This study investigated time-dependent variations in the activities of adenosine deaminase (ADA),... more This study investigated time-dependent variations in the activities of adenosine deaminase (ADA), an adenosine-metabolizing enzyme, and myeloperoxidase (MPO), an oxidation reaction-catalyzing enzyme, in control and streptozotocin (STZ)-induced diabetic rat liver. The animals were sacrificed at six different times of day (1, 5, 9, 13, 17 and 21 hours after lights on - HALO). The hepatic activity of ADA did not change depending on the STZ treatment whereas MPO activity was significantly higher in the diabetics than in the controls. Hepatic ADA activity was dependent on the time of sacrifice with the lowest activity at 21 HALO and the highest activity at 5 HALO. Both enzyme activities failed to show any significant interaction between STZ treatment and time of sacrifice, which means that diabetes does not influence the 24 h pattern of these activities. Since MPO, a heme protein localized in the leukocytes, is involved in the killing of microorganisms, increased MPO activity in diabetic...
Research communications in molecular pathology and pharmacology, 2003
The aim of this study was to compare the effects of different techniques used for deendothelizati... more The aim of this study was to compare the effects of different techniques used for deendothelization on responses to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilators and vasoconstrictor (phenylephrine) in the isolated rat thoracic aorta. Four different methods were used for de-endothelization: (1) mechanical (wire), (2) physical (distilled water), (3) chemical (Triton X-100 and saponin) and (4) enzymatic (trypsin). The results showed that mechanical rubbing with rough-surfaced wire was the most effective procedure amongst five different techniques used for deendothelization in the isolated rat thoracic rings. Denudation by wire abolished endothelium-dependent relaxation successfully without much interfering smooth muscle vasodilating and contracting properties of the agonists. It seems that physical, chemical and enzymatic techniques are not suitable for endothelial denudation in the isolated thoracic rat aorta preparations. These endothelium...
Archives internationales de pharmacodynamie et de thérapie, 1981
The influence of a histidine decarboxylase (HD) inhibitor, GYKI 11.121, on the action of angioten... more The influence of a histidine decarboxylase (HD) inhibitor, GYKI 11.121, on the action of angiotension II (AII) was investigated in the isolated continuously superfused rabbit aortic strip and perfused rat lung. An A II analog, Sar1-Ile5-A II, was also used only in aortic strip experiments. The myotropic effects of both peptides on the rabbit aorta were found to be inhibited when GYKI 11.121 was added to the superfusion medium. However, the vasoconstrictor effect of A II was found to be enhanced in the isolated rat lung following the addition of GYKI 11.121 to the perfusion medium. These findings are explained by the presence of a histaminergic component in the myotropic action of A II peptides.
Aims: To investigate intra- and inter-ethnic differences in three widespread (E158K, V257M and E3... more Aims: To investigate intra- and inter-ethnic differences in three widespread (E158K, V257M and E308G) and two African-specific (D132H and L360P) flavin-containing monooxygenase 3 (FMO3) polymorphisms. Materials & methods: Allele frequencies were determined by TaqMan® allelic discrimination assay in 2152 healthy volunteers from Europe (Swedes, Italians and Turks), East Asia (Japanese) and sub-Saharan Africa (nine ethnic groups covering eastern, southern and western regions), followed by haplotype and linkage analysis. Results: Significant subpopulation differences (p < 0.001) in allele frequencies were found for E158K, V257M and E308G in Europeans and regional differences (p < 0.01) for D132H among Africans. No carrier of P360 was identified. Cis-linkage between G308 and K158 was confirmed with the compound variant (K158/G308) being found in a high proportion (12.0–38.3%) of non-African subjects, but rarely (1.3%) among Africans. Conclusions: Distribution of functionally releva...
Time-dependent variations of the vasodilator effects of sodium nitroprusside and glyceryl trinitr... more Time-dependent variations of the vasodilator effects of sodium nitroprusside and glyceryl trinitrate on isolated smooth muscle have been studied on rings of rat thoracic aorta, both endothelium-intact and endothelium-denuded. For most of the concentrations of sodium nitroprusside used the induced relaxations were significantly dependent on the time the tissues were obtained. However, significant temporal differences were obtained for glyceryl trinitrate-induced relaxations at lower concentrations only for both endothelium-intact and endothelium-denuded preparations. EC50 values of sodium nitroprusside and glyceryl trinitrate (i.e. the concentrations inducing half the maximum response) were also significantly different and they had quite similar rhythmic features both in endothelium-intact and in endothelium-denuded preparations. These results clearly show that the in-vitro sensitivity of rat thoracic aorta to nitrodilator agents varies over a 24-h period and thus depends on when the...
1. Effect of histamine (HA) (10(-4)-10(-2) M) on spontaneously beating rat atrium was investigate... more 1. Effect of histamine (HA) (10(-4)-10(-2) M) on spontaneously beating rat atrium was investigated. HA produced a biphasic effect which is composed of an initial negative chronotropy followed by a positive chronotropic phase, at each single dose. 2. At a submaximal dose of HA (3 x 10(-3) M) we have investigated the effects of some antagonists on the biphasic effect profile. 3. Propranolol (10(-7) M) depressed the secondary phase by abolishing the biphasic pattern of the effect of HA leading it to a monophasic one (negative chronotropy). 4. On the other hand, combination with atropine (10(-7) M) was shown to reduce the negative inotropic effect (in the secondary phase) which was produced by HA in the presence of propranolol. 5. The initial negative chronotropic phase was significantly enhanced by propranolol and reduced by pheniramine (10(-6) M). 6. Pheniramine also potentiated the positive chronotropy at the secondary phase of the response, but cimetidine (10(-4) M) has no significant effect on both phases. 7. Theophylline (10(-4) M) abolished the initial negative chronotropic phase, but did not influence the secondary phase. Dipyridamole (10(-5) M) did not affect the secondary phase of the response of HA, but increased the initial negative chronotropic effect.
The aim of this study was to examine: the 24 h variation of 6-phosphogluconate dehydrogenase and ... more The aim of this study was to examine: the 24 h variation of 6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase activities, key enzymes for the maintenance of intracellular NADPH concentration, in rat liver in control and streptozotocin-induced diabetic animals. Adult male rats were fed ad libitum and synchronized on a 12:12 h light-dark cycle (lights on 08:00 h). One group of animals was treated with streptozotocin (STZ, 55 mg/kg, intraperitoneal) to induce experimental diabetes. Eight weeks after STZ injection, the animals were sacrificed at six different times of day--1, 5, 9, 13, 17 and 21 Hours After Lights On (HALO)--and livers were obtained. Enzyme activities were determined spectrophotometrically in triplicate in liver homogenates and expressed as units per mg protein. 6-phosphogluconate dehydrogenase activity was measured by substituting 6-phosphogluconate as substrate. Glucose-6-phosphate dehydrogenase activity was determined by monitoring NADPH production. Treatment, circadian time, and interaction between treatment and circadian time factors were tested by either one or two way analysis of variance (ANOVA). Two-way ANOVA revealed that 6-phosphogluconate dehydrogenase activity significantly depended on both the treatment and time of sacrifice. 6-phosphogluconate dehydrogenase activity was higher in control than diabetic animals; whereas, glucose-6-phosphate dehydrogenase activity did not vary over the 24 h in animals made diabetic by STZ treatment. Circadian variation in the activity of 6-phosphogluconate dehydrogenase was also detected in both the control and STZ treatment groups (one-way ANOVA). Time-dependent variation in glucose-6-phosphate dehydrogenase activity during the 24 h was detected in control but not in diabetic rats. No significant interaction was detected between STZ-treatment and time of sacrifice for both hepatic enzyme activities. These results suggest that the activities of NADPH-generating enzymes exhibit 24 h variation, which is not influenced by diabetes.
The biological-time-dependent variation in the vasodilator effect of verapamil on rat thoracic ao... more The biological-time-dependent variation in the vasodilator effect of verapamil on rat thoracic aorta was assessed in both endothelium-intact and denuded preparations. Groups of adult male rats were housed in light from 08:00 to 20:00 and in darkness from 20:00 to 08:00 and sacrificed at six different times of the day (1, 5, 9, 13, 17, and 21 hours after lights on; HALO). Verapamil caused concentration-dependent relaxations in both endothelium-intact and denuded aortic rings precontracted with phenylephrine (Phe). In endothelium-intact rings, neither the AUC nor the EC50 values for verapamil exhibited significant biological-time-dependent effects, as determined by one-way analysis of variance (ANOVA). In endothelium-denuded rings, AUC values did vary in a statistically significant manner according to the biological time of study, while the EC50 values did not. Endothelium denudation led to an increase in EC50 values at almost every time point. Statistically significant interactions between the biological time of study and treatment (intact vs. denuded endothelium) in both AUC and EC50 values were documented by two-way ANOVA; this indicated differences in the clock-time staging of verapamil-induced relaxation in endothelium-denuded versus intact aortic rings.
We investigated the effect of an injected bolus of 5 mg kg(-1) heparin at one circadian stage (08... more We investigated the effect of an injected bolus of 5 mg kg(-1) heparin at one circadian stage (08:30 to 11:00) on blood coagulation during different months of the year. Activated clotting times (ACTs) were assessed before and 5 min after heparin dosing to ensure extracorporeal circulation during open-heart surgery. The ACT data of 1083 presumably day-active Turkish patients (816 men and 267 women, mostly older than 46 years) who underwent coronary bypass surgery between 08:30 and 11:00 in the years from 1994 to 1997 were analyzed for annual rhythmicity. The ACT values obtained just before and 5 min after heparinization were subjected to cosinor analysis using a 365.25-day period to assess seasonality in basal ACT level and heparin effect. A small-amplitude annual rhythm with a wintertime peak was documented in the morning ACT in the group of 1083 patients. Rhythms of similar magnitude and staging were also detected in heparin effect on ACT in the 1083 patients and in subgroups categorized by gender. Circannual rhythmicity in the heparin effect on ACT was also documented in the elderly (&gt; or = 45 years old), but not young (18-45 years old) patients. The annual mean effect of heparin on the ACT was statistically significantly greater in younger than older patients. The relatively low-amplitude circannual rhythm in heparin effect on ACT (approximately 10% of the annual mean) is not viewed as being meaningful in patient preparation for bypass surgery for the 5 mg kg(-1) level of heparin dose.
Although considerable evidence implicates involvement of nitric oxide (NO) in circadian regulatio... more Although considerable evidence implicates involvement of nitric oxide (NO) in circadian regulation, little is known about possible 24 h variations in basal NO metabolism. In this study, daily variations in serum nitrite levels were studied in locally bred mice and rats during the months of September and October. The serum was separated from blood samples obtained at six different times of the day and night (1 h, 5 h, 9 h, 13 h, 17 h, and 21 h after lights off [HALO] from male albino mice and rats). As an index of in vivo NO generation, serum nitrite levels (determined by the diazotization method) in rats exhibited significant temporal fluctuation (unpaired Student t test), with the concentration highest at 5 HALO and 21 HALO and lowest at 9 HALO. No such temporal variation was detected in mice in these studies conducted on locally bred animals in the autumn.
This study investigated time-dependent variations in the activities of adenosine deaminase (ADA),... more This study investigated time-dependent variations in the activities of adenosine deaminase (ADA), an adenosine-metabolizing enzyme, and myeloperoxidase (MPO), an oxidation reaction-catalyzing enzyme, in control and streptozotocin (STZ)-induced diabetic rat liver. The animals were sacrificed at six different times of day (1, 5, 9, 13, 17 and 21 hours after lights on - HALO). The hepatic activity of ADA did not change depending on the STZ treatment whereas MPO activity was significantly higher in the diabetics than in the controls. Hepatic ADA activity was dependent on the time of sacrifice with the lowest activity at 21 HALO and the highest activity at 5 HALO. Both enzyme activities failed to show any significant interaction between STZ treatment and time of sacrifice, which means that diabetes does not influence the 24 h pattern of these activities. Since MPO, a heme protein localized in the leukocytes, is involved in the killing of microorganisms, increased MPO activity in diabetic...
Research communications in molecular pathology and pharmacology, 2003
The aim of this study was to compare the effects of different techniques used for deendothelizati... more The aim of this study was to compare the effects of different techniques used for deendothelization on responses to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilators and vasoconstrictor (phenylephrine) in the isolated rat thoracic aorta. Four different methods were used for de-endothelization: (1) mechanical (wire), (2) physical (distilled water), (3) chemical (Triton X-100 and saponin) and (4) enzymatic (trypsin). The results showed that mechanical rubbing with rough-surfaced wire was the most effective procedure amongst five different techniques used for deendothelization in the isolated rat thoracic rings. Denudation by wire abolished endothelium-dependent relaxation successfully without much interfering smooth muscle vasodilating and contracting properties of the agonists. It seems that physical, chemical and enzymatic techniques are not suitable for endothelial denudation in the isolated thoracic rat aorta preparations. These endothelium...
Archives internationales de pharmacodynamie et de thérapie, 1981
The influence of a histidine decarboxylase (HD) inhibitor, GYKI 11.121, on the action of angioten... more The influence of a histidine decarboxylase (HD) inhibitor, GYKI 11.121, on the action of angiotension II (AII) was investigated in the isolated continuously superfused rabbit aortic strip and perfused rat lung. An A II analog, Sar1-Ile5-A II, was also used only in aortic strip experiments. The myotropic effects of both peptides on the rabbit aorta were found to be inhibited when GYKI 11.121 was added to the superfusion medium. However, the vasoconstrictor effect of A II was found to be enhanced in the isolated rat lung following the addition of GYKI 11.121 to the perfusion medium. These findings are explained by the presence of a histaminergic component in the myotropic action of A II peptides.
Aims: To investigate intra- and inter-ethnic differences in three widespread (E158K, V257M and E3... more Aims: To investigate intra- and inter-ethnic differences in three widespread (E158K, V257M and E308G) and two African-specific (D132H and L360P) flavin-containing monooxygenase 3 (FMO3) polymorphisms. Materials & methods: Allele frequencies were determined by TaqMan® allelic discrimination assay in 2152 healthy volunteers from Europe (Swedes, Italians and Turks), East Asia (Japanese) and sub-Saharan Africa (nine ethnic groups covering eastern, southern and western regions), followed by haplotype and linkage analysis. Results: Significant subpopulation differences (p < 0.001) in allele frequencies were found for E158K, V257M and E308G in Europeans and regional differences (p < 0.01) for D132H among Africans. No carrier of P360 was identified. Cis-linkage between G308 and K158 was confirmed with the compound variant (K158/G308) being found in a high proportion (12.0–38.3%) of non-African subjects, but rarely (1.3%) among Africans. Conclusions: Distribution of functionally releva...
Time-dependent variations of the vasodilator effects of sodium nitroprusside and glyceryl trinitr... more Time-dependent variations of the vasodilator effects of sodium nitroprusside and glyceryl trinitrate on isolated smooth muscle have been studied on rings of rat thoracic aorta, both endothelium-intact and endothelium-denuded. For most of the concentrations of sodium nitroprusside used the induced relaxations were significantly dependent on the time the tissues were obtained. However, significant temporal differences were obtained for glyceryl trinitrate-induced relaxations at lower concentrations only for both endothelium-intact and endothelium-denuded preparations. EC50 values of sodium nitroprusside and glyceryl trinitrate (i.e. the concentrations inducing half the maximum response) were also significantly different and they had quite similar rhythmic features both in endothelium-intact and in endothelium-denuded preparations. These results clearly show that the in-vitro sensitivity of rat thoracic aorta to nitrodilator agents varies over a 24-h period and thus depends on when the...
1. Effect of histamine (HA) (10(-4)-10(-2) M) on spontaneously beating rat atrium was investigate... more 1. Effect of histamine (HA) (10(-4)-10(-2) M) on spontaneously beating rat atrium was investigated. HA produced a biphasic effect which is composed of an initial negative chronotropy followed by a positive chronotropic phase, at each single dose. 2. At a submaximal dose of HA (3 x 10(-3) M) we have investigated the effects of some antagonists on the biphasic effect profile. 3. Propranolol (10(-7) M) depressed the secondary phase by abolishing the biphasic pattern of the effect of HA leading it to a monophasic one (negative chronotropy). 4. On the other hand, combination with atropine (10(-7) M) was shown to reduce the negative inotropic effect (in the secondary phase) which was produced by HA in the presence of propranolol. 5. The initial negative chronotropic phase was significantly enhanced by propranolol and reduced by pheniramine (10(-6) M). 6. Pheniramine also potentiated the positive chronotropy at the secondary phase of the response, but cimetidine (10(-4) M) has no significant effect on both phases. 7. Theophylline (10(-4) M) abolished the initial negative chronotropic phase, but did not influence the secondary phase. Dipyridamole (10(-5) M) did not affect the secondary phase of the response of HA, but increased the initial negative chronotropic effect.
The aim of this study was to examine: the 24 h variation of 6-phosphogluconate dehydrogenase and ... more The aim of this study was to examine: the 24 h variation of 6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase activities, key enzymes for the maintenance of intracellular NADPH concentration, in rat liver in control and streptozotocin-induced diabetic animals. Adult male rats were fed ad libitum and synchronized on a 12:12 h light-dark cycle (lights on 08:00 h). One group of animals was treated with streptozotocin (STZ, 55 mg/kg, intraperitoneal) to induce experimental diabetes. Eight weeks after STZ injection, the animals were sacrificed at six different times of day--1, 5, 9, 13, 17 and 21 Hours After Lights On (HALO)--and livers were obtained. Enzyme activities were determined spectrophotometrically in triplicate in liver homogenates and expressed as units per mg protein. 6-phosphogluconate dehydrogenase activity was measured by substituting 6-phosphogluconate as substrate. Glucose-6-phosphate dehydrogenase activity was determined by monitoring NADPH production. Treatment, circadian time, and interaction between treatment and circadian time factors were tested by either one or two way analysis of variance (ANOVA). Two-way ANOVA revealed that 6-phosphogluconate dehydrogenase activity significantly depended on both the treatment and time of sacrifice. 6-phosphogluconate dehydrogenase activity was higher in control than diabetic animals; whereas, glucose-6-phosphate dehydrogenase activity did not vary over the 24 h in animals made diabetic by STZ treatment. Circadian variation in the activity of 6-phosphogluconate dehydrogenase was also detected in both the control and STZ treatment groups (one-way ANOVA). Time-dependent variation in glucose-6-phosphate dehydrogenase activity during the 24 h was detected in control but not in diabetic rats. No significant interaction was detected between STZ-treatment and time of sacrifice for both hepatic enzyme activities. These results suggest that the activities of NADPH-generating enzymes exhibit 24 h variation, which is not influenced by diabetes.
The biological-time-dependent variation in the vasodilator effect of verapamil on rat thoracic ao... more The biological-time-dependent variation in the vasodilator effect of verapamil on rat thoracic aorta was assessed in both endothelium-intact and denuded preparations. Groups of adult male rats were housed in light from 08:00 to 20:00 and in darkness from 20:00 to 08:00 and sacrificed at six different times of the day (1, 5, 9, 13, 17, and 21 hours after lights on; HALO). Verapamil caused concentration-dependent relaxations in both endothelium-intact and denuded aortic rings precontracted with phenylephrine (Phe). In endothelium-intact rings, neither the AUC nor the EC50 values for verapamil exhibited significant biological-time-dependent effects, as determined by one-way analysis of variance (ANOVA). In endothelium-denuded rings, AUC values did vary in a statistically significant manner according to the biological time of study, while the EC50 values did not. Endothelium denudation led to an increase in EC50 values at almost every time point. Statistically significant interactions between the biological time of study and treatment (intact vs. denuded endothelium) in both AUC and EC50 values were documented by two-way ANOVA; this indicated differences in the clock-time staging of verapamil-induced relaxation in endothelium-denuded versus intact aortic rings.
We investigated the effect of an injected bolus of 5 mg kg(-1) heparin at one circadian stage (08... more We investigated the effect of an injected bolus of 5 mg kg(-1) heparin at one circadian stage (08:30 to 11:00) on blood coagulation during different months of the year. Activated clotting times (ACTs) were assessed before and 5 min after heparin dosing to ensure extracorporeal circulation during open-heart surgery. The ACT data of 1083 presumably day-active Turkish patients (816 men and 267 women, mostly older than 46 years) who underwent coronary bypass surgery between 08:30 and 11:00 in the years from 1994 to 1997 were analyzed for annual rhythmicity. The ACT values obtained just before and 5 min after heparinization were subjected to cosinor analysis using a 365.25-day period to assess seasonality in basal ACT level and heparin effect. A small-amplitude annual rhythm with a wintertime peak was documented in the morning ACT in the group of 1083 patients. Rhythms of similar magnitude and staging were also detected in heparin effect on ACT in the 1083 patients and in subgroups categorized by gender. Circannual rhythmicity in the heparin effect on ACT was also documented in the elderly (&gt; or = 45 years old), but not young (18-45 years old) patients. The annual mean effect of heparin on the ACT was statistically significantly greater in younger than older patients. The relatively low-amplitude circannual rhythm in heparin effect on ACT (approximately 10% of the annual mean) is not viewed as being meaningful in patient preparation for bypass surgery for the 5 mg kg(-1) level of heparin dose.
Although considerable evidence implicates involvement of nitric oxide (NO) in circadian regulatio... more Although considerable evidence implicates involvement of nitric oxide (NO) in circadian regulation, little is known about possible 24 h variations in basal NO metabolism. In this study, daily variations in serum nitrite levels were studied in locally bred mice and rats during the months of September and October. The serum was separated from blood samples obtained at six different times of the day and night (1 h, 5 h, 9 h, 13 h, 17 h, and 21 h after lights off [HALO] from male albino mice and rats). As an index of in vivo NO generation, serum nitrite levels (determined by the diazotization method) in rats exhibited significant temporal fluctuation (unpaired Student t test), with the concentration highest at 5 HALO and 21 HALO and lowest at 9 HALO. No such temporal variation was detected in mice in these studies conducted on locally bred animals in the autumn.
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