Role of insulin resistance and leptin in the effect of intermittent feeding with a high-protein ketogenic diet on body composition in rats.

OBJECTIVES: The prevalence of obesity and overweight in children has been increasing rapidly worldwide and threatens society with various chronic diseases that these children are born with. High-protein ketogenic diets and intermittent nutrition are thought to be protective against obesity and metabolic syndrome MetS. However, the exact effects and results, insulin resistance, and the role of leptin in the functioning mechanism of these diets have not been fully elucidated. The aim of this study was to investigate the roles of insulin resistance and leptin hormone on the effects of body composition with a high-protein ketogenic diet and intermittent nutrition combination. METHODS: Thirty-two young non-obese rats were randomly divided into four equal groups. Both the standard diet and the high-protein ketogenic diet were given ad libitum and intermittently to the rats for 6 wk. The body weight and fat mass of the rats were measured at the end of the experiment. The fasting glucose, leptin, insulin, high- and low-density lipoprotein, and triacylglycerols were measured with the blood samples. RESULTS: The lowest body weight was observed in the intermittent and high-protein ketogenic diet group, followed by the free high-protein ketogenic diet and standard intermittent diet group, respectively. Also, the lowest body fat mass was observed in the intermittent and high-protein ketogenic diet group, followed by the standard intermittent diet group. Although there was no change in leptin, insulin, high- and low-density lipoprotein, and triacylglycerol levels in any group, the lowest blood glucose rate was observed in the intermittent and high-protein ketogenic diet group. CONCLUSION: The results of the present study revealed that an intermittent high-protein ketogenic diet is more effective than others in weight loss without disrupting biochemical health parameters, and the applied diets do not prevent growth and development.

Aortic ischemia-reperfusion injury and potency of fluoxetine.

Objectives: Due to cross-clamping of the aorta during aortic aneurysm surgeries, ischemia-reperfusion (IR) develops, and it may cause damage to the aorta itself or even to remote organs by oxidative stress or inflammation. Fluoxetine (FLX) which might be used in the preoperative period for its tranquilizing effect also has antioxidant effects in short-term use. The purpose of our study is to examine whether FLX protects aorta tissue, against the damage caused by IR. Materials and Methods: Three groups of Wistar rats were formed randomly. 1) Control group (sham-operated), 2) IR group (60 min ischemia+120 min perfusion), and 3) FLX+IR group (FLX dose was 20 mg/kg for 3 days IP before IR). At the end of each procedure, aorta samples were collected, and oxidant-antioxidant, anti-inflammatory, and anti-apoptotic status of the aorta were evaluated. Histological examinations of the samples were provided. Results: Levels of LOOH, MDA, ROS, TOS, MPO, TNFα, IL-1ß, IL-6, NF-kB, MMP-9, caspase-9, 8-OHdG, NO, and HA were found to be significantly increased in the IR group compared with control (P<0.05) and SOD, GSH, TAS, and IL-10 levels were significantly lower (P<0.05). FLX significantly decreased LOOH, MDA, ROS, TOS, MPO, TNFα, IL-1ß, IL-6, NF-kB, MMP-9, caspase-9, 8-OHdG, NO, and HA levels in the FLX+IR group compared with IR group (P<0.05) and increased IL-10, SOD, GSH, and TAS (P<0.05). FLX administration prevented the deterioration of aortic tissue damage. Conclusion: Our study is the first study that demonstrates FLX-mediated suppression of IR injury in the infrarenal abdominal aorta by antioxidant, anti-inflammatory, and anti-apoptotic properties.

The Protective Effects of Thymosin-ß-4 in a Rat Model of Ischemic Acute Kidney Injury.

BACKGROUND: Despite the progress in the treatment of acute kidney injury (AKI), current curative approaches fail to provide adequate treatment. In this study, we aimed to investigate the possible protective effects of thymosin-ß-4(Tß4) on an ischemic AKI model in rats. METHODS: Rats were randomly assigned into four groups (n = 8/group): The control group (sham-operated), the ischemia-reperfusion (I/R) group; renal ischemia (90 min) by infrarenal abdominal aortic occlusion followed by reperfusion (3 h), the Tß4 + I/R group; treated with Tß4 before I/R, and the I/Tß4/R group; treated with Tß4 just before reperfusion. Besides renal function determination (creatinine (Cr) and blood urea nitrogen (BUN)); histological evaluation was also conducted. Renal tissue caspase-9, matrix metalloproteinase (MMP-9) activities, and hyaluronan levels were measured. Additionally, renal tissue oxidative stress (lipid hydroperoxide, malondialdehyde, superoxide dismutase, glutathione, pro-oxidant-antioxidant balance, ferric reducing antioxidant power, nitric oxide), inflammation (tumor necrosis factor-α, interleukin-1ß, interleukin-6, nuclear factor-κß) were evaluated. RESULTS: I/R increased the level of caspase-9, MMP-9 activity, and hyaluronan (p < 0.001) and these were significantly decreased in both Tß4 groups. Moreover, I/R led to increases in oxidative stress and inflammation parameters (p < 0.001) while the levels of antioxidants were decreased. Nevertheless, Tß4 in both groups were able to restore oxidative stress and inflammation parameters. Furthermore, Tß4 attenuated histologic injury caused by I/R (p < 0.01) and diminished serum urea-creatinine levels (p < 0.001). CONCLUSION: These results suggest that Tß4 has significant improving effects in ischemic acute kidney injury. This beneficial effect might be a result of the inhibition of extracellular matrix remodeling and apoptosis cascade via modulation in renal redox status and inflammation.

Protective Effect of Thymosin ß4 against Abdominal Aortic Ischemia-Reperfusion-Induced Acute Lung Injury in Rats.

Background and objectives: Ischemia-reperfusion (IR) caused by infrarenal abdominal aorta cross-clamping is an important factor in the development of ischemia-reperfusion injury in various distant organs. Materials and Methods: We investigated potential antioxidant/anti-inflammatory effects of thymosin beta 4 (Tß4) in a rat model of abdominal aortic surgery-induced IR. Tß4 (10 mg/kg, intravenous (i.v.)) was administered to rats with IR (90-min ischemia, 180-min reperfusion) at two different periods. One group received Tß4 1 h before ischemia, and the other received 15 min before the reperfusion period. Results: Results were compared to control and non-Tß4-treated rats with IR. Serum, bronchoalveolar lavage fluid and lung tissue levels of oxidant parameters were higher, while antioxidant levels were lower in the IR group compared to control. IR also increased inflammatory cytokine levels. Tß4 reverted these parameters in both Tß4-treated groups compared to the untreated IR group. Conclusions: Since there is no statistical difference between the prescribed results of both Tß4-treated groups, our study demonstrates that Tß4 reduced lung oxidative stress and inflammation following IR and prevented lung tissue injury regardless of timing of administration.

Remote myocardial injury: the protective role of fluoxetine.

Aortic cross-clamping-induced ischemia-reperfusion (IR) is an important factor in the development of postoperative acute cardiac injury following abdominal aortic surgery. We investigated the possible anti-oxidant/anti-inflammatory effects of fluoxetine (FLX), which is used widely as a preoperative anxiolytic on cardiac injury induced by IR of the infrarenal abdominal aorta. FLX was administered to IR-performed (60 min of ischemia and 120 min of reperfusion) rats for 3 days, once daily at 20 mg/kg i.p. dosage. Results were compared to control and non-FLX-treated IR-performed rats. Serum creatine kinase (CK) and CK-MB levels, lipid hydroperoxide, thiobarbituric acid reactive substances, and pro-oxidant/anti-oxidant balance levels in the IR group were significantly higher whereas superoxide dismutase activity, glutathione, and ferric reducing/anti-oxidant power levels were lower than for the control. IR also increased myeloperoxidase activity, tumor necrosis factor-α, interleukin-1ß, and interleukin-6 and decreased interleukin-10 levels. FLX decreased CK, CK-MB, lipid hydroperoxide, thiobarbituric acid reactive substances, and pro-oxidant/anti-oxidant balance levels while increasing superoxide dismutase activity, glutathione, and ferric reducing/anti-oxidant power levels. FLX also decreased myeloperoxidase activity, tumor necrosis factor-α, interleukin-1ß, and interleukin-6 levels and increased interleukin-10 levels compared to IR. FLX attenuated the morphological changes associated with cardiac injury. Our study clearly demonstrates that FLX confers protection against aortic IR-induced cardiac injury, tissue leucocyte infiltration, and cellular integrity via its anti-oxidant/anti-inflammatory effects.

The effects of fluoxetine on circulating oxidative damage parameters in rats exposed to aortic ischemia-reperfusion.

Oxidative stress and reperfusion injury may develop in different ischemia-reperfusion (IR) models. Growing evidence links altered lipid protein redox-homeostasis with IR. The effect of fluoxetine (FLX; N-methyl-3-[4-(trifluoromethyl) phenoxy] benzenepropanamine), on the lipid protein redox-homeostasis mechanisms in the rats exposed to aortic IR is unclear. We aimed to investigate the effects of FLX on circulating protein oxidation and lipid peroxidation parameters, such as ischemia modified albumin (IMA), lipid hydroperoxide (LOOH), prooxidant antioxidant balance (PAB), erythrocyte glutathione (GSH), CuZn-superoxide dismutase (CuZn-SOD), ferric reducing antioxidant power (FRAP), as potential IR biomarkers. Wistar rats were randomized into three groups (n=7/group): 1) Control (sham laparotomy); 2) IR without FLX, (60min ischemia and 120min reperfusion); 3) IR with FLX (FLX+IR) (FLX 20mg/kg/day, i.p. for three days before surgery). All of the aforementioned parameters (IMA, LOOH, PAB, GSH, CuZn-SOD, and FRAP) were measured spectrophotometrically. IMA, LOOH, and PAB levels in IR group were significantly higher than the control (P<0.01 respectively) and fluoxetine groups (P<0.01, P<0.01, and P<0.05 respectively), whereas CuZn-SOD activities, GSH and FRAP were significantly lower in IR groups. Fluoxetine group significantly reduced IMA when compared to IR group (P<0.001) and control group (P<0.01). With respect to IMA, LOOH and PAB, impaired redox homeostasis is substantially more prominent in aortic IR. The antidepressant FLX has profitable effects on circulating redox status in rats exposed to aortic IR. FLX administration before IR might decrease the surgery-enhanced free radical production; taken together, the antioxidant effects of FLX supplementation should be considered in future studies.

Fluoxetine ameliorates imbalance of redox homeostasis and inflammation in an acute kidney injury model

Ischemia-reperfusion (IR) has been reported to be associated with augmented reactive oxygen radicals and cytokines. Currently, we aimed to examine the influence of fluoxetine, which is already used as a preoperative anxiolytic, in the context of IR induced by occlusion of infrarenal abdominal aorta (60 min of ischemia) and its effects on renal oxidative status, inflammation, renal function, and cellular integrity in reperfusion (120 min post-ischemia). Male rats were randomly assigned as control, IR, and pretreated groups. The pretreated group animals received fluoxetine (20 mg/kg, i.p.) once daily for 3 days. Renal tissue oxidative stress, myeloperoxidase activity, proinflammatory cytokines (tumor necrosis factor-alfa, interleukin-1beta, interleukin-6), histology, and function were assessed. As an anti-inflammatory cytokine, interleukin-10 was also assessed. IR led to a significant increase in lipid hydroperoxide, malondialdehyde, and pro-oxidant antioxidant balance and decrease in superoxide dismutase activity and ferric reducing/antioxidant power level (p < 0.05), but fluoxetine was able to restore these parameters. High concentrations of tumor necrosis factor-alfa, interleukin-1beta, interleukin-6, and myeloperoxidase activity caused by IR were significantly decreased in kidney tissue with fluoxetine. In addition, interleukin-10 levels were high in fluoxetine pretreated group. IR resulted in disrupted cellular integrity, infiltration of tissue with leukocytes, and decreased serum creatinine-urea levels (p < 0.05). Fluoxetine significantly restored impaired redox balance and inflammation parameters of rats subjected to IR to baseline values. This beneficial effect of fluoxetine on redox balance might be addressed to an improvement in renal function (AU)

Fluoxetine ameliorates imbalance of redox homeostasis and inflammation in an acute kidney injury model.

Ischemia-reperfusion (IR) has been reported to be associated with augmented reactive oxygen radicals and cytokines. Currently, we aimed to examine the influence of fluoxetine, which is already used as a preoperative anxiolytic, in the context of IR induced by occlusion of infrarenal abdominal aorta (60 min of ischemia) and its effects on renal oxidative status, inflammation, renal function, and cellular integrity in reperfusion (120 min post-ischemia). Male rats were randomly assigned as control, IR, and pretreated groups. The pretreated group animals received fluoxetine (20 mg/kg, i.p.) once daily for 3 days. Renal tissue oxidative stress, myeloperoxidase activity, proinflammatory cytokines (tumor necrosis factor-α, interleukin-1ß, interleukin-6), histology, and function were assessed. As an anti-inflammatory cytokine, interleukin-10 was also assessed. IR led to a significant increase in lipid hydroperoxide, malondialdehyde, and pro-oxidant antioxidant balance and decrease in superoxide dismutase activity and ferric reducing/antioxidant power level (p < 0.05), but fluoxetine was able to restore these parameters. High concentrations of tumor necrosis factor-α, interleukin-1ß, interleukin-6, and myeloperoxidase activity caused by IR were significantly decreased in kidney tissue with fluoxetine. In addition, interleukin-10 levels were high in fluoxetine pretreated group. IR resulted in disrupted cellular integrity, infiltration of tissue with leukocytes, and decreased serum creatinine-urea levels (p < 0.05). Fluoxetine significantly restored impaired redox balance and inflammation parameters of rats subjected to IR to baseline values. This beneficial effect of fluoxetine on redox balance might be addressed to an improvement in renal function.

The effect of fluoxetine on ischemia-reperfusion after aortic surgery in a rat model.

BACKGROUND: Aortic ischemia-reperfusion (IR) is an important factor in the development of postoperative acute lung injury after abdominal aortic surgery. The aim of the present study was to examine the effect of fluoxetine (Flx), a selective serotonin reuptake inhibitor widely used as a preoperative anxiolytic, on lung injury induced by abdominal aortic IR in rats. METHODS: Wistar rats were randomized into three groups (n = 7 per group): (1) control (sham laparotomy); (2) IR without Flx (60-min ischemia and 120-min reperfusion); (3) IR with Flx (Flx + IR) (Flx 20 mg/kg/d, intraperitoneally for 3 d before surgery). Lung tissue samples and bronchoalveolar lavage (BAL) were obtained for biochemical analysis of oxidative status. Ischemia-modified albumin (IMA) level and protein concentrations in BAL and lung wet to dry weight ratios were determined. Histologic evaluation of the lung tissues was also performed. RESULTS: IR without Flx led to significant increase in lipid hydroperoxide, malondialdehyde, and pro-oxidant-antioxidant balance and decrease in superoxide dismutase, glutathione, and ferric reducing antioxidant power activities (P < 0.05 versus control), whereas Flx was able to restore these parameters (P > 0.05 versus control) and decrease IMA level (P < 0.01 versus control) and protein concentration (P < 0.05 versus control) in BAL and wet to dry lung weight ratio. Histologic evaluation showed that Flx attenuated the morphologic changes associated with lung injury. CONCLUSIONS: The results indicate that Flx confers protection against aortic IR-induced lung oxidative stress and cellular integrity. IMA levels in BAL may be used as a follow-up marker for the efficacy of treatment in lung injury.

The effects of acute intermittent hypoxia on cardiovascular parameters in normotensive and chronic hypobaric hypoxia-induced hypertensive rabbits.

The effects of both chronic hypoxia and acute intermittent hypoxia (AIH) on cardiovascular system are unclear. We designed this study to develop a rabbit model of hypertension by exposure to chronic hypobaric hypoxia (CHH) and to investigate the effects of AIH on hypertensive rabbits. Present study was performed in 13 albino rabbits that divided into CHH and control groups. To develop hypertension, the rabbits were placed in a hypobaric chamber (390 mmHg; 22 hours/day, 30 days). Afterwards, AIH protocol was applied (8% FIO2 (Fraction of Inspired Oxygen) 1 min + 5 min normoxia, 20 cycles, 2 hours) to rabbits anesthetized with urethane and alpha-chloralose. Mean arterial pressure (MAP), heart rate (HR) and hematocrit values have been determined. Also asymmetric dimethylarginine (ADMA), endothelial nitric oxide synthase (eNOS), endothelin-1 and norepinephrine values have been analyzed in blood. We developed a model of hypertension in rabbits via exposure to severe CHH and we believe that ADMA is an important parameter in the development and permanence of CHH-induced hypertension. The main finding of this sudy was the depressor effect of AIH on blood pressure and heart rate in CHH- induced hypertension model. Finally, we believe that AIH protocol may be applicable for prevention and treatment of hypertension if properly developed.

The effect of chronic long-term intermittent hypobaric hypoxia on bone mineral density in rats: role of nitric oxide.

Intermittent hypoxia is the most common pattern of hypoxic exposure in humans. The effect of chronic long-term intermittent hypobaric hypoxia (CLTIHH) on bone metabolism is not investigated. We examined the effect of CLTIHH on bone metabolism and the role of nitric oxide (NO) in this process. The rats were divided into three groups in this study. The animals in groups I and II have been exposed to CLTIHH. The animals in group II were also treated with nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester. To obtain CLTIHH, rats were placed in a hypobaric chamber (430 mm Hg; 5 h/day, 5 days/week, 5 weeks). The group III (control) rats breathed room air in the same environment. At the begining of the experiments, bone mineral density (BMD) of the animals were measured, and blood samples were collected from the tail vein. After the 5-week CLTIHH period, the same measurements were repeated. Parathyroid hormone, calcium, phosphate, bone alkaline phosphatase (b-ALP), NO, interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha levels were determined. The cytokines, NO levels, and BMD in CLTIHH-induced rats were higher compared with baseline and control values. The cytokines, b-ALP, and BMD increased while NO levels decreased in the group II compared with baseline values. BMD values of group II were lower than group I but higher than control group. Our results suggested that CLTIHH has positive effects on bone density. Intermittent hypoxia protocols may be developed for treatment and prevention of osteopenia and osteoporosis.

Alterations of central hypercapnic respiratory response induced by acute central administration of serotonin re-uptake inhibitor, fluoxetine.

Long-term neurochemical changes are responsible for therapeutic actions of fluoxetine. The role of increased central concentration of serotonin by inhibiting its re-uptake via fluoxetine on the central hypercapnic ventilatory response is complex and little is known. We aimed to research the effect of acute intracerebroventricular (ICV) injection of fluoxetine on hypercapnic ventilatory response in the absence of peripheral chemoreceptor impulses and the role of 5-HT2 receptors on responses. Eighteen anesthetized albino rabbits were divided as Fluoxetine and Ketanserin groups. For ICV administration of fluoxetine and ketanserin, a cannula was placed in the left lateral ventricle by the stereotaxic method. Respiratory frequency (fR), tidal volume (V(T)) and ventilation minute volume (V(E)) were recorded in both groups. ICV fluoxetine (10.12 mmol/kg) injection during normoxia caused significant increases in V(T) and V(E) (both P < 0.01) in the fluoxetine group. When the animals were switched to hypercapnia f/min, V(T) and V(E) increased significantly. The increases in percentage values in V(T) and V(E) in Fluoxetine + Hypercapnia phase were higher than those during hypercapnia alone (P < 0.01 and P < 0.05, respectively). On blocking of 5-HT2 receptors by ketanserin (0.25 mmol/kg), the ventilatory response to Fluoxetine was abolished and the degree of increases in V(T) and V(E) in the Ketanserin + Hypercapnia phase were lower than those during hypercapnia alone (P < 0.01 and P < 0.001, respectively). We concluded that acute central fluoxetine increases normoxic ventilation and also augments the stimulatory effect of hypercapnia on respiratory neuronal network by 5-HT2 receptors in the absence of peripheral chemoreceptor impulses.

The effects of chronic long-term intermittent hypobaric hypoxia on blood rheology parameters.

The effect of chronic long-term intermittent hypobaric hypoxia (CLTIHH) on blood rheology is not completely investigated. We designed this study to determine the effect of CLTIHH on blood rheology parameters. Present study was performed in 16 male Spraque-Dawley rats that divided into CLTIHH and Control groups. To obtain CLTIHH, rats were placed in a hypobaric chamber (430 mmHg; 5 hours/day, 5 days/week, 5 weeks). The control rats stayed in the same environment as the CLTIHH rats but they breathed room air. In the blood samples aspirated from the heart, hematocrit, whole blood viscosity, plasma viscosity, plasma fibrinogen concentration, erythrocyte rigidity index and oxygen delivery index were determined. The whole blood viscosity, plasma viscosity, hematocrit and fibrinogen concentration values in the CLTIHH group were found to be higher than those of the control group. However, no significant difference was found in erythrocyte rigidity index and oxygen delivery index between the groups. Our results suggested that CLTIHH elevated whole blood viscosity by increasing plasma viscosity, fibrinogen concentration and hematocrit value without effecting the erythrocyte deformability. Hence, CLTIHH that may occur in intermittent high altitude exposure and some severe obstructive sleep apnea (OSA) patients may be responsible for hemorheologic changes in those subjects.

Intracerebroventricular serotonin reduces the degree of acute hypoxic ventilatory depression in peripherally chemodenervated rabbits.

Hypoxia causes changes in the rate of synthesis or release of neurotransmitters in the brain. The accumulation of serotonin (5-HT) in the central nervous system might cause hypoxic respiratory depression. In the present study, we aimed to examine the role of central 5-HT on normoxic and acute hypoxic ventilatory depression (AHVD) in peripheral chemoreceptors denervated rabbits. All experiments were performed in peripherally chemodenervated rabbits anesthetized with intravenous injection of urethane (400 mg/kg) and alpha-chloralose (40 mg/kg). For intracerebroventricular (ICV) administration of 5-HT (20 microg/kg) and ketanserin (10 microg/kg), a cannula was placed in left lateral ventricle by stereotaxic method. Respiratory frequency (fR), tidal volume (VT), ventilation minute volume (VE) and systemic arterial bood pressure (BP) were recorded in each experimental phases and mean arterial pressure was calculated (MAP). Heart rate (HR) was also determined from the pulsation of BP. The effects of ICV serotonin and ICV ketanserin on the indicated parameters during air breathing (normoxia) and breathing of hypoxia (8% O2--92% N2) were investigated. During hypoxia, fR, VT, VE, MAP and HR decreased, and AHVD was thus obtained. ICV injection of 5-HT during normoxia caused significant increases in VT (P < 0.001) and in VE (P < 0.01). On the other hand, ICV 5-HT injection reduced the degree of AHVD in peripherally chemodenervated rabbits during hypoxia (fR; P < 0.05, VT; P < 0.05 and VE; P < 0.01). After ICV injection of ketanserin, the enhancement of 5-HT on VE was prevented during normoxia. On the breathing of hypoxic gas after ICV ketanserin, the degree of AHVD was augmented. In conclusion, our findings suggested that central 5-HT increases normoxic ventilation and reduces the degree of AHVD during hypoxia and that ICV ketanserin prevents the stimulatory effect of 5-HT on respiration and augments AHVD.

The reflex effects on the respiratory regulation of the CO2 at the different flow rate and concentration.

PURPOSE: The purpose of this study was to investigate the activation of the respiratory centers during insufflation of the larynx with CO2 at different flow rates and concentrations. MATERIALS AND METHODS: The experiments were carried out in spontaneous air breathing rabbits, anesthetized with thiopental sodium (25 mg kg(-1) i.v.). The larynx was separated from the oropharyngeal cavity and the trachea. The tidal volume (VT) and respiratory frequency (f min(-1)) were recorded from the lower tracheal cannula. The respiratory minute volume (VE) was calculated, the action potentials from the right phrenic nerve were recorded and the inspiratory (TI) and expiratory (TE) periods and the mean inspiratory flow rate (VT/TI) were calculated. The larynx was insufflated at flow rates of 500 mL min(-1) and 750 mL min(-1), with 7 and 12% CO2-Air by means of a respiratory pump. RESULTS: Insufflation of the larynx, with both gas mixtures, decreased the f and VT significantly. The TI and TE were found to increase significantly due to the decreasing in f. There was a significant decrease in VT/TI ratio. Following bilateral midcervical vagotomy, on the passing of both gas mixtures, significant decreases were observed in the VT, and the responses of f, TI and TE were abolished. After cutting the superior laryngeal nerve, the responses of the VT to both gas mixtures were abolished. CONCLUSION: In conclusion, the results of this study purpose that the stimulation of the laryngeal mechanoreceptors by the effect of hypercapnia decreases the activation of the respiratory center.

Respiratory alterations due to chronic long-term intermittent hypobaric hypoxia in rabbits: importance of peripheral chemoreceptors.

BACKGROUND: None of the studies carried out so far investigated the effect of denervation of peripheral chemoreceptors on basal ventilation and respiratory responses to acute hypoxia in subjects exposed to chronic long-term intermittent hypobaric hypoxia (CLTIHH). We aimed to research (i) the effect of CLTIHH (430 mmHg, 5 h/day, 5 days/week, 5 weeks) on basal ventilation and respiratory responses to hypoxia and (ii) the effects of CLTIHH on central respiratory mechanisms after peripheral chemodenervation. METHODS: Sixteen adult albino rabbits were divided into two groups: CLTIHH (n = 8) and control (n = 8). The tidal volume (V(T)) and respiratory frequency (f/min) were initially recorded in both groups and respiratory minute volume (V(E)) was calculated. PaO(2), PaCO(2), and pHa values were determined. RESULTS: The initial values of f/min and V(E) in CLTIHH group were significantly higher than that of control group. After exposure to hypoxic gas mixture (8% O(2)-92% N(2)), the elevations in f/min, V(T), and V(E) in CLTIHH group were significantly higher than those of control group. After denervation of peripheral chemoreceptors, the decrease in V(E) in CLTIHH group was found to be significantly less than that of control group. When the animals in control group were allowed to breathe hypoxic gas mixture, f/min, V(T,) and V(E) decreased significantly and hypoxic depression was obtained. In contrast, hypoxic depression did not occur in the CLTIHH group. CONCLUSIONS: Our results suggested that CLTIHH increases the basal ventilation and hypoxic respiratory responses and that enhanced ventilatory responses were due not only to the augmentation of peripheral chemoreceptor activity but also to the augmentation of central respiratory activity.

Potential effects of L-NAME on alcohol-induced oxidative stress.

AIM: Nitric oxide (NO) is a highly reactive oxidant synthesized from L-arginine by nitric oxide synthase (NOS). NO may cause injury through the generation of potent radicals. Nw- nitro-L-arginine methyl ester (L-NAME) is a non-selective inhibitor of NOS. We aimed to evaluate whether L-NAME treatment had protective effects against oxidative stress in rats intragastrically fed with ethanol during a 4 wk-period. METHODS: Thirty-six male Wistar rats were divided into 3 equal groups: group 1 (control group-isocaloric dextrose was given), group 2 (6 g/kg.d ethanol-induced group) and group 3 (both ethanol 6 g/kg.d and L-NAME 500 mg/L in drinking water-given group). Animals were sacrificed at the end of 4 wk-experimental period, and intracardiac blood and liver tissues were obtained. Biochemical measurements were performed both in plasma and in homogenized liver tissues. Alanine amino transferase (ALT), aspartate amino transferase (AST), malondialdehyde (MDA), NO, superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels were measured by spectrophotometry. RESULTS: ALT and AST in group 2 (62 U/L and 128 U/L, respectively) were higher than those in group 1 (24 U/L and 38 U/L) and group 3 (37 U/L and 81 U/L) (P<0.001 for both). Plasma and tissue levels of MDA in group 2 (4.66 micromol/L and 0.55 nmol/mg protein) were higher than in group 1 (2.65 micromol/L and 0.34 nmol/mg protein) and group 3 (3.43 micromol/L and 0.36 nmol/mg protein) (P<0.001 for both). Plasma and liver tissue levels of NO in group 2 (54.67 micromol/L and 586.50 nmol/mg protein) were higher than in group 1 (34.67 micromol/L and 435.33 nmol/mg protein) and group 3 (27.50 micromol/L and 412.75 nmol/mg protein) (P<0.001 for both). Plasma and liver tissue SOD activities in group 2 (15.25 U/mL and 5.38 U/ mg protein, respectively) were lower than in group 1 (20.00 U/mL and 8.13 U/ mg protein) and group 3 (19.00 U/mL and 6.93 U/ mg protein) (P<0.001 for both). Plasma and liver tissue CAT activities in group 2 (145 U/mL and 37 U/ mg protein, respectively) were lower than in group 1 (176 U/mL and 73 U/mg protein) and group 3 (167 U/mL and 61 U/mg protein) (P<0.001 for both). Meanwhile, erythrocytes and liver tissue levels of GSH in group 2 (4.12 mg/g Hb and 5.38 nmol/mg protein, respectively) were lower than in group 1 (5.52 mg/g Hb and 4.49 nmol/mg protein) and group 3 (5.64 mg/g Hb and 4.18 nmol/mg protein) (P<0.001 for both). CONCLUSION: Our findings show that L-NAME may produce a restorative effect on ethanol-induced liver damage via decreasing oxidative stress and increasing antioxidant status.

The role of peripheral chemoreceptor activity on the respiratory responses to hypoxia and hypercapnia in anaesthetised rabbits with induced hypothyroidism.

The purpose of this study was to investigate the role of peripheral chemoreceptor activity on the hypoxic and hypercapnic ventilatory drives in rabbits with induced hypothyroidism. Experiments were carried out in control and hypothyroid rabbits. Hypothyroidism was induced by an administration of an iodide-blocker, methimazole in food (75 mg/100 g food) for ten weeks. At the end of the tenth week, triiodothyronine (T3) and thyroxine (T4) levels significantly decreased (P<0.001) while thyroid stimulating hormone (TSH) increased (P<0.001). Tidal volume (VT), respiratory frequency (f/min), ventilation minute volume (VE) and systemic arterial blood pressure (BP) were recorded during the breathing of the normoxic, hypoxic (8% O2-92% N2) and hypercapnic (6% CO2-Air) gas mixtures, in the anaesthetised rabbits of both groups. At the end of each experimental phase, PaO2, PaCO2, and pHa were measured. The same experimental procedure was repeated after peripheral chemoreceptor denervation in both groups. VT significantly decreased in some of the rabbits with hypothyroidism during the breathing of the hypoxic gas mixture (nonresponsive subgroup) (P<0.05). After chemodenervation, a decrease in VT was observed in this nonresponsive subgroup during normoxia (P<0.05). The percent decrease in VT in nonresponsive subgroup of hypothyroid rabbits after chemodenervation was lower than that of the chemodenervated control animals (P<0.01). When these rabbits with hypothyroidism were allowed to breath the hypercapnic gas mixtures, increases in VT and VE were not significant. In conclusion, although there is a decrease in peripheral chemoreceptor activity in hypothyroidism, it does not seem to be the only cause of decrease in ventilatory drive during hypoxia and hypercapnia.

The effects of vagal stimulation on laryngeal vascular resistance and intraluminal pressure in the dog.

In anaesthetized dogs (sodium pentobarbitone 30 mg/kg, i.v.) laryngeal vascular resistance was measured by unilateral perfusion at constant flow of the branch of the cranial superior thyroid artery that supplies the larynx. Arterial perfusion was at constant flow and inflow pressure was divided by flow to give laryngeal vascular resistance (R(LV)). Intraluminal laryngeal pressure (P(L)) and systemic arterial blood pressure (BP) were also measured. Stimulation (20 V, 20 Hz, 0.2 milliseconds) of the central end of cervical vagus caused an increase in R(LV) (+22.9+/-6.1%) and a decrease in P(L) (-12.1+/-4.4%). Stimulation (10 V, 10 Hz, 0.2 milliseconds) of the central end of the recurrent laryngeal nerve (RLN) reduced RLV (-3.4+/-0.8%) and P(L) (-7.5+/-4.1%). Stimulation of the peripheral end of the RLN decreased R(LV) (-7.1+/-1.9%) and increased PL (+21.6+/-7.7%). Stimulation of the central end of the superior laryngeal nerve (SLN) increased R(LV) (+17.9+/-3.2%) and P(L) (+59.8+/-2.7%), whereas stimulation of the peripheral end of the SLN decreased R(LV) (-4.8+/-1.6%) and P(L) (-4.1+/-2.4%). After treatment with alpha-adrenoreceptor antagonist phentolamine (0.5 mg/kg, i.v.), stimulation of the central end of cervical vagus nerve reduced R(LV) by 25% and decreased BP. Phentolamine caused a decrease in BP and reduced the magnitude of increase in R(LV) in response to stimulation of central end of SLN. After atropine sulphate (0.5-2.0 mg/kg, i.v.), the stimulation of both central and peripheral ends of RLN reduced R(LV). The decrease in R(LV) during stimulation of peripheral end of SLN was reduced by atropine. Thereafter, pancuronium bromide (0.06-0.1 mg/kg, i.v.) was given and dogs were artifically ventilated. After paralyzed, stimulation of the central end of the SLN decreased R(LV) (+26.0+/-4.5%) but produced no change in P(L), It is concluded that parasympathetic motor fibers in the RLN and SLN are effective for the laryngeal vascularity and non-adrenergic system may be responsible for laryngeal vasoconstriction. laryngeal vasculature; vagal stimulation; phentolamine; atropine

Hypoxic initiation of pulmonary hypertension is mediated by serotonin secretion from neuroepithelial bodies in chemodenervated dogs.

The purpose of this study was to investigate the stimulatory effect of hypoxia on the secretion of serotonin by neuroepithelial bodies (NEB) as well as to determine the relation between its level and changes in pulmonary arterial pressure (PAP) and also to determinate the effect of serotonin antagonists (pizotifen and methysergide) on the responses of pulmonary and systemic arterial pressures. The experiments were carried out in peripheral chemoreceptor-denervated dogs anesthetized with Na penthabarbital (30 mg/kg i.v.). On the breathing of normoxic and hypoxic (7% O2-93% N2) gas mixtures and on the injection of KCN (80 microg/kg i.v.), PAP, systemic arterial blood pressure (BP), tidal volume (VT), respiratory frequency (f/min), ventilation minute volume (VE) were determined. Also PAP and BP were recorded before and after the injection of pizotifen (0.5 mg/kg i.v.) and methysergide (1 mg/kg i.v.) during normoxic or hypoxic gas mixture breathing. At the end of each experimantal phase, serotonin level, PaO2, PaCO2 and pHa values in blood samples obtained from left ventricle and femoral artery were determined. On the breathing of the hypoxic gas mixture of the chemodenervated dogs, VT, VE and BP significantly decreased (P < 0.001, P < 0.001, P < 0.01). The mean value of PAP and serotonin levels (ventricular and femoral) were found significantly increased when compared with the corresponding normoxic values (P < 0.001, P < 0.05). On the other hand, injection of KCN produced no significant changes in PAP, serotonin levels, BP and respiratory parameters. After the injection of pizotifen, PAP was significantly increased in hypoxia (P < 0.01). After the injection of methysergide, the response of PAP was completely abolished during the breathing of hypoxic gas mixture. The finding of the abolition of response of PAP to hypoxia after the injection of methysergide indicates that serotonin release from NEB may be responsible for the elevation of PAP in hypoxic hypoxia.