Iclal Cakici - Academia.edu (original) (raw)

Papers by Iclal Cakici

Research paper thumbnail of Peroxynitrite produces relaxations on the rat anococcygeus muscle

Life Sciences, 2000

Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprussid... more Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprusside (SNP) on isolated rat anococcygeus muscle were investigated. Administration of 0.1-1.0 mM ONOO- or 0.01-100.0 microM SNP produced concentration-dependent relaxations on the phenylephrine (2 microM)-precontracted muscle. Time courses of these relaxations to ONOO- and SNP were not similar and decomposed ONOO- caused a biphasic response composed of an initial contraction followed by a relaxation. NT (0.01-0.1 mM) either incubated for 20 min prior to precontraction or given during precontraction plateau did not attenuate precontraction or ONOO(-)-induced relaxations. Results of the present study demonstrate that ONOO- relaxes rat anococcygeus muscle specifically while its stable metabolite NT has no effect.

Research paper thumbnail of Clinical study on the bioequivalence of two tablet formulations of flurbiprofen

European Journal of Drug Metabolism and Pharmacokinetics, 2009

Flurbiprofen (CAS 5104-49-4) is a member of phenylalkanoic acid derivative group of nonsteroid an... more Flurbiprofen (CAS 5104-49-4) is a member of phenylalkanoic acid derivative group of nonsteroid anti-inflammatory drugs. It exhibits anti-inflammatory, analgesic and antipyretic activities. Two different tablets containing flurbiprofen (FLU) were investigated in 24 healthy volunteers to prove the bioequivalence between both treatments after single oral dose administrations. Fluroben 100 mg tablet and 100 mg tablet of the originator product were used as test and reference preparation respectively. The study was performed open label, randomized, two period cross-over design with 15 days wash out period. Blood samples were taken up to 24 hours for pharmacokinetic profiling. The plasma concentrations of flurbiprofen were determined with validated HPLC-UV method. Maximum plasma concentration (Cmax) of FLU 19,143.65 ng/ml and 19,164.22 ng/ml were found for test and reference formulation respectively. Areas under the plasma concentration time curve AUC(0-infinity), of 118 501.4 ng.h/ml and 111,339.8 ng.h/ml were calculated test and reference formulation respectively. Primary target parameters AUC (0-infinity) and Cmax, both of them were tested parametrically by analysis of variance (ANOVA); 90% confidence intervals were between 100.5%-111.18% for AUC(0-infinity), and 87.6%-115.0% for Cmax. All these values were within the acceptance range (80%-125%) for bioequivalence studies.

Research paper thumbnail of The mechanism of the late preconditioning effect of 3-nitropropionic acid

Archives of Pharmacal Research, 2008

The aim of the present study was to investigate the mechanism of effect of 3-nitropropionic acid-... more The aim of the present study was to investigate the mechanism of effect of 3-nitropropionic acid-(3-NP) induced late preconditioning in rat heart. For this purpose 20-30 min before 3-NP (20 mg/kg, i.p.) injection, the rats were treated intraperitoneally with 5-hydroxydecanoate (40 mg/kg, 5-HD, mitochondrial K(ATP)-channel blocker), L-NAME (100 mg/kg, NOS inhibitor), N-2-mercaptopropionylglycine (100 mg/kg, MPG, free radical scavenger), or superoxide dismutase+catalase (10000+10000 IU/kg, SOD+CAT). Control rats received saline only without 3-NP pretreatment. After two days, hearts were isolated and perfused at a constant pressure in a Langendorff apparatus. 15-min global ischemia followed by 30-min reperfusion was applied to all hearts. Pretreatment of 3-NP significantly reduced infarct size, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) levels, and incidence of ventricular tachycardia (VT) compared with the control group receiving saline only. 5-HD, L-NAME, MPG, or SOD+CAT treatment statistically reversed 3-NP-induced reduction in infarct size. Although CK-MB, LDH levels, and incidence of VT were also reduced by L-NAME, MPG, or SOD+CAT treatment, only 5-HD significantly inhibited beneficial effects of 3-NP on all of the parameters above. These results showed that mito-K(ATP) channels play a pivotal role in late preconditioning effect of 3-NP in the isolated rat heart. However, other mediators such as reactive oxygen species and NO may be, at least in part, involved in mechanisms of this effect.

Research paper thumbnail of Digoxin-induced cardiac toxicity in the anaesthetized guinea-pigs and effect of heparin infusion

We have examined the effects of heparin infusion on the arrhythmias induced by digoxin. Digoxin t... more We have examined the effects of heparin infusion on the arrhythmias induced by digoxin. Digoxin treatment consisted of 0.6 mg kg-1 given i.v. 15 min after the beginning of heparin infusion. Heparin infusions (1.7 IU, 3.4 IU and 6.8 IU kg-1 min-1) were begun 15 min before digoxin injection and continued for another 30 min. ECG, blood pressure, heart rate and arrhythmias were recorded starting 15 min before and continuing for 60 min after the digoxin injection. Heparin at the infusion rates of 3.4 IU and 6.8 IU kg-1.min-1 reduced significantly the arrhythmia scores. On the other hand, heparin did not significantly alter the arterial blood pressure and heart rate values affected by digoxin.

Research paper thumbnail of Epithelium-dependent responses of serotonin in a co-axial bioassay system

Serotonin (10-6-10 -4 M) produced relaxations in a concentration-dependent (at 10 -6 and 10 -5 M ... more Serotonin (10-6-10 -4 M) produced relaxations in a concentration-dependent (at 10 -6 and 10 -5 M concentrations) manner followed by a contraction (at 10 -4 M concentration) in a co-axial system, which consisted of guinea-pig trachea as a donor organ for epithelial derived-relaxing factor(s) and phenylephrine-precontracted rat anococcygeus muscle as assay tissue. Serotonin produced a concentration-dependent contraction only in precontracted rat anococc, ygeus muscle mounted alone or mounted co-axially within epithelium-denuded trachea. Indomethacin (10 -6 M) significantly inhibited the initial relaxations (from 25.1 + 7.8 to 7.8 + 5.0% and from 35.6 + 8.7 to 10.4 + 8.3% at 10 -6 and 10 -5 M concentrations of serotonin), but did not affect the contraction. Imipramine (10 -8 M) and hydrocortisone (3 × 10 -5 M) reduced the initial relaxations (from 20.5 + 1.6 to 3.8 + 1.5% and from 32.1 + 6.4 to 18.9 + 3.9% at 10 -6 M and 10 -5 M concentrations of serotonin, respectively) and also converted the serotonin (10 -4 M)-induced contraction to a relaxation. In the co-axial system with trachea from guinea-pigs previously sensitized with i.p. injected egg-ovalbumin, the serotonin-induced biphasic response was converted to a contractile response only after ovalbumin challenge. Histopathologic changes were observed in the epithelium of challenged tracheas taken from sensitized guinea-pigs and alterations of serotonin-induced epithelium-dependent responses were attributed to the morphological and/or functional damage of tracheal epithelium caused by ovalbumin challenge. In the modified co-axial system, phenylephrine-induced contractions faded quickly when the rat anococcygeus muscle was mounted in epithelium-intact guinea-pig trachea, and the percentage fade was significantly higher (92.3 + 2.8%) than that obtained when the anococcygeus muscle was mounted in epithelium-denuded trachea (56.9 + 8.4%) or when it was mounted alone (44.6 + 7.7%). Our results suggest that guinea-pig tracheal epithelium is capable of modulating the responsiveness of rat anococcygeus muscle to serotonin by affecting the basal or stimulated release of some inhibitory mediators.

Research paper thumbnail of The role of nitric oxide in digoxin-induced arrhythmias in guinea-pigs

Pharmacology &amp Toxicology

We have investigated the effects of nitric oxide synthase inhibitor (L-NAME), nitric oxide precur... more We have investigated the effects of nitric oxide synthase inhibitor (L-NAME), nitric oxide precursor (L-arginine) and nitric oxide donor (sodium nitroprusside) on digoxin-induced arrhythmias both in guinea-pig isolated hearts and in anaesthetised animals. Sodium nitroprusside (0.1 mumol kg-1 min.-1 for 70 min.) caused a marked inhibition in mortality and arrhythmia score but L-NAME (10 mg kg-1) and L-arginine (30 mg kg-1 intravenous bolus followed by 10 mg kg-1 min.-1 for 60 min.) treatments were ineffective in anaesthetised guinea-pigs. None of the drugs markedly affected the time of onset of first arrhythmias or ventricular fibrillation incidence. In isolated heart experiments, nitric oxide generated by either L-arginine (1 mM) or sodium nitroprusside (1 mM) significantly reduced the arrhythmia score whereas L-NAME (1 mM) had no effect. Ventricular fibrillation incidence was totally abolished by sodium nitroprusside and none of the hearts treated with L-arginine had an irreversible ventricular fibrillation. L-NAME decreased ventricular tachycardia duration but increased ventricular fibrillation duration. There were no marked changes in the time of onset of first arrhythmias with these drugs in in vitro experiments. These results suggest that nitric oxide may play a modulatory role in the digoxin-induced arrhythmias in guinea-pigs.

Research paper thumbnail of Effects of peroxynitrite on the reactivity of diabetic rat aorta

Pharmacology

Endogenous nitric oxide (NO) reacts with superoxide to form peroxynitrite, which is capable of ei... more Endogenous nitric oxide (NO) reacts with superoxide to form peroxynitrite, which is capable of either oxidizing or nitrating various biological substrates. We compared the vasodilatory effect of exogenous peroxynitrite with the effects of decomposed peroxynitrite or sodium nitrite in precontracted aorta isolated from streptozotocin-induced diabetic and age-matched control rats. Peroxynitrite (10 nmol/l to 300 micromol/l) produced a concentration-dependent relaxation in aortic rings with or without endothelium. Relaxation was also observed with a higher concentration of its decomposition product or sodium nitrite, although these relaxations were considerably slower and with reduced sensitivity. Endothelium-containing rings were less sensitive to the vasorelaxant effect of peroxynitrite than the endothelium-denuded rings in control (pD(2) was 5.19 +/- 0.06 in rings with endothelium and 5.86 +/- 0.03 in rings without endothelium, p < 0.01) but not in diabetic aorta (pD(2) was 5.97 +...

Research paper thumbnail of Chemical preconditioning effect of 3-nitropropionic acid in anesthetized rat heart

Life Sciences

Short ischemic episodes increase tolerance against subsequent severe ischemia in the heart. Nitro... more Short ischemic episodes increase tolerance against subsequent severe ischemia in the heart. Nitropropionate (3-NP), an irreversible inhibitor of succinic dehydrogenase of the mitochondrial complex II, was shown to induce protective effect against ischemic brain injury. The aim of this study was to investigate the possible protective effect of 3-NP on regional ischemia in preconditioned rat heart in vivo. Hearts were assigned into three groups: first, in order to induce ischemic preconditioning (IP) 5 min ischemia separated by 10 min reperfusion protocol was used; second, non-preconditioned group was used as control; and third, 3-NP (20 mg/kg, i.p.) was injected 3 h before the surgical procedure in order to induce chemical preconditioning. In all these groups, 30 min regional ischemia was followed by 60 min reperfusion. Infarct size, bax expression, number of ventricular ectopic beats (VEB), duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) were significantly...

Research paper thumbnail of Does prevention of free radical reactions influence digoxin-arrhythmias?

General pharmacology, 1999

In the present study, the possible role of oxygen-derived free radicals (OFR) on digoxin- (0.6 mg... more In the present study, the possible role of oxygen-derived free radicals (OFR) on digoxin- (0.6 mg/kg(-1) IV bolus) induced arrhythmias of anesthetized guinea-pigs has been investigated. Guinea-pigs (300400 g) of either sex were anesthetized with urethane (1.5 g/kg(-1),IP), and their trachea for respiration, left common carotid artery for blood pressure monitoring, and right jugular vein for drug administration were cannulated. ECG and haemodynamics were recorded throughout the experiments. None of the agents used [N-acetyl-L-cysteine (20 mg/kg(-1)IV bolus), or SOD (30,000 IU/kg(-1) IV bolus) + catalase (15,000 IU/kg(-1) IV bolus)] significantly inhibited the arrhythmias except desferrioxamine which reduced the incidence of ventricular fibrillation and arrhythmia score. Desferrioxamine, by acting intracellularly unlike other agents used, might prevent the reduction of Fe(+3) by ascorbate and superoxide anion thus inhibiting the formation of cytotoxic hydroxyl radical in this experime...

Research paper thumbnail of Bradykinin-Induced Responses in a Coaxial Bioassay System Composed of Rat Anococcygeus Muscle and Guinea Pig Trachea

General Pharmacology: The Vascular System, 1998

1. Epithelium-dependent effects of bradykinin (BK) were investigated in a coaxial bioassay system... more 1. Epithelium-dependent effects of bradykinin (BK) were investigated in a coaxial bioassay system which consisted of guinea pig trachea as donor organ and rat anococcygeus muscle as test tissue.

Research paper thumbnail of Antinociceptive effects of H1- and H2-antihistaminics in mice

General Pharmacology: The Vascular System, 1993

1. Two methods were used to study the analgesic effects of subcutaneous injections of antihistami... more 1. Two methods were used to study the analgesic effects of subcutaneous injections of antihistaminics in mice: the p-benzoquinone(PBQ)-writhing test and caudal compression test.

Research paper thumbnail of Peroxynitrite produces relaxations on the rat anococcygeus muscle

Life Sciences, 2000

Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprussid... more Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprusside (SNP) on isolated rat anococcygeus muscle were investigated. Administration of 0.1-1.0 mM ONOO- or 0.01-100.0 microM SNP produced concentration-dependent relaxations on the phenylephrine (2 microM)-precontracted muscle. Time courses of these relaxations to ONOO- and SNP were not similar and decomposed ONOO- caused a biphasic response composed of an initial contraction followed by a relaxation. NT (0.01-0.1 mM) either incubated for 20 min prior to precontraction or given during precontraction plateau did not attenuate precontraction or ONOO(-)-induced relaxations. Results of the present study demonstrate that ONOO- relaxes rat anococcygeus muscle specifically while its stable metabolite NT has no effect.

Research paper thumbnail of Enhancement of luminol chemiluminescence by cysteine and glutathione

The Analyst, 2000

Cysteine enhancement of cobalt(II)-catalysed chemiluminescence of hydrogen peroxide and luminol o... more Cysteine enhancement of cobalt(II)-catalysed chemiluminescence of hydrogen peroxide and luminol occurs in carbonate buffer (but not in borate buffer), whether cysteine mixes with hydrogen peroxide before it mixes with luminol-cobalt(II) or vice versa. Enhancement was measured by the ratio of the signals in the presence and absence of cysteine; standard errors were generally < 5% of the mean ratio. Cystine in sufficiently acidic solution also enhances the chemiluminescence but otherwise diminishes the emission. The emission is also inhibited by glutathione. A mixed solution of cysteine and cystine gives rise to enhanced signals. In all the above cases, enhancement occurs only in the presence of a cobalt(II) catalyst. Luminol-peroxynitrite chemiluminescence is enhanced by cysteine and by glutathione without the presence of a catalyst.

Research paper thumbnail of The Mechanisms of Peroxynitrite-Induced Relaxations in Isolated Rat Anococcygeus Muscle

Pharmacology, 2002

We have previously reported that peroxynitrite (ONOO -) caused relaxations on isolated rat anococ... more We have previously reported that peroxynitrite (ONOO -) caused relaxations on isolated rat anococcygeus muscle and in the present study the possible mechanisms of the relaxant effect were investigated. ONOO -(0.03-1.0 mmol/l)-induced relaxations were reduced significantly by the presence of an ATP-sensitive potassium channel (K + ATP channel) blocker, glibenclamide (0.3 Ìmol/ l), or 1H-(1,2,4)oxadiazolo(4,3-·)quinoxalin-1-one (ODQ) (30.0 Ìmol/l), a guanylyl cyclase inhibitor. However, 3aminobenzamide (3.0 mmol/l), an inhibitor of poly(ADPribose)synthase, did not influence the relaxant effect of ONOO -(1.0 mmol/l). Results of the present study implicate that activation of K + ATP channels and/or cGMP/K + ATP channel interaction might play a role in the relaxant responses to ONOOin isolated rat anococcygeus muscle.

Research paper thumbnail of Temperature-Dependent Specific Desensitization in the Rat Anococcygeus Muscle to Angiotensin II

Pharmacology, 1989

The effect of angiotensin II (A II) on isolated rat anococcygeus muscle was investigated. A II, w... more The effect of angiotensin II (A II) on isolated rat anococcygeus muscle was investigated. A II, when used submaximally (4 X 10(-9) mol/l), produced a rapid contraction of the rat anococcygeus muscle. However, a profound tachyphylaxis developed with repeated administrations. This tachyphylaxis is specific in nature, since the tissue responded normally to noradrenaline even after the establishment of a complete tachyphylaxis to the peptide. Incubation with phentolamine or indometacin had no effect on the A II-induced tachyphylaxis. On the other hand, a marked prevention of tachyphylaxis was obtained by lowering the bath temperature to 31 or 25 degrees C. These results indicate that neither noradrenaline nor prostaglandin release participate in the development of tachyphylaxis to A II in rat anococcygeus muscle, and this tachyphylaxis can be prevented by lowering the temperature of the bath solution.

Research paper thumbnail of DOES REMOTE ORGAN ISCHAEMIA TRIGGER CARDIAC PRECONDITIONING DURING CORONARY ARTERY SURGERY?

Pharmacological Research, 2000

The aim of this study is to provide biochemical evidence of the occurrence of cardiac preconditio... more The aim of this study is to provide biochemical evidence of the occurrence of cardiac preconditioning via remote organ ischaemia on the patients undergoing coronary artery surgery. Eight male patients were randomly allocated into two groups. Blood samples were collected via coronary perfusion catheter immediately before cardiopulmonary bypass Ž . Ž . Ž . point 0 , prior to declamping aorta point 1 and 5 min after declamping the aorta point 2 Ž . Ž . to determine creatinine phosphokinase CPK , CPK-MB and lactate dehydrogenase LDH levels in the control group. A tourniquet wrapped around the right upper extremity of the patient was inflated and deflated twice to perform 3 min of ischaemia separated with 2 min of reperfusion in the preconditioning group. Blood samples were withdrawn as described for the control group. Only LDH levels at point 2 were found to be significantly higher than the control group's. These data implied that preconditioning appeared to protect myocardium by enhancing anaerobic glycolysis.

Research paper thumbnail of COMPARISON OF NITRIC OXIDE PRODUCTION BY MONOCYTE/MACROPHAGES IN HEALTHY SUBJECTS AND PATIENTS WITH ACTIVE PULMONARY TUBERCULOSIS

Pharmacological Research, 1998

The aim of the present study was to determine the NO production by human cultured Ž . macrophages... more The aim of the present study was to determine the NO production by human cultured Ž . macrophages m and to compare the NO production between healthy subjects and patients with active pulmonary tuberculosis. The bioassay method was used for assessment Ž y1 . of validation. Lipopolysaccharide 125 ng ml -activated m from healthy and diseased subjects released a substantial amount of NO. NO synthase inhibitor, N G -nitro-L-arginine Ž y1 . methyl ester, 0.1 mmol l suppressed NO synthesis significantly in m of healthy subjects. Nitrite formation measured by the diazotization method in the supernatants taken from cultured m of tuberculous patients were significantly lower than the healthy subjects. The supernatants obtained in both subjects caused relaxations of guinea-pig aorta Ž y1 . reversed by methylene blue 10 mol l . There was a significant difference between relaxations of healthy and diseased supernatants. Nitrite formation measured by the bioassay method in the supernatants taken from cultured m of tuberculous patients was significantly higher than the healthy subjects. It was concluded that NO production appeared to be decreased in tuberculosis. The reason for decreased production of NO in tuberculosis may be related to the interaction of several cytokines andror eicosanoids by means of the disease related induction of immune reactions.

Research paper thumbnail of EFFECTS OF WEB 2086 ON THE PROTECTIVE ROLE OF PRECONDITIONING AGAINST ARRHYTHMIAS IN RATS

Pharmacological Research, 1998

The purpose of the present study was to investigate a possible role of platelet activating factor... more The purpose of the present study was to investigate a possible role of platelet activating factor (PAF) in ischaemic preconditioning (PC). Since both PC and PAF act through protein kinase C (PKC), PAF could play a role in PC. To test this hypothesis, anaesthetized, open-chest male rats were subjected to four different protocols. Group I was subjected to 30 min of left coronary artery occlusion. In Group II, WEB 2086 (10 mg kg-1 i.v. bolus+1 mg kg-1 h-1 i.v. infusion) a selective PAF antagonist was given to non-preconditioned rats 23 min before the 30-min occlusion period. In Group III and IV ischaemic PC was elicited by one cycle of 3 min occlusion and 5 min reperfusion and also in Group IV, WEB 2086 (10 mg kg-1 i.v. bolus+1 mg kg-1 h-1 i.v. infusion) was given 23 min before the 30 min occlusion period. Ventricular ectopic beats (VEB), ventricular tachycardia (VT), and ventricular fibrillation (VF) that occurred during 30 min occlusion were determined. WEB 2086 administration or PC reduced the VEBs significantly. Incidence of VT and VF were not affected by WEB 2086 compared with control values, although PC decreased the incidence of VT and VF. WEB 2086 administration did not attenuate PC-induced improvement of arrhythmia parameters. These data demonstrated that a specific PAF antagonist, WEB 2086 did not abolish PC-induced protection against arrhythmias.

Research paper thumbnail of EFFECTS OF FREE RADICAL PRODUCTION AND SCAVENGERS ON OCCLUSION–REPERFUSION INDUCED ARRHYTHMIAS

Pharmacological Research, 1998

Ventricular arrhythmias were studied in rat isolated hearts subjected to coronary artery occlusio... more Ventricular arrhythmias were studied in rat isolated hearts subjected to coronary artery occlusion and reperfusion. Free radicals in the perfusate were detected by continuous flow Ž . luminol-enhanced chemiluminescence. Administration of purine 2.3 mM and xanthine Ž y1 y1 . oxidase 0.12 U ml min did not significantly modify the severity of reperfusioninduced arrhythmias but did generate free radicals. No free radical generation was detected Ž . during the period of coronary artery occlusion or reperfusion. Superoxide dismutase SOD 20᎐80 U ml y1 did not alter the severity of reperfusion arrhythmias but, in the presence of 80 U ml y1 SOD, occlusion-induced arrhythmias were augmented. SOD did not produce any effect on haemodynamics at the concentrations tested. Ventricular arrhythmias and cardiac haemodynamics were also not significantly changed by the combination of scav-Ž y1 . Ž y 1 . Ž . engers, SOD 10 U ml , catalase 100 U ml and mannitol 20 mM . These data suggest that the superoxide free radical is unlikely to be the primary cause of reperfusion induced arrhythmias in rat isolated hearts subjected to regional ischaemia.

Research paper thumbnail of Participation of the components of L-arginine/nitric oxide/cGMP cascade by chemically-induced abdominal constriction in the mouse

Life Sciences, 2000

The purpose of this study was to investigate the role of the L-arginine/nitric oxide (NO)/cGMP pa... more The purpose of this study was to investigate the role of the L-arginine/nitric oxide (NO)/cGMP pathway in p-benzoquinone-induced writhing model in mouse. L-arginine, a NO precursor, displayed antinociceptive effects at the doses of 0.125Ð1.0 mg/kg. When the doses of L-arginine were increased gradually to 10Ð100 mg/kg, a dose-dependent triphasic pattern of nociception-antinociception-nociception was obtained. The NO synthase (NOS) inhibitor, N G -nitro-L-arginine methyl ester (L-NAME) (18.75Ð 150 mg/kg), possessed antinociceptive activity. Methylene blue (MB), a guanylyl cyclase and/or NOS inhibitor, (5Ð160 mg/kg) also produced a dose-dependent triphasic response. When L-arginine (50 mg/ kg) was combined with L-NAME (75 mg/kg), L-arginine-induced antinociception did not change sig-niÞcantly. Cotreatment of L-arginine with 5 mg/kg MB signiÞcantly decreased MB-induced antinociception and reversed the nociception induced by 40 mg/kg MB to antinociception. It is concluded that the components of L-arginine/nitric oxide/cGMP cascade may participate in nociceptive processes both peripherally and centrally by a direct effect on nociceptors or by the involvement of other related pathways of nociceptive processes induced by NO.

Research paper thumbnail of Peroxynitrite produces relaxations on the rat anococcygeus muscle

Life Sciences, 2000

Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprussid... more Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprusside (SNP) on isolated rat anococcygeus muscle were investigated. Administration of 0.1-1.0 mM ONOO- or 0.01-100.0 microM SNP produced concentration-dependent relaxations on the phenylephrine (2 microM)-precontracted muscle. Time courses of these relaxations to ONOO- and SNP were not similar and decomposed ONOO- caused a biphasic response composed of an initial contraction followed by a relaxation. NT (0.01-0.1 mM) either incubated for 20 min prior to precontraction or given during precontraction plateau did not attenuate precontraction or ONOO(-)-induced relaxations. Results of the present study demonstrate that ONOO- relaxes rat anococcygeus muscle specifically while its stable metabolite NT has no effect.

Research paper thumbnail of Clinical study on the bioequivalence of two tablet formulations of flurbiprofen

European Journal of Drug Metabolism and Pharmacokinetics, 2009

Flurbiprofen (CAS 5104-49-4) is a member of phenylalkanoic acid derivative group of nonsteroid an... more Flurbiprofen (CAS 5104-49-4) is a member of phenylalkanoic acid derivative group of nonsteroid anti-inflammatory drugs. It exhibits anti-inflammatory, analgesic and antipyretic activities. Two different tablets containing flurbiprofen (FLU) were investigated in 24 healthy volunteers to prove the bioequivalence between both treatments after single oral dose administrations. Fluroben 100 mg tablet and 100 mg tablet of the originator product were used as test and reference preparation respectively. The study was performed open label, randomized, two period cross-over design with 15 days wash out period. Blood samples were taken up to 24 hours for pharmacokinetic profiling. The plasma concentrations of flurbiprofen were determined with validated HPLC-UV method. Maximum plasma concentration (Cmax) of FLU 19,143.65 ng/ml and 19,164.22 ng/ml were found for test and reference formulation respectively. Areas under the plasma concentration time curve AUC(0-infinity), of 118 501.4 ng.h/ml and 111,339.8 ng.h/ml were calculated test and reference formulation respectively. Primary target parameters AUC (0-infinity) and Cmax, both of them were tested parametrically by analysis of variance (ANOVA); 90% confidence intervals were between 100.5%-111.18% for AUC(0-infinity), and 87.6%-115.0% for Cmax. All these values were within the acceptance range (80%-125%) for bioequivalence studies.

Research paper thumbnail of The mechanism of the late preconditioning effect of 3-nitropropionic acid

Archives of Pharmacal Research, 2008

The aim of the present study was to investigate the mechanism of effect of 3-nitropropionic acid-... more The aim of the present study was to investigate the mechanism of effect of 3-nitropropionic acid-(3-NP) induced late preconditioning in rat heart. For this purpose 20-30 min before 3-NP (20 mg/kg, i.p.) injection, the rats were treated intraperitoneally with 5-hydroxydecanoate (40 mg/kg, 5-HD, mitochondrial K(ATP)-channel blocker), L-NAME (100 mg/kg, NOS inhibitor), N-2-mercaptopropionylglycine (100 mg/kg, MPG, free radical scavenger), or superoxide dismutase+catalase (10000+10000 IU/kg, SOD+CAT). Control rats received saline only without 3-NP pretreatment. After two days, hearts were isolated and perfused at a constant pressure in a Langendorff apparatus. 15-min global ischemia followed by 30-min reperfusion was applied to all hearts. Pretreatment of 3-NP significantly reduced infarct size, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) levels, and incidence of ventricular tachycardia (VT) compared with the control group receiving saline only. 5-HD, L-NAME, MPG, or SOD+CAT treatment statistically reversed 3-NP-induced reduction in infarct size. Although CK-MB, LDH levels, and incidence of VT were also reduced by L-NAME, MPG, or SOD+CAT treatment, only 5-HD significantly inhibited beneficial effects of 3-NP on all of the parameters above. These results showed that mito-K(ATP) channels play a pivotal role in late preconditioning effect of 3-NP in the isolated rat heart. However, other mediators such as reactive oxygen species and NO may be, at least in part, involved in mechanisms of this effect.

Research paper thumbnail of Digoxin-induced cardiac toxicity in the anaesthetized guinea-pigs and effect of heparin infusion

We have examined the effects of heparin infusion on the arrhythmias induced by digoxin. Digoxin t... more We have examined the effects of heparin infusion on the arrhythmias induced by digoxin. Digoxin treatment consisted of 0.6 mg kg-1 given i.v. 15 min after the beginning of heparin infusion. Heparin infusions (1.7 IU, 3.4 IU and 6.8 IU kg-1 min-1) were begun 15 min before digoxin injection and continued for another 30 min. ECG, blood pressure, heart rate and arrhythmias were recorded starting 15 min before and continuing for 60 min after the digoxin injection. Heparin at the infusion rates of 3.4 IU and 6.8 IU kg-1.min-1 reduced significantly the arrhythmia scores. On the other hand, heparin did not significantly alter the arterial blood pressure and heart rate values affected by digoxin.

Research paper thumbnail of Epithelium-dependent responses of serotonin in a co-axial bioassay system

Serotonin (10-6-10 -4 M) produced relaxations in a concentration-dependent (at 10 -6 and 10 -5 M ... more Serotonin (10-6-10 -4 M) produced relaxations in a concentration-dependent (at 10 -6 and 10 -5 M concentrations) manner followed by a contraction (at 10 -4 M concentration) in a co-axial system, which consisted of guinea-pig trachea as a donor organ for epithelial derived-relaxing factor(s) and phenylephrine-precontracted rat anococcygeus muscle as assay tissue. Serotonin produced a concentration-dependent contraction only in precontracted rat anococc, ygeus muscle mounted alone or mounted co-axially within epithelium-denuded trachea. Indomethacin (10 -6 M) significantly inhibited the initial relaxations (from 25.1 + 7.8 to 7.8 + 5.0% and from 35.6 + 8.7 to 10.4 + 8.3% at 10 -6 and 10 -5 M concentrations of serotonin), but did not affect the contraction. Imipramine (10 -8 M) and hydrocortisone (3 × 10 -5 M) reduced the initial relaxations (from 20.5 + 1.6 to 3.8 + 1.5% and from 32.1 + 6.4 to 18.9 + 3.9% at 10 -6 M and 10 -5 M concentrations of serotonin, respectively) and also converted the serotonin (10 -4 M)-induced contraction to a relaxation. In the co-axial system with trachea from guinea-pigs previously sensitized with i.p. injected egg-ovalbumin, the serotonin-induced biphasic response was converted to a contractile response only after ovalbumin challenge. Histopathologic changes were observed in the epithelium of challenged tracheas taken from sensitized guinea-pigs and alterations of serotonin-induced epithelium-dependent responses were attributed to the morphological and/or functional damage of tracheal epithelium caused by ovalbumin challenge. In the modified co-axial system, phenylephrine-induced contractions faded quickly when the rat anococcygeus muscle was mounted in epithelium-intact guinea-pig trachea, and the percentage fade was significantly higher (92.3 + 2.8%) than that obtained when the anococcygeus muscle was mounted in epithelium-denuded trachea (56.9 + 8.4%) or when it was mounted alone (44.6 + 7.7%). Our results suggest that guinea-pig tracheal epithelium is capable of modulating the responsiveness of rat anococcygeus muscle to serotonin by affecting the basal or stimulated release of some inhibitory mediators.

Research paper thumbnail of The role of nitric oxide in digoxin-induced arrhythmias in guinea-pigs

Pharmacology &amp Toxicology

We have investigated the effects of nitric oxide synthase inhibitor (L-NAME), nitric oxide precur... more We have investigated the effects of nitric oxide synthase inhibitor (L-NAME), nitric oxide precursor (L-arginine) and nitric oxide donor (sodium nitroprusside) on digoxin-induced arrhythmias both in guinea-pig isolated hearts and in anaesthetised animals. Sodium nitroprusside (0.1 mumol kg-1 min.-1 for 70 min.) caused a marked inhibition in mortality and arrhythmia score but L-NAME (10 mg kg-1) and L-arginine (30 mg kg-1 intravenous bolus followed by 10 mg kg-1 min.-1 for 60 min.) treatments were ineffective in anaesthetised guinea-pigs. None of the drugs markedly affected the time of onset of first arrhythmias or ventricular fibrillation incidence. In isolated heart experiments, nitric oxide generated by either L-arginine (1 mM) or sodium nitroprusside (1 mM) significantly reduced the arrhythmia score whereas L-NAME (1 mM) had no effect. Ventricular fibrillation incidence was totally abolished by sodium nitroprusside and none of the hearts treated with L-arginine had an irreversible ventricular fibrillation. L-NAME decreased ventricular tachycardia duration but increased ventricular fibrillation duration. There were no marked changes in the time of onset of first arrhythmias with these drugs in in vitro experiments. These results suggest that nitric oxide may play a modulatory role in the digoxin-induced arrhythmias in guinea-pigs.

Research paper thumbnail of Effects of peroxynitrite on the reactivity of diabetic rat aorta

Pharmacology

Endogenous nitric oxide (NO) reacts with superoxide to form peroxynitrite, which is capable of ei... more Endogenous nitric oxide (NO) reacts with superoxide to form peroxynitrite, which is capable of either oxidizing or nitrating various biological substrates. We compared the vasodilatory effect of exogenous peroxynitrite with the effects of decomposed peroxynitrite or sodium nitrite in precontracted aorta isolated from streptozotocin-induced diabetic and age-matched control rats. Peroxynitrite (10 nmol/l to 300 micromol/l) produced a concentration-dependent relaxation in aortic rings with or without endothelium. Relaxation was also observed with a higher concentration of its decomposition product or sodium nitrite, although these relaxations were considerably slower and with reduced sensitivity. Endothelium-containing rings were less sensitive to the vasorelaxant effect of peroxynitrite than the endothelium-denuded rings in control (pD(2) was 5.19 +/- 0.06 in rings with endothelium and 5.86 +/- 0.03 in rings without endothelium, p < 0.01) but not in diabetic aorta (pD(2) was 5.97 +...

Research paper thumbnail of Chemical preconditioning effect of 3-nitropropionic acid in anesthetized rat heart

Life Sciences

Short ischemic episodes increase tolerance against subsequent severe ischemia in the heart. Nitro... more Short ischemic episodes increase tolerance against subsequent severe ischemia in the heart. Nitropropionate (3-NP), an irreversible inhibitor of succinic dehydrogenase of the mitochondrial complex II, was shown to induce protective effect against ischemic brain injury. The aim of this study was to investigate the possible protective effect of 3-NP on regional ischemia in preconditioned rat heart in vivo. Hearts were assigned into three groups: first, in order to induce ischemic preconditioning (IP) 5 min ischemia separated by 10 min reperfusion protocol was used; second, non-preconditioned group was used as control; and third, 3-NP (20 mg/kg, i.p.) was injected 3 h before the surgical procedure in order to induce chemical preconditioning. In all these groups, 30 min regional ischemia was followed by 60 min reperfusion. Infarct size, bax expression, number of ventricular ectopic beats (VEB), duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) were significantly...

Research paper thumbnail of Does prevention of free radical reactions influence digoxin-arrhythmias?

General pharmacology, 1999

In the present study, the possible role of oxygen-derived free radicals (OFR) on digoxin- (0.6 mg... more In the present study, the possible role of oxygen-derived free radicals (OFR) on digoxin- (0.6 mg/kg(-1) IV bolus) induced arrhythmias of anesthetized guinea-pigs has been investigated. Guinea-pigs (300400 g) of either sex were anesthetized with urethane (1.5 g/kg(-1),IP), and their trachea for respiration, left common carotid artery for blood pressure monitoring, and right jugular vein for drug administration were cannulated. ECG and haemodynamics were recorded throughout the experiments. None of the agents used [N-acetyl-L-cysteine (20 mg/kg(-1)IV bolus), or SOD (30,000 IU/kg(-1) IV bolus) + catalase (15,000 IU/kg(-1) IV bolus)] significantly inhibited the arrhythmias except desferrioxamine which reduced the incidence of ventricular fibrillation and arrhythmia score. Desferrioxamine, by acting intracellularly unlike other agents used, might prevent the reduction of Fe(+3) by ascorbate and superoxide anion thus inhibiting the formation of cytotoxic hydroxyl radical in this experime...

Research paper thumbnail of Bradykinin-Induced Responses in a Coaxial Bioassay System Composed of Rat Anococcygeus Muscle and Guinea Pig Trachea

General Pharmacology: The Vascular System, 1998

1. Epithelium-dependent effects of bradykinin (BK) were investigated in a coaxial bioassay system... more 1. Epithelium-dependent effects of bradykinin (BK) were investigated in a coaxial bioassay system which consisted of guinea pig trachea as donor organ and rat anococcygeus muscle as test tissue.

Research paper thumbnail of Antinociceptive effects of H1- and H2-antihistaminics in mice

General Pharmacology: The Vascular System, 1993

1. Two methods were used to study the analgesic effects of subcutaneous injections of antihistami... more 1. Two methods were used to study the analgesic effects of subcutaneous injections of antihistaminics in mice: the p-benzoquinone(PBQ)-writhing test and caudal compression test.

Research paper thumbnail of Peroxynitrite produces relaxations on the rat anococcygeus muscle

Life Sciences, 2000

Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprussid... more Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprusside (SNP) on isolated rat anococcygeus muscle were investigated. Administration of 0.1-1.0 mM ONOO- or 0.01-100.0 microM SNP produced concentration-dependent relaxations on the phenylephrine (2 microM)-precontracted muscle. Time courses of these relaxations to ONOO- and SNP were not similar and decomposed ONOO- caused a biphasic response composed of an initial contraction followed by a relaxation. NT (0.01-0.1 mM) either incubated for 20 min prior to precontraction or given during precontraction plateau did not attenuate precontraction or ONOO(-)-induced relaxations. Results of the present study demonstrate that ONOO- relaxes rat anococcygeus muscle specifically while its stable metabolite NT has no effect.

Research paper thumbnail of Enhancement of luminol chemiluminescence by cysteine and glutathione

The Analyst, 2000

Cysteine enhancement of cobalt(II)-catalysed chemiluminescence of hydrogen peroxide and luminol o... more Cysteine enhancement of cobalt(II)-catalysed chemiluminescence of hydrogen peroxide and luminol occurs in carbonate buffer (but not in borate buffer), whether cysteine mixes with hydrogen peroxide before it mixes with luminol-cobalt(II) or vice versa. Enhancement was measured by the ratio of the signals in the presence and absence of cysteine; standard errors were generally < 5% of the mean ratio. Cystine in sufficiently acidic solution also enhances the chemiluminescence but otherwise diminishes the emission. The emission is also inhibited by glutathione. A mixed solution of cysteine and cystine gives rise to enhanced signals. In all the above cases, enhancement occurs only in the presence of a cobalt(II) catalyst. Luminol-peroxynitrite chemiluminescence is enhanced by cysteine and by glutathione without the presence of a catalyst.

Research paper thumbnail of The Mechanisms of Peroxynitrite-Induced Relaxations in Isolated Rat Anococcygeus Muscle

Pharmacology, 2002

We have previously reported that peroxynitrite (ONOO -) caused relaxations on isolated rat anococ... more We have previously reported that peroxynitrite (ONOO -) caused relaxations on isolated rat anococcygeus muscle and in the present study the possible mechanisms of the relaxant effect were investigated. ONOO -(0.03-1.0 mmol/l)-induced relaxations were reduced significantly by the presence of an ATP-sensitive potassium channel (K + ATP channel) blocker, glibenclamide (0.3 Ìmol/ l), or 1H-(1,2,4)oxadiazolo(4,3-·)quinoxalin-1-one (ODQ) (30.0 Ìmol/l), a guanylyl cyclase inhibitor. However, 3aminobenzamide (3.0 mmol/l), an inhibitor of poly(ADPribose)synthase, did not influence the relaxant effect of ONOO -(1.0 mmol/l). Results of the present study implicate that activation of K + ATP channels and/or cGMP/K + ATP channel interaction might play a role in the relaxant responses to ONOOin isolated rat anococcygeus muscle.

Research paper thumbnail of Temperature-Dependent Specific Desensitization in the Rat Anococcygeus Muscle to Angiotensin II

Pharmacology, 1989

The effect of angiotensin II (A II) on isolated rat anococcygeus muscle was investigated. A II, w... more The effect of angiotensin II (A II) on isolated rat anococcygeus muscle was investigated. A II, when used submaximally (4 X 10(-9) mol/l), produced a rapid contraction of the rat anococcygeus muscle. However, a profound tachyphylaxis developed with repeated administrations. This tachyphylaxis is specific in nature, since the tissue responded normally to noradrenaline even after the establishment of a complete tachyphylaxis to the peptide. Incubation with phentolamine or indometacin had no effect on the A II-induced tachyphylaxis. On the other hand, a marked prevention of tachyphylaxis was obtained by lowering the bath temperature to 31 or 25 degrees C. These results indicate that neither noradrenaline nor prostaglandin release participate in the development of tachyphylaxis to A II in rat anococcygeus muscle, and this tachyphylaxis can be prevented by lowering the temperature of the bath solution.

Research paper thumbnail of DOES REMOTE ORGAN ISCHAEMIA TRIGGER CARDIAC PRECONDITIONING DURING CORONARY ARTERY SURGERY?

Pharmacological Research, 2000

The aim of this study is to provide biochemical evidence of the occurrence of cardiac preconditio... more The aim of this study is to provide biochemical evidence of the occurrence of cardiac preconditioning via remote organ ischaemia on the patients undergoing coronary artery surgery. Eight male patients were randomly allocated into two groups. Blood samples were collected via coronary perfusion catheter immediately before cardiopulmonary bypass Ž . Ž . Ž . point 0 , prior to declamping aorta point 1 and 5 min after declamping the aorta point 2 Ž . Ž . to determine creatinine phosphokinase CPK , CPK-MB and lactate dehydrogenase LDH levels in the control group. A tourniquet wrapped around the right upper extremity of the patient was inflated and deflated twice to perform 3 min of ischaemia separated with 2 min of reperfusion in the preconditioning group. Blood samples were withdrawn as described for the control group. Only LDH levels at point 2 were found to be significantly higher than the control group's. These data implied that preconditioning appeared to protect myocardium by enhancing anaerobic glycolysis.

Research paper thumbnail of COMPARISON OF NITRIC OXIDE PRODUCTION BY MONOCYTE/MACROPHAGES IN HEALTHY SUBJECTS AND PATIENTS WITH ACTIVE PULMONARY TUBERCULOSIS

Pharmacological Research, 1998

The aim of the present study was to determine the NO production by human cultured Ž . macrophages... more The aim of the present study was to determine the NO production by human cultured Ž . macrophages m and to compare the NO production between healthy subjects and patients with active pulmonary tuberculosis. The bioassay method was used for assessment Ž y1 . of validation. Lipopolysaccharide 125 ng ml -activated m from healthy and diseased subjects released a substantial amount of NO. NO synthase inhibitor, N G -nitro-L-arginine Ž y1 . methyl ester, 0.1 mmol l suppressed NO synthesis significantly in m of healthy subjects. Nitrite formation measured by the diazotization method in the supernatants taken from cultured m of tuberculous patients were significantly lower than the healthy subjects. The supernatants obtained in both subjects caused relaxations of guinea-pig aorta Ž y1 . reversed by methylene blue 10 mol l . There was a significant difference between relaxations of healthy and diseased supernatants. Nitrite formation measured by the bioassay method in the supernatants taken from cultured m of tuberculous patients was significantly higher than the healthy subjects. It was concluded that NO production appeared to be decreased in tuberculosis. The reason for decreased production of NO in tuberculosis may be related to the interaction of several cytokines andror eicosanoids by means of the disease related induction of immune reactions.

Research paper thumbnail of EFFECTS OF WEB 2086 ON THE PROTECTIVE ROLE OF PRECONDITIONING AGAINST ARRHYTHMIAS IN RATS

Pharmacological Research, 1998

The purpose of the present study was to investigate a possible role of platelet activating factor... more The purpose of the present study was to investigate a possible role of platelet activating factor (PAF) in ischaemic preconditioning (PC). Since both PC and PAF act through protein kinase C (PKC), PAF could play a role in PC. To test this hypothesis, anaesthetized, open-chest male rats were subjected to four different protocols. Group I was subjected to 30 min of left coronary artery occlusion. In Group II, WEB 2086 (10 mg kg-1 i.v. bolus+1 mg kg-1 h-1 i.v. infusion) a selective PAF antagonist was given to non-preconditioned rats 23 min before the 30-min occlusion period. In Group III and IV ischaemic PC was elicited by one cycle of 3 min occlusion and 5 min reperfusion and also in Group IV, WEB 2086 (10 mg kg-1 i.v. bolus+1 mg kg-1 h-1 i.v. infusion) was given 23 min before the 30 min occlusion period. Ventricular ectopic beats (VEB), ventricular tachycardia (VT), and ventricular fibrillation (VF) that occurred during 30 min occlusion were determined. WEB 2086 administration or PC reduced the VEBs significantly. Incidence of VT and VF were not affected by WEB 2086 compared with control values, although PC decreased the incidence of VT and VF. WEB 2086 administration did not attenuate PC-induced improvement of arrhythmia parameters. These data demonstrated that a specific PAF antagonist, WEB 2086 did not abolish PC-induced protection against arrhythmias.

Research paper thumbnail of EFFECTS OF FREE RADICAL PRODUCTION AND SCAVENGERS ON OCCLUSION–REPERFUSION INDUCED ARRHYTHMIAS

Pharmacological Research, 1998

Ventricular arrhythmias were studied in rat isolated hearts subjected to coronary artery occlusio... more Ventricular arrhythmias were studied in rat isolated hearts subjected to coronary artery occlusion and reperfusion. Free radicals in the perfusate were detected by continuous flow Ž . luminol-enhanced chemiluminescence. Administration of purine 2.3 mM and xanthine Ž y1 y1 . oxidase 0.12 U ml min did not significantly modify the severity of reperfusioninduced arrhythmias but did generate free radicals. No free radical generation was detected Ž . during the period of coronary artery occlusion or reperfusion. Superoxide dismutase SOD 20᎐80 U ml y1 did not alter the severity of reperfusion arrhythmias but, in the presence of 80 U ml y1 SOD, occlusion-induced arrhythmias were augmented. SOD did not produce any effect on haemodynamics at the concentrations tested. Ventricular arrhythmias and cardiac haemodynamics were also not significantly changed by the combination of scav-Ž y1 . Ž y 1 . Ž . engers, SOD 10 U ml , catalase 100 U ml and mannitol 20 mM . These data suggest that the superoxide free radical is unlikely to be the primary cause of reperfusion induced arrhythmias in rat isolated hearts subjected to regional ischaemia.

Research paper thumbnail of Participation of the components of L-arginine/nitric oxide/cGMP cascade by chemically-induced abdominal constriction in the mouse

Life Sciences, 2000

The purpose of this study was to investigate the role of the L-arginine/nitric oxide (NO)/cGMP pa... more The purpose of this study was to investigate the role of the L-arginine/nitric oxide (NO)/cGMP pathway in p-benzoquinone-induced writhing model in mouse. L-arginine, a NO precursor, displayed antinociceptive effects at the doses of 0.125Ð1.0 mg/kg. When the doses of L-arginine were increased gradually to 10Ð100 mg/kg, a dose-dependent triphasic pattern of nociception-antinociception-nociception was obtained. The NO synthase (NOS) inhibitor, N G -nitro-L-arginine methyl ester (L-NAME) (18.75Ð 150 mg/kg), possessed antinociceptive activity. Methylene blue (MB), a guanylyl cyclase and/or NOS inhibitor, (5Ð160 mg/kg) also produced a dose-dependent triphasic response. When L-arginine (50 mg/ kg) was combined with L-NAME (75 mg/kg), L-arginine-induced antinociception did not change sig-niÞcantly. Cotreatment of L-arginine with 5 mg/kg MB signiÞcantly decreased MB-induced antinociception and reversed the nociception induced by 40 mg/kg MB to antinociception. It is concluded that the components of L-arginine/nitric oxide/cGMP cascade may participate in nociceptive processes both peripherally and centrally by a direct effect on nociceptors or by the involvement of other related pathways of nociceptive processes induced by NO.