مجله فیزیولوژی و فارماکولوژی ایران
پیاپی 2 (تابستان 1396)

Hormonal disturbances in critical periods of fetal development can lead to changes in the physiology or morphology of an organ. The aim of the present study was to examine reproductive system in female rats exposed to a single dose of testosterone in one of their last fetal development days.

Testosterone (20 mg in 1 ml solvent) was subcutaneously injected to pregnant rats on gestational day 20. Control group received the solvent. Body weights of female offspring were measured at birth, at days of 15, 30, 45 and 60 of age and in adulthood, ano-genital distance (AGD) was determined at days of 6, 30 and 60 of age. Hormones and morphology of reproductive system and ovary tissue were examined in these offspring in adulthood. The comparison of two groups was performed using the Independent-sam ple student t-test.

In the offspring of experimental group, AGD, clitoris length, testosterone and LH concentrations were significantly increased but estradiol and anti-Mullerian hormone concentrations were significantly decreased (p<0.05). Moreover, the number of preantral and antral follicles was increased. However, the numbers of preovulatory follicles and corpora lutea were decreased but these changes were not significant statistically.

Exposure of female fetuses to a single dose of testosterone on day 20 of development leads to appearance of some developmental changes in external reproductive system and the appearance of disturbance in hormones secretion in adulthood.

Defects in endoplasmic reticulum (ER) homeostasis are common in different diseases, such as diabetes. It is now well established that ion channels of ER membrane have a critical role in ER luminal homeostasis. Our previous studies showed the presence of a 346 pS potassium channel in ER. Therefore, in this study, we examined and compared the activities of this channel in control and diabetic rats using single-channel recording techniques.

Diabetes mellitus was established in male Wistar rats 2 weeks after single injection of streptozotocin 45 mg/kg, i.p. Ion channel of rough endoplasmic reticulum of diabetic hepatocytes was incorporated into the bilayer lipid membrane and the characterization of K+ channel was then evaluated.

Based on our previous data, endoplasmic reticulum membrane has a potassium channel with a main conductance of 346 pS, which is sensitive to 4-Aminopyridine and voltage-insensitive at ± 30 mV. In the present study, it was demonstrated that the channel conductance was decreased to 259 pS in diabetes mellitus. Interestingly, the channel Po-voltage relation demonstrated that channel Po significantly lower in diabetic rats compared to normal rats at different voltages.

Our data showed that the biophysical properties of potassium channel were significantly altered under diabetic condition. We propose that the hepatocyte ER potassium channels are involved in diabetes pathology, and it may be considered as a target for therapeutic plans.

Central Nitrergic and GABAergic play several roles in central nervous system. Release and modulation of some neurotransmitters can be affected by nitric oxide. This study was performed to find the effect of intracerebroventricular (ICV) injection of L-arginine as a donor of nitric oxide on the relative mRNA expression of GAD1 and GAD2 in the brain stem of neonatal chicken.

Fifteen Leghorn neonatal chicks were divided into a control group (no injection), sham group (ICV injection of Evans-Blue 0.1%) and test group (ICV injection of 800 nM L-arginine.

ICV injection of L-arginine significantly decreased the relative mRNA expression of GAD1 and GAD2 (p < 0.05). The relative mRNA expression of these two genes in sham group and control group was similar (p > 0.05).

It seems that the effect of nitric oxide on GABAergic system in some physiological behaviors such as food intake is mediated by diminishing of the relative mRNA expression of GAD1 and GAD2.

In this study, effects of digoxin on the cardiac electrophysiology and mechanical properties were examined in a rat model of heart failure induced by doxorubicin.

In order to induce heart failure, doxorubicin 5 mg/kg was injected to rat, i.p., once per week for 3 weeks. Heart failure was confirmed after 5 weeks, by measuring electrical, mechanical and histological changes in 12 isolated hearts. Isolated Langendorff perfused hearts were then treated with digoxin (0.1-80 µM) during a 60 min period and functional outcomes were assessed.

Effect of digoxin on the heart was biphasic. In concentrations below 80 µM (the first phase) digoxin significantly increased LVDP (left ventricular diastolic pressure) and RPP (heart rate × LVDP) .LVDP and RPP were also increased at the concentrations higher than 80 µM (the second phase). However, coronary flow, heart rate, left ventricular developed pressure and cardiac output were significantly decreased in the second phase.

Effects of digoxin on doxorubicin cardiomyopathy are biphasic. Electrical and functional changes in the second phase can be considered as an indicator of digoxin cardiotoxicity.

Aerobic exercise breaks down body fat and free fatty acids (FFA) and therefore, plays an important role in cardiovascular health. On the other hand, sauna bath increases FFA levels. The purpose of this study was to compare the effect of a single bout of aerobic activity and sauna bath on blood FFA levels.

Fifteen male college soccer players (age: 24.5 ± 2.5 years, weight: 72 ± 8 kg and Vo2max = 47 ml/kg/min) voluntarily participated in this study. Research protocols performed in two phases. In the first phase, subjects were exposed for 20 min to a sauna bath with 80 °C temperature. Two weeks later (the second phase), the same subjects ran on the treadmill for 20 min till their heart rate reach 120-135 beat/min. Systolic and diastolic pressure, heart rate, and body temperature were measured before and immediately after the phases. Moreover, in order to measure FFA, blood samples were collected before and immediately after the phases. FFA was measured by ELISA method.

Sauna bath significantly increased systolic pressure but decreased diastolic pressure (p < 0.01). Running on treadmill significantly increased both systolic and diastolic pressure (p < 0.01). The changes in systolic and diastolic pressures induced by sauna bath had significant difference with the changes induced by running on treadmill (p < 0.01). Both sauna bath and aerobic activity significantly increased FFA (p < 0.01). However, there was no significant difference between sauna bath and aerobic activity in the increase in FFA (p > 0.05).

Both single bout aerobic activity and sauna bath release FFA into the blood. Since there is no physical activity in sauna bath, FFA released by sauna bath probably go back to the lipid tissue and store.

Arsenic trioxide (ATO) is used in treatment of APL. One of the major side effects of this drug is liver toxicity. So, introduction of an animal model for this toxic effect could be useful to evaluate hepato-protective compounds. As different hepatotoxic doses of arsenic have been reported in the literature, in this study we decided to develop a model of liver toxicity based on the protocol of ATO therapy in APL patients.

Considering the protocol of ATO therapy in APL patients (0.14 mg/day for 21 days) and FDA-suggested formula for dose translation between humans and animals, dose 1.7 mg/kg/day was used. To achieve the best time to take ATO administered without causing mortality, ATO was administered for 10 and 21 days to the male mice. At the end of the treatment period, liver tissue samples were dissected and then homogenized in physiologic buffer. The oxidative stress parameters including catalase and superoxide dismutase activity, lipid peroxidation and antioxidant capacity of the samples were determined using standard protocols. Damage to the liver tissue was determined by histopathological studies.

Histopathological examinations indicated severe damage to the liver in the 21-day treated period. The damage was accompanied with significant increase in the lipid peroxidation (p < 0.05), catalase activity (p < 0.05), and superoxide dismutase activity (p < 0.01) in the ATO treated mice for 21days.

Treatment of mice with ATO 1.7 mg/kg for 21 days could resemble ATO-induced hepatotoxicty in human.

Intra-hypothalamic neural pathways including neuropeptide Y (NPY), opioids and kisspeptin are among the most important regulators of reproductive function. Morphine decreases NPY and kisspeptin (Kiss1) gene expression, while kisspeptin or naloxone increases NPY gene expressions. In the present study the role of kisspeptin/GPR54 pathway was investigated in mediating morphine's effects on hypothalamic NPY gene expression in male rats.

Forty five male Wistar rats weighing 230-250 g in 9 groups (in each group n = 5) received saline, morphine (5 mg/kg), naloxone (2 mg/kg), kisspeptin (1nM), peptide 234 (1 nM) or co-injection of naloxone/morphine, kisspeptin/morphine, kisspeptin/naloxone, and morphine/peptide234. Naloxone and morphine were injected subcutaneously, while kisspeptin and peptide 234 were injected into third cerebral ventricle.  The hypothalamus of the animals was removed and relative NPY mRNA levels measured by RT-PCR.

Morphine significantly decreased NPY gene expression, while kisspeptin significantly increased the expression. NPY gene expression was significantly increased by kisspeptin/morphine compared to saline. However, the expression was significantly decreased by kisspeptin/morphine compared to kisspeptin alone. The injection of kisspeptin/naloxone increased NPY gene expression compared to saline, naloxone or kisspeptin alone. This increase was statistically significant compared to saline or naloxone groups. Morphine/peptide234 decreased NPY gene expression compared to saline or morphine but the decrease was only statistically significant compared to saline.

It seems that in addition kisspeptin/GPR54 pathway, other intra-hypothalamic neural pathways are also involved in the inhibitory effects of morphine on NPY neurons activity.

Curcumin, the major compound of turmeric of the ginger, is known to possess a wide range of therapeutic and pharmacological properties but its application is limited due to low bioavailability and water solubility. The recent achievements of nanotechnology provide a novel approach in treatment of drug abuse and addiction. This study was conducted to investigate the effects of dendrosomal nano-curcumin administration on morphine dependence in rats by self-administration technique.

Male rats (250-300 g) were anaesthetized. Then, their right jugular vein was catheterized.   After recovery period, the animals were placed in the self-administration apparatus for 2 hours daily for 12 days. Animals received 0.1 ml of saline or saline containing 5 mg/ml of morphine, by infusion pump for 10 sec. Half an hour before placing in apparatus, dendrosomal nano-curcumin 10 mg/kg was injected i.p., and its effect on self-administration of morphine was assessed.

Morphine induced dependence and significantly increased the number of active lever in comparison to passive lever in morphine group. Significant changes were also observed in active levers between saline and morphine groups. Though, the number of active lever pressing in dendrosomal nano-curcumin treated group was significantly
(p < 0.05) reduced in comparison with the morphine group.

Dendrosomal nano-curcumin inhibits the reward system and prevents the reinforcing effects of morphine.