneally daily for another week], group 4, lisinopril plus cyclosporin A treated group [treatment with lisinopril [10 mg/kg/day] orally for one week, then co-administration, of both lisinopril and cyclosporin A for another one week using the aforementioned doses] and group 5, lisinopril-treated group [rats received lisinopril [10 mg/kg/day] orally for two weeks]. At the end of the study, blood samples were withdrawn from rats of all groups for determination of serum creatinine. Afterwards, rats were sacrificed and the kidneys were obtained. Sections from the kidney were stained by hematoxylin and oesin and immunohistochemically using anti-Bcl-2 antibodies for assessment of both necrosis and apoptosis, respectively. Cyclosporin A administration for one week significantly raised the serum creatinine level. Also, it produced histopathological changes confined to the proximal convoluted tubules in the form of moderate to severe focal necrosis, and produced strong Bcl-2 cytoplasm immunostaining. Treatment with lisinopril for one week, then co-administration, of both lisinopril and cyclosporin A, decreased significantly the cyclosporin A-induced elevation of serum creatinine, decreased the focal necrosis in the proximal convoluted tubules [Chi square=13.3], and produced weak Bcl-2 cytoplasm immunostaining [Chi square=7.27]. This denotes that the ACE inhibitor ameliorated the toxic insult induced by CsA by favoring induction of apoptosis as denoted by diminishing the Rcl-2 cytoplasmnostaining. From the above data, it could be concluded that lisinopril has a proapoptotic effect in the kidney after cyclosporin A-induced nephrotoxicity