Physiology and Pharmacology
Volume:18 Issue: 2, 2014

Cardiovascular diseases are still the main cause of mortality around the world. Therefore, it is essential to develop practical means to reduce their burden. A wealth of evidence supports the role of physical exercise in attenuating many of the risk factors of cardiovascular diseases. Moreover, endurance training warrants protection against myocardial infarction. Exercise, even if performed only in a few days, can protect the heart against ischemia-reperfusion (IR) injury, and this protection will be even more in longer exercises. It is yet to be clarified how exercise maneuvers provide protection against IR. However, it is suggested that some molecular and cellular mechanisms in addition to metabolic and hormonal alterations are seemingly involved in exercise-induced cardioprotection (EICP), such as increased capacity of antioxidant system, higher expression of heat shock proteins, improvement in ATP-sensitive potassium channels, change in nitric oxide production, and adaptive cardiac mitochondrial modulations. This paper discusses the current data on molecular and cellular mechanisms of EICP. Understanding the molecular basis of EICP against IR injury will provide us with the required knowledge for development of preventive and therapeutic approaches. In addition, exercise characteristics leading to more pronounced cardioprotection will be concisely addressed.

Resveratrol (3,5,4-trihydroxystilbene) a non-flavonoid polyphenol found in some plants like grapes, peanuts and pomegranates, possesses a wide range of biological effects. Evidence indicates that resveratrol has beneficial effects on nervous system to induce neuroprotection. However, the cellular mechanisms of the effects are not fully determined. In the present study, the cellular actions of resveratrol on intrinsic electrophysiological properties of the rat hippocampal CA1 pyramidal neurons were examined. The spontaneous and evoked firing properties of CA1 pyramidal neurons in adult rats exposed to resveratrol (100 µM) were examined using whole cell patch clamp recording under current clamp condition and the results were compared with control and vehicle treated groups. Treatment with resveratrol caused changes in neuronal firing characteristics. Application of resveratrol shifted the resting membrane potential (RMP) toward hyperpolarizing voltage (from -58.62±0.89 mV in control to -67.06±0.89 mV after resveratrol). The after hyperpolarization potential (AHP) amplitude was significantly (P < 0.001) increased following extracellular application of resveratrol. In addition, resveratrol treatment caused changes in evoked responses of pyramidal neurons. Its treatment induced a significant (P<0.05) increase in the peak amplitude of action potential in response to 100-300pA depolarizing current pulses. Furthermore, resveratrol-treated neurons displayed a significantly (P<0.05) increased time to peak in response to 400 and 500 pA depolarizing currents, when compared with either control or vehicle-treated groups. In addition, rise time to half-amplitude, rise tau and decay tau of action potential were significantly (P<0.01, P<0.01 and P<0.01, respectively) increased following resveratrol application. Resveratrol treatment changes the action potential parameters, hyperpolarizes the RMP and reduces the neuronal excitability and probably thereby may induce neuroprotective effects.

Studies support the idea that low levels of vitamin D are associated with a higher risk of heart disease. Losartan has also been prescribed as a drug commonly used for treating hypertension. The aim of the current study was to investigate the effects of 1,25-dihydroxyvitamin D in combination with a non-hypotensive dose of losartan on myocardial infarct size, reperfusion-induced arrhythmia and cardiac expression of survival factors in the ischemicreperfused rat heart. Male rats were randomly divided into untreated ischemia-reperfused rats (IR group) and groups pretreated with losartan (Los+IR) or vitamin D3 (VitD+IR) or both of them (Los+VitD+IR). Animals were subjected to 30 min of left coronary artery occlusion followed by 120 min of reperfusion. Infarct size measurement was performed using tetrazolium chloride. Incidence of arrhythmia was analysed according to Lambeth convention. Gene expression was evaluated by real time RT-PCR technique. In VitD+IR and Los+IR groups the infarct size did not differ significantly. In Los+VitD+IR group, the infarct size was decreased by 21.4±7.3% (P<0.001 vs. IR, P<0.05 vs. VitD+IR, P<0.01 vs. Los+IR). The number of ventricular ectopic beats was 201±32 beats in Los+VitD+IR group (P<0.001 vs. IR, P<0.01 vs. VitD+IR, P<0.05 vs Los+IR). The increase of thioredoxin-1 and catalase transcription levels was not significant in Los+IR and VitD+IR groups, however, in Los+VitD+IR group the mRNA levels of these survival factors were markedly increased (P<0.001 vs IR). Co-administration of a non-hypotensive dose of losartan and vitamin D3 protects the heart against ischemia-reperfusion injury accompanied by an increase in transcription of prosurvival factors.

Cancer, a fatal disease, is the second leading cause of death reason exceeded only by cardiovascular disease. Breast cancer is common well known cancers in woman and is the second leading cause of death after lung cancer. In recent years researchers have focused on diet based on herbal medicine for the prevention and treatment of certain types of cancer. In this study, the cytotoxic properties of grape (Rishbaba) seed extract on MCF-7 human breast cancer cells were determined using MTT assay. Doxorubicin, an anti-cancer control drug, was used with the extract in combination therapy. The data showed that incubation of cells with grape extract significantly reduced cell viability. Furthermore, concomitant treatment of cells with extract and anti-cancer drug produced a significant cytotoxic effect as compared to extract or drugs alone. Seeded grapes (vs seedless forms) probably have beneficial effects on the prevention and treatments of human breast cancer. In addition, their combination with chemotherapeutic agent doxorubicin may effectively induce cell death and could be be a potent modality to treat this type of cancer with reduced side effects.

The aim of this study was to investigate the effect of angiotensin II (Ang II) and losartan injections into paraventricular nucleus (PVN) on renal ischemia-reperfusion injury. After right nephrectomy in male rats, a cannula was inserted into the right PVN. One week later, renal ischemia-reperfusion (IR) injury was induced by clamping the left renal artery for 45 min, and then the kidney was reperfused for 24 h. An Ang II AT1 receptor antagonist, losartan (0.3 μg) was injected into the PVN 20 minutes before the induction of ischemia, followed by 3 ng of Ang II after 10 minutes. Blood, urine and kidney samples in addition to the brain area containing the PVN were collected to evaluate different indices. Renal sympathetic nerve activity (RSNA) was recorded in all groups. Angiotensin II injection into PVN caused significant increases in renal functional (plasma creatinine and BUN as well as urinary NAG activity) and histological indices in comparison to IR group (p<0.05). Losartan injection before Ang II into PVN significantly reduced these markers (p<0.05). In addition, angiotensin II caused significant increases in oxidative stress in PVN (higher MDA and lower SOD) and RSNA compared to the IR group (p<0.05). Losartan improved these markers significantly (p<0.05). This study showed that Ang II injection into PVN increases oxidative stress in PVN and renal sympathetic nerve activity through AT1 receptors and exaggerates renal ischemia-reperfusion injury.

In this study the antidepressant effect of a new morpholino betalactam composition, 1-(3- morpholinopropyl)-4-(naphthalene-2-yl)-3-phenoxyazetidin-2-one (EB9) administered at three doses, was investigated in an animal model of depression. The CNS stimulant, muscle coordination and toxic effects of this compound were also tested. Morpholino betalactam at 10, 15 and 20 mg/kg, imipramine at 5, 10 and 20 mg/kg as a positive control and two solvents, distilled water and DMSO as negative controls were administered to white male mice. After a forced swimming pretest, the mice received two i.p. injections, the first one immediately after, and the second one five hours after the pretest. The duration of immobility and climbing behaviors, at 1 and 23.5 hours after the first injection were recorded as acute and subacute effects, respectively. For the evaluation of muscle coordination, rotarod test was used. Total activity test was done to test the CNS stimulant effect. Toxicity of the compound at the doses of 300-400 mg/kg was also studied and its LD50 was calculated. The new morpholino betalactam compound significantly reduced the immobility time and increased the climbing time in the forced swimming test, without showing any significant effect on the total activity and rotarod test results. At the dose of 400 mg/kg, the compound caused liver damage and its LD50 was estimated to be 325 mg/kg. Morpholino betalactam may have antidepressant effect in human at doses which are not toxic.

Coenzyme Q10 is a powerful antioxidant that has the ability to reduce the damage caused by oxidative stress and is predominantly found in the inner mitochondrial membrane. This study was conducted to determine the effect of coenzyme Q10 on neuropathic pain in an animal model of spinal cord injury. In order to induce neuropathic pain, thoracic segments of the spinal cord (T6-T8) were compressed by homeostatic clip. Two doses of coenzyme Q10 (50 and 100 μg) in a volume of 10 μl was injected intrathecally. Behavioural tests were conducted in the third week after injury. Allodynia and hyperalgesia symptoms were assessed using analgesiometer, von Frey filaments, acetone and plantar tests. Behavioral assessments were performed before and 15 min after the injections. Data were analyzed using SPSS 20.0 statistical software. Coenzyme Q10 at the dose of 100 μg significantly attenuated the thermal hyperalgesia compared to vehicle and also compared to the pre-injection time (P< 0.05). In addition, administration of 100 μg of Q10 significantly reduced mechanical allodynia compared to the vehicle (P< 0.05). However, this reduction was not significant compared to the pre-injection time. Injection of coenzyme Q10 in the subarachnoid space alleviates some symptoms of neuropathic pain following spinal cord compression injury.

17β-Estradiol is a neuroactive steroid and its pain modulatory role has been well studied previously. 17β-Estradiol modulates nociception by binding to its receptors and also by allosteric interaction with other membrane - bound receptors such as glutamate and GABAA receptors. Paragigantocellularis lateralis (LPGi) is also involved in pain modulation and perception, in addition to its well-known autonomic functions such as regulation of circulation. In order to study the effect of intra-LPGi injection of 17β-estradiol on both acute and persistent pain, 50 μl of 4% formalin was injected into the male rats’ hind paw, then fo rmalin-induced paw jerking behaviour was recorded for 60 min. The results of this study indicated that intra-LPGi injection of 17β-estradiol attenuated the second phase, but not the acute phase of formalin induced pain (P< 0.001). The estrogen receptor antagonist (ICI182,780) counteracted 17β-estradiol’s effect, but could not reverse the antinociceptive effect of 17β -estradiol to its basic level. It may be concluded that a part of the analgesic effect of 17β-estradiol in formalin induced inflammatory pain is mediated by intracellular estrogen receptors; the other part of this effect is possibly mediated through allosteric interactions with other membrane-bound receptors such as glutamate and GABAA receptors.

Ecstasy is an amphetamine derivative, which its use has been consistently increasing over the past years. Ecstasy interacts with the glutamatergic system and it is known that glutamate receptors have a key role in learning and memory. The aim of this study was to investigate the interaction of ecstasy and glutamatergic system on learning and memory. Fifty-six male Wistar rats weighting (250±50 g) were randomly divided into 8 groups, which received injections for 7 consecutive days. Spatial memory was assessed using Morris Water Maze, performed for 5 consecutive days after the treatment period. The swim speed showed no significant difference among the groups. The mean latency time in finding the hidden platform was increased during test trial in the ecstasy, MK-801 (a glutamate antagonist) and ecstasy + MK-801 groups compared to the control (P < 0.05), while it was decreased during test trial in ecstasy, NMDA and ecstasy + NMDA groups compared to the control (P< 0.05). The mean latency distance in finding the hidden platform was increased during test trial in ecstasy, MK-801 and ecstasy + MK-801 groups compared to the control (P < 0.05), and decreased during test trial in ecstasy, NMDA and ecstasy + NMDA groups compared to the control (P<0.05). Results showed that ecstasy with NMDA treatment attenuated the reduced spatial memory by ecstasy. Ecstasy with MK-801 potentiated the reduced spatial memory by ecstasy.

Sub-chronic swim stress is known to induce a prolonged hyperalgesia, which is mediated through NMDA and opioid systems. Nitric oxide is a soluble gas, which acts as a retrograde messenger that modulates the release of mentioned neurotransmitters. It is also involved in nociception and memory. The aim of this study was to evaluate the role of NO pathway in nociception and memory disruption induced by sub-chronic swim stress. Three sessions forced swimming stress protocols were applied to rats. Before each swimming session, pretreatment with L-NAME (10 mg/kg, i.p.), L-Arginine (10 mg/kg, i.p.) or saline was made. Passive avoidance learning, nociception and anxiety-like behavior were evaluated 24 hours after last swim stress session. Results showed that step through latency was decreased after swim stress and it could be inhibited by pretreatment with L-NAME. Swim stress increased anxiety-like behavior in the open field test, which could be inhibited by pretreatment with L-NAME and L-Arginine. Reduced thermal threshold was observed in the nociceptive measurement after swim stress. Pretreatment with L-NAME could reverse this reduced threshold. The results of this study indicate that sub-chronic swim stress impairs nociception and passive avoidance learning. It seems that NO pathway have a modulatory role in these alterations.

Previous studies have shown that zinc deficiency and castration could increase anxiety, while administration of zinc or testosterone has anxiolytic effects. This study examined the effect of zinc chloride administration on anxiety in gonadectomized male rats. For this purpose, adult male Wistar rats (weighing 200-250 g) were castrated. One month after surgery, different doses of zinc chloride (0, 5, 7.5 and 10 mg/kg; IP) were administered 30 min before the elevated plus maze test. Time spent and the number of entries in open arms was recorded as measures of anxiety and the number of closed arm entries recorded as locomotor activity. 1) Zinc chloride significantly decreased the time spent and the number of entries in the open arms in gonadectomized rats compared to the control group. 2) Zinc chloride administration could not decrease anxiety, even in the testosterone pretreated gonadectomized male rats. Our findings showed that zinc significantly increased anxiety in gonadectomized rats. Since our previous findings showed that zinc chloride decreased the anxiety level in intact male rats, it seems that zinc chloride effects on anxiety would change in relation to the presence or absence of the gonads and it might interact with androgenic system through an effect on the testis.