Bisphenol A decreases the spontaneous contractions of rat uterus in vitro through a nitrergic mechanism.

BACKGROUND: Bisphenol A (BPA), a chemical used in the manufacture of plastics, has toxic effects on various systems of the human body including the reproductive system. BPA possesses estrogenic activity and is implicated in altering oogenesis, ovulation, and fertility. In addition to ovulatory changes, uterine contractility is an important factor for fertility. However, the effects of BPA on myometrial contractions are not known. Therefore, we examined the effect of BPA on rat uterine contractions. METHODS: The uterus was isolated from adult rats showing estrous phase, and spontaneous in vitro contractions were recorded (35±1 °C). The effect of cumulative concentrations of BPA was determined. Further, the involvement of nitric oxide (NO) and guanylyl cyclase (GC) for the BPA-induced changes on uterine contractility was evaluated using the NO synthase inhibitor (L-NAME) or GC inhibitor (methylene blue). RESULTS: BPA decreased the amplitude and frequency of spontaneous uterine contractions in a concentration-dependent manner. A decrease of 50% occurred at 1 and 3 µM for amplitude and frequency, respectively. L-NAME (N-ω-nitro-l-arginine methyl ester) blocked the BPA-induced decrease in amplitude at all concentrations but antagonized the frequency only at the maximum concentration (10 µM). Methylene blue (a GC inhibitor) did not block the BPA-induced responses but for the frequency at 10 µM of BPA. CONCLUSIONS: The results indicate that BPA decreased the amplitude and frequency of spontaneous uterine contractions by involving the nitrergic mechanism; however, the GC mechanism is not involved in the depression.

Lignocaine augments the in-vitro uterine contractions involving NO-guanylyl cyclase dependent mechanisms.

AIMS: Lignocaine is used during intrapartum and postpartum period but there are conflicting reports regarding the effect of lignocaine on uterine contractility. Therefore, this study was undertaken to delineate the effect of lignocaine on uterine contractility and the underlying mechanisms. MAIN METHODS: The in vitro contractions were recorded from the uterine segments obtained from adult rats (in estrous phase) and also from human myometrial tissue. Effect of lignocaine on spontaneous uterine contractions was recorded in the absence or presence of antagonists. Effect of sodium nitroprusside (SNP, NO donor) on uterine contractility was assessed. The NO2- was assayed (indicator of NO activity) from the supernatant after exposing the myometrial tissue to lignocaine in the absence or the presence of L-NAME or hemoglobin. KEY FINDINGS: Lignocaine (100µM) increased the amplitude of uterine contractions by 75% with no alterations in frequency. Similar magnitude of increase was seen with human myometrial tissue also. The spontaneous activities were absent in Ca2+-free or in nifedipine (10µM) containing medium. Heparin (IP3 blocker, 10IU/ml), but not the indomethacin (10µM) blocked the lignocaine-induced augmentation. L-NAME (NOS inhibitor, 10µM) or methylene blue (guanylyl cyclase inhibitor, 100µM) partially blocked the lignocaine-induced augmentation. SNP (30µM) increased the amplitude of spontaneous uterine contractions. Lignocaine increased the NO2- content (indicator of NO activity) of uterine tissue and the increase was blocked by L-NAME or hemoglobin. SIGNIFICANCE: Present observations indicate that lignocaine augments the amplitude of uterine contractions via Ca2+-dependent mechanisms involving NO-G cyclase-dependent mechanisms.

B1-kinin receptors modulate Mesobuthus tamulus venom-induced vasosensory reflex responses in anesthetized rats.

OBJECTIVE: Intra-arterial injection of Mesobuthus tamulus (BT) venom produces reflex vasosensory responses modulating cardiorespiratory parameters in albino rats. The present study was conducted to understand the role of kinin receptors in modulating vasosensory reflexes evoked by BT venom. MATERIALS AND METHODS: In urethane-anesthetized rats, tracheostomy was performed to keep the airway patent. The femoral artery was cannulated proximally, as well as distally, to record the blood pressure (BP) and to inject the chemicals, respectively. Electrocardiographic and respiratory excursions were recorded to compute the heart rate (HR) and respiratory rate (RR). A group of animals was pretreated with saline/kinin receptor antagonists intra-arterially (B1/B2 receptor antagonists) before the injection of venom. RESULTS: After intra-arterial injection of BT venom (1 mg/kg), there was an immediate increase in RR, which reached to 40% within 30 s, followed by a decrease of 40%. Further, there was sustained increase in RR (50%) up to 60 min. The BP started to increase at 40 s, peaking at 5 min (50%), and remained above the initial level up to 60 min. The bradycardiac response started after 5 min which peaked (50% of initial) at 25 min and remained at that level up to 60 min. In B1 receptor antagonist (des-Arg) pretreated animals, venom-induced cardiovascular responses were attenuated (by 20-25% in mean arterial pressure and HR) significantly but not in B2 receptor antagonist (Hoe-140) pretreated animals. Either of the antagonists failed to alter the RR responses. CONCLUSIONS: BT venom-induced vasosensory reflex responses modulating cardiovascular parameters are mediated via B1-kinin receptors in anesthetized rats.

Captopril augments acetylcholine-induced bronchial smooth muscle contractions in vitro via kinin-dependent mechanisms.

Angiotensin converting enzyme (ACE) inhibitors therapy is aassociated with bothersome dry cough as an adverse effect. The mechanisms underlying this adverse effect are not clear. Therefore, influence of captopril (an ACE inhibitor) on acetylcholine (ACh)-induced bronchial smooth muscle contractions was investigated. Further, the mechanisms underlying the captopril-induced changes were also explored. In vitro contractions of rat bronchial smooth muscle to cumulative concentrations of ACh were recorded before and after exposure to captopril. Further, the involvement of kinin and inositol triphosphate (IP3) pathways for captopril-induced alterations were explored. ACh produced concentration-dependent (5-500 µM) increase in bronchial smooth muscle contractions. Pre-treatment with captopril augmented the ACh-induced contractions at each concentration significantly. Pre-treatment with aprotinin (kinin synthesis inhibitor) or heparin (inositol triphosphate, IP3-inhibitor), blocked the captopril-induced augmentation of bronchial smooth muscle contractions evoked by ACh. Further, captopril-induced augmentation was absent in calcium-free medium. These results suggest that captopril sensitizes bronchial smooth muscles to ACh-induced contractions. This sensitization may be responsible for dry cough associated with captopril therapy.

Morphine blocks the Mesobuthus tamulus venom-induced augmentation of phenyldiguanide reflex and pulmonary edema in anesthetized rats.

OBJECTIVE: Pulmonary edema, a manifestation of scorpion envenomation syndrome, is attributed to cardiogenic or noncardiogenic factors. Morphine is a drug used for cardiogenic pulmonary edema and its effect on Mesobuthus tamulus (MBT) venom-induced changes is not known. Therefore, we hypothesized that morphine blocks the MBT venom-induced augmentation of phenyldiguanide (PDG) reflex and pulmonary edema. MATERIALS AND METHODS: Experiments were performed on anesthetized adult female rats. Trachea and jugular vein were cannulated, and the electrocardiographic potentials were recorded by connecting needle electrodes in limb lead II configuration. PDG (10 ΅g/kg, IV, bolus injection) responses were elicited by bolus injection initially, after saline/morphine (1 mg/kg) and after injecting MBT venom (100 µg/kg). The time-response area of the PDG-induced bradycardiac response after treatment was calculated as % of the initial PDG response area. At the end of experiments, lungs were excised for determination of pulmonary water content. RESULTS: PDG produced bradycardiac response that lasted for >60 s. MBT venom augmented the PDG reflex response by 2.5 times. In morphine pretreated group, augmentation of bradycardiac response induced by MBT venom was absent. MBT venom increased the pulmonary water content, and the increase was absent in morphine pretreated animals. CONCLUSION: The results reveal that morphine prevents the MBT venom-induced augmentation of PDG reflex response and pulmonary edema. Thus, morphine can be useful in scorpion envenomation syndrome associated with pulmonary edema.

Indomethacin Exacerbates Oleic Acid-Induced Acute Respiratory Distress Syndrome in Adult Rats.

Acute respiratory distress syndrome (ARDS) is an acute fulminant condition associated with acute lung injury and inflammation leading to hypoxemia, pulmonary edema and respiratory failure. Even though prostaglandins are inflammatory mediators, the role of prostaglandins in ARDS is still not clear. Therefore, we examined the involvement of prostaglandin in experimentally induced ARDS by using prostaglandin synthesis inhibitor, indomethacin. Experiments were conducted on anesthetized adult rats (total n=15). Cannulation of trachea, jugular vein and carotid artery was done in these rats. Recording of respiratory excursions (for respiratory frequency; RF), ECG (for heart rate; HR) and blood pressure, before and after lethal dose of oleic acid (75 µL i.v.) was done for 120 min or till death of the animals. Arterial blood sample was collected 15 min after oleic acid injection to determine PaO2/FiO2 ratio. Lungs were excised at the end of experiment for estimation of pulmonary water content. Administration of oleic acid produced progressive increase in the RF up to 45 min followed by decrease. Subsequently, the respiration stopped and all the animals died by 75 min (mean survival time = 64±8.2 min). HR and mean arterial pressure (MAP) exhibited an immediate decrease followed by an increase up to 45 min. Thereafter, the HR and MAP progressively decreased. PaO2/FiO2 ratio in this group was 182±2.6 mm Hg and pulmonary water content was significantly greater than saline control group. However in indomethacin pretreated rats, injection of oleic acid produced instantaneous decrease in RF and all the animals died within 10 min (mean survival time = 6.6±1.07 min). HR and MAP followed the same pattern as seen with RF. Pulmonary water content in indomethacin pretreated animals was also significantly greater than control group. These observations indicate that indomethacin exacerbates the OA-induced ARDS. Thus, prostaglandins play an important role in the pathophysiology of OA-induced ARDS.

Toxic Chemical from Plastics Attenuates Phenylbiguanide-induced Cardio-respiratory Reflexes in Anaesthetized Rats.

Bisphenol A (BPA) attenuated phenylbiguanide (PBG)-induced cardio-respiratory reflexes involving decreased vagal afferent activity. BPA leaches out from plastics thus it is expected that chronic exposure to plastic boiled (PBW) water will also produce similar changes. Therefore, the present study was undertaken to evaluate the effects of chronic ingestion of PBW on PBG evoked reflexes and were compared with BPA. Adult female rats were ingested BPA containing pellets (2 µg/kg body weight)/PBW/tap water (ad libitum) for 30 days. On day 30, the animals were anaesthetized and BP, ECG and respiratory excursions were recorded. Further, PBG was injected intravenously to evoke cardio-respiratory reflexes and at the end lungs were excised for histopathological examination. BPA concentration in PBW was 6.6 µg/ml estimated by HPLC. In rats receiving tap water, PBG produced bradycardia, hypotension and tachypnoea. In PBW/BPA treated groups, PBG-induced reflexes were attenuated significantly along with emphysematous and consolidative changes in lungs. The present results indicate that PBW attenuates the protective cardio-respiratory reflexes and also produces histopathological changes in lungs.

Reflex hypertensive response induced by capsaicin involves endothelin-dependent mechanisms.

Capsaicin, a nociceptive agent produces triphasic pressure response in rats. The mechanisms underlying capsaicin-induced pressure responses are not clear. Therefore, the present study was undertaken to determine the mechanisms involved in capsaicin - induced pressure responses. The trachea, jugular vein and femoral artery were cannulated in anaesthetized rats. Capsaicin (10 µg/kg; i.v) - induced reflex changes in the blood pressure, respiratory excursions and ECG were recorded before/after vagotomy in the absence/presence of antagonists. Capsaicin produced the triphasic pressure response characterized by immediate fall, recovery (intermediate phase) and delayed progressive fall. After vagotomy, the immediate hypotension was abolished and the intermediate pressure response was potentiated as a hypertensive response while the delayed hypotensive response persisted. The time-matched heart rate changes (bradycardia) and respiratory changes (tachypnea in delayed phase) were abolished after vagotomy. Pretreatment with endothelin receptor antagonist (bosentan; 10 mg/kg) blocked the capsiaicn-induced intermediate hypertensive response in vagotomised animals but not the delayed hypotension. Pretreatment with nitric oxide synthase (NOS) inhibitor (L-NAME; 30 pg/kg), prostaglandin synthase inhibitor (indomethacin; 10 mg/kg) and kinin synthase inhibitor (aprotinin; 6000 KIU) did not block the delayed hypotensive response. These results demonstrate that capsaicin-induced intermediate hypertensive response involves endothelin-dependent mechanisms and the delayed hypotensive response is independent of nitrergic, prostaglandinergic or kininergic mechanisms.

Vagal efferent stimulation protects against Mesobuthus tamulus venom-induced acute respiratory distress syndrome in rats.

Mesobuthus tamulus (MBT) venom and oleic acid (OA) have been shown to produce acute respiratory distress syndrome (ARDS) involving different mechanisms. The role of vagally mediated anti-inflammatory pathway in ARDS is poorly understood. Therefore, the effects of vagal efferent stimulation on these two models of ARDS were examined. Experiments were performed on anesthetized adult rats. Parameters like ventilatory changes (respiratory frequency and minute ventilation), hypoxemic status (PaO2/FiO2 ratio; P/F ratio), survival time, pulmonary water content and histopathological evidences of lung injury were determined to assess the severity of ARDS. In addition, heart rate (HR) and mean arterial pressure (MAP) were monitored. Injection of OA/MBT venom produced respiratory alterations, hypoxemia, pulmonary edema and histopathological changes demonstrating the development of ARDS. In both the groups, animals died around 60 min. Tachypnea and hyperventilation were seen after OA while bradypnea and hypoventilation were seen after MBT venom. Pulmonary edema was absent in vagotomised animals in MBT venom group but not in OA group. Further, electrical stimulation of the cut peripheral ends of vagii prolonged the survival time and attenuated all the parameters of MBT venom-induced ARDS significantly. In case of OA, there was improvement in histopathological changes but the survival time of animals was not prolonged. Stimulation of α7-nicotinic receptors (by pretreatment with GTS-21) exacerbated OA as well as MBT venom-induced ARDS. The present results indicate that vagal efferent stimulation protects against MBT venom-induced ARDS.

Mesobuthus tamulus venom induces acute respiratory distress syndrome in rats involving additional mechanisms as compared to oleic acid model.

The present study was undertaken to determine whether acute respiratory distress syndrome (ARDS) is produced after Mesobuthus tamulus (MBT) envenomation and compared it with oleic acid (OA)-induced ARDS. The trachea, jugular vein and femoral artery were cannulated in anesthetized adult rats. Lethal dose of MBT venom (5 mg/kg) or OA (75 µL) was administered intravenously and the time-dependent changes in respiratory frequency (RF), heart rate (HR) and mean arterial pressure (MAP) were recorded. Minute ventilation (MV) and the PaO2/FiO2 (P/F) ratio were also determined. At the end lungs were excised, one lung was used for histopathological examination and the other was used for determination of pulmonary water content physically. MBT venom or OA produced hypoxemia, pulmonary pathology (alveolar damage, infiltration of inflammatory cells, capillary damage and exudation) and pulmonary edema implicating for ARDS. However, the hypoxemia in MBT venom group was associated with decreased MV, apnea/bradypnea, and bradycardia whereas, in OA group it was seen with increased MV, tachypnea, and tachycardia. Lack of effect of hypoxemic drive on RF/MV or HR in MBT venom group unlike OA group, suggests the involvement of medullary centers. The present results demonstrate that MBT venom produces ARDS. However MBT venom-induced ARDS involves pulmonary as well as extrapulmonary mechanisms.

Characterization of oleic acid-induced acute respiratory distress syndrome model in rat.

Animal studies using oleic acid (OA) model to produce acute respiratory distress syndrome (ARDS) have been inconsistent. Therefore, the present study was undertaken to establish an acute model of ARDS in rats using OA and to characterize its effect on cardio-respiratory parameters and lethality. The trachea, jugular vein and femoral artery of anesthetized adult rats were cannulated. A dose of OA (30-90 microL; iv) was injected in each animal and changes in respiratory frequency (RF), heart rate (HR) and mean arterial pressure (MAP) were recorded. Minute ventilation and PaO2/FiO2 (P/F) ratio were also determined. At the end, lungs were excised for determination of pulmonary water content and histological examination. At all doses of OA, there was immediate decrease followed by increase in RF, however at 75 and 90 microL of OA, RF decreased abruptly and the animals died by 63 +/- 8.2 min and 19 +/- 6.3 min; respectively. In all the groups, HR and MAP changes followed the respiratory changes. The minute ventilation increased in a dose-dependent manner while the values of P/F ratio decreased correspondingly. Pulmonary edema was induced at all doses. Histological examination of the lung showed alveolar damage, microvascular congestion, microvascular injury, infiltration of inflammatory cells, pulmonary edema and necrosis in a dose-dependent manner. With these results, OA can be used to induce different grades of ARDS in rats and OA doses of 50, 60 and 75 microL resemble mild, moderate and severe forms of ARDS respectively. Hence, OA model serves as a useful tool to study the pathophysiology of ARDS.

Pulmonary oedema producing toxin from Mesobuthus tamulus venom augments cardio-respiratory reflexes through B2 kinin receptors.

The current study was undertaken to compare the effects of pulmonary oedema producing toxin (PO-Tx) isolated from Mesobuthus tamulus venom on cardio-respiratory reflexes with exogenously administered bradykinin (BK) and to delineate the type of BK receptors mediating these responses. Jugular venous injection of phenyldiguanide (PDG) in anaesthetized rats produced reflex bradycardia, hypotension and apnoea. The PDG-induced reflex was augmented (two folds) by PO-Tx. The pulmonary water content in PO-Tx treated group was also increased. The PO-Tx-induced reflex changes as well as pulmonary oedema were blocked by-Hoe-140 implicating the involvement of B2 kinin receptors. Exogenous BK also produced augmentation (two folds) of the PDG-induced reflexes and increased the pulmonary water content. The BK-induced augmentation was blocked by pre-treatment with des-Arg10 Hoe 140 (a B1 receptor antagonist) and Hoe 140 (B2 receptor antagonist). However, these antagonists did not prevent the development of BK-induced pulmonary oedema. Present results indicate that PO-Tx augmented the PDG-induced reflex responses similar to BK and the PO-Tx induced augmentation of reflexes is mediated through B2 receptors.

A study to investigate capsaicin-induced pressure response in vagotomized rats.

OBJECTIVES: Capsaicin is used to evoke pulmonary C reflexes and produces complex pressure responses along with apnea/tachypnea, and bradycardia. In the present study, the mechanisms involved in capsaicin-induced pressure responses were explored. MATERIALS AND METHODS: Tracheal, jugular venous, and femoral artery cannulations were performed in anesthetized adult rats. Blood pressure, respiratory excursions, and electrocardiogram were recorded. Cardiorespiratory reflex changes evoked by jugular venous injection of capsaicin (10 µg/kg) were recorded in vagotomized and antagonist pretreated animals. RESULTS: Capsaicin produced triphasic pressure response exhibiting immediate hypotension, intermediate recovery, and delayed hypotension. Time-matched respiratory changes showed apnea, bradypnea, and tachypnea, respectively. Bradycardia occurred at immediate and intermediate phases. After vagotomy, immediate hypotension was abolished; the intermediate recovery was potentiated as hypertensive response; and the delayed hypotension persisted. In case of respiration, the immediate bradypnea persisted and delayed tachypnea was abolished; while heart rate changes at immediate and intermediate phases were abolished. Antagonists of α1-adrenoceptor (prazosin or terazosin, 0.5 mg/kg), ß-adrenoceptor (propranolol, 1 mg/kg), AT1 receptor (losartan, 10 mg/kg) and Ca(2+) channel (diltiazem, 1 mg/kg) failed to block the capsaicin-induced intermediate hypertensive response in vagotomized animals. CONCLUSIONS: These observations implicate the existence of mechanisms other than adrenergic, angiotensinergic, or Ca(2+) channel-dependent mechanisms for mediating the capsaicin-induced intermediate hypertensive response in vagotomized animals.

Pulmonary surfactants and their role in pathophysiology of lung disorders.

Surfactant is an agent that decreases the surface tension between two media. The surface tension between gaseous-aqueous interphase in the lungs is decreased by the presence of a thin layer of fluid known as pulmonary surfactant. The pulmonary surfactant is produced by the alveolar type-II (AT-II) cells of the lungs. It is essential for efficient exchange of gases and for maintaining the structural integrity of alveoli. Surfactant is a secretory product, composed of lipids and proteins. Phosphatidylcholine and phosphatidylglycerol are the major lipid constituents and SP-A, SP-B, SP-C, SP-D are four types of surfactant associated proteins. The lipid and protein components are synthesized separately and are packaged into the lamellar bodies in the AT-II cells. Lamellar bodies are the main organelle for the synthesis and metabolism of surfactants. The synthesis, secretion and recycling of the surfactant lipids and proteins is regulated by complex genetic and metabolic mechanisms. The lipid-protein interaction is very important for the structural organization of surfactant monolayer and its functioning. Alterations in surfactant homeostasis or biophysical properties can result in surfactant insufficiency which may be responsible for diseases like respiratory distress syndrome, lung proteinosis, interstitial lung diseases and chronic lung diseases. The biochemical, physiological, developmental and clinical aspects of pulmonary surfactant are presented in this article to understand the pathophysiological mechanisms of these diseases.

Bisphenol A attenuates phenylbiguanide-induced cardio-respiratory reflexes in anaesthetized rats.

Bisphenol A (BPA), a toxic chemical released from plastics, produces respiratory arrest and hypotension after a latency. The latency was similar to the reflex apnoea induced by the vagal C fibre stimulation. Therefore, the present study was undertaken to examine the effects of chronic and acute exposure to BPA on cardio-respiratory reflexes elicited by phenylbiguanide (PBG). Acute and chronic experiments were performed on adult female rats. In chronic experiments, the animals were ingested with pellets containing BPA (2 µg/kg body weight) or without BPA (time-matched control) for 30 days. Subsequently, the animals were anaesthetized and prepared for recording blood pressure, ECG and respiratory excursions. PBG was injected through jugular vein to evoke reflexes in these animals. In acute experiments, the PBG reflexes were obtained before and after injecting BPA/ethanol. Also vagal afferent activity was recorded in some rats. In time-matched control rats, PBG produced bradycardia, hypotension and tachypnoea over a period of time. The maximal changes were around 50-65%. In BPA treated group, the PBG-induced heart rate and respiratory frequency changes were attenuated significantly. Acute exposure of animals to BPA (35 mg/kg body weight) for 30 min also attenuated the PBG-induced responses significantly. The attenuation of the PBG reflex responses by BPA in acute experiments was associated with decreased vagal afferent activity. The present results indicate that BPA attenuates the protective cardio-respiratory reflexes due to decreased vagal afferent activity.

Mechanisms underlying the augmentation of phenylbiguanide and capsaicin induced cardiorespiratory reflexes by Mesobuthus tamulus venom.

Phenylbiguanide (PBG) and capsaicin evoke cardiorespiratory reflexes utilizing two separate pathways. It is known that Indian Red Scorpion (Mesobuthus tumulus; MBT) venom augments PBG (5-HT(3)) responses but, the effect of MBT venom on capsaicin (TRPV1)-induced response is not known. Therefore, the present study was undertaken to ascertain whether MBT venom also augments the capsaicin-induced reflex responses involving mechanisms similar to PBG. Experiments were performed on anaesthetized adult rats. Blood pressure, respiratory excursions and ECG were recorded. At the end of each experiment pulmonary water content was determined. PBG (10 µg/kg) produced hypotension, bradycardia and apnoea-bradypnoea. Capsaicin (10 µg/kg) also produced hypotension, bradycardia and apnoea-bradypnoea. MBT venom (100 µg/kg) augmented PBG as well as capsaicin-induced responses and produced pulmonary oedema (increased pulmonary water content). Prostaglandin synthase inhibitor (indomethacin; 10 mg/kg) blocked the venom-induced augmentation of PBG and capsaicin reflexes. Kinin synthase inhibitor (aprotinin; 6000 KIU) and guanylate cyclase (GC) inhibitor (methylene blue; 5 mg/kg) blocked the venom-induced augmentation of PBG response but not the capsaicin response. However, pulmonary oedema was blocked by these antagonists. Phosphodiesterase V inhibitor (sildenafil; 100 µg/kg) augmented the PBG response but not the capsaicin response, though pulmonary oedema was seen in both the groups. The present results indicate that MBT venom also augments the capsaicin-induced responses. The augmentation of capsaicin response involves PGs and pulmonary oedema-independent mechanisms whereas, the augmentation of PBG response involves kinin mediated GC-cGMP pathway and pulmonary oedema-dependent mechanisms.

Acute toxicity of bisphenol A in rats.

Bisphenol A (BPA), an estrogenic compound, is used in manufacturing plastics and is known to produce toxic effects on various systems in man and animals. Since the use of plastics in day-to-day life is increasing, exposure to BPA will also increase. Therefore, this study was undertaken to determine the median lethal dose (LD50) of BPA via intraperitoneal and intravenous route in adult rats (by Dixon's up and down method) and also to know the acute systemic changes (in blood pressure, respiration and ECG) produced by lethal dose of BPA. Adult female albino rats of Charles Foster strain were used in the study. LD50 of BPA was 841 and 35.26 mg/kg body weight for ip and iv route, respectively. Injection of lethal dose of BPA (40 mg/kg body weight) produced acute toxicity manifesting as immediate respiratory arrest and hypotension after the injection of BPA followed by bradycardia. The animals died within 7.3 +/- 0.7 min. Volume of ethanol (vehicle; 0.1 mL) present in the lethal dose of BPA was not lethal and had no effect on respiration, blood pressure and heart rate. The results provide evidence that the acute exposure to BPA produces lethality with a very narrow range of lethal and survival dose for iv route. Further, the lethality appears to be due to respiratory arrest and hypotension.

Bisphenol A depresses compound action potential of frog sciatic nerve in vitro involving Ca(2+)-dependent mechanisms.

Bisphenol-A (BPA), a toxic chemical from polycarbonate plastics, is known for behavioural and neural abnormalities. These neuro-behavioural changes reflect the changes in neural activity. However the effect of BPA on nerve action potential is not available. Therefore, present investigation was undertaken to study the effect of BPA on compound action potential (CAP) of frog sciatic nerve. Bundle containing small group of nerve fibres in a sciatic nerve was dissected and placed in a Perspex chamber perfused with Ringer solution. Suction electrodes were applied to the cut ends of the nerve for stimulating and recording purposes. The stimulation of one end (with supramaximal strength) produced CAP in the recording electrode. BPA (1-100 µM) decreased the amplitude and repolarization time of CAP in a concentration-dependent manner, without any alteration in latency, rise time and threshold. The decrease in amplitude was directly correlated with decrease in repolarization time (r=0.76). The BPA-induced decreases were absent in Ca(2+)-free medium or in presence of L-type Ca(2+)-channel antagonist (nifedipine/deltiazem). T and P type Ca(2+) channel antagonist (Ni(2+)) failed to block the BPA-induced responses. Pre-treatment with an Erα antagonist (tamoxifen) blocked the BPA-induced decrease in CAP parameters. These observations indicate that the BPA decreased the amplitude and repolarization time of CAP involving L-type Ca(2+)-channel dependent mechanisms. Further involvement of Erα in the modulation of Ca(2+) channels is a possibility.

Involvement of AMPA receptors for Mesobuthus tamulus Pocock venom-induced depression of monosynaptic reflex in neonatal rat spinal cord in vitro.

Glutamate is a putative neurotransmitter at Ia-alpha motoneuron synapse in the spinal cord and mediate the action via N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. Since NMDA receptors are not involved in M. tamulus Pocock (MBT) venom-induced depression of spinal monosynaptic reflex (MSR), the present study was undertaken to evaluate the role of AMPA receptors in mediating the depression of MSR by MBT venom. The experiments were performed on isolated hemisected spinal cord from 4-6 day old rats. Stimulation of a dorsal root with supramaximal voltage evoked MSR and polysynaptic reflex (PSR) potentials in the corresponding segmental ventral root. Superfusion of MBT venom (0.3 microg/ml) depressed the spinal reflexes in a time-dependent manner. The maximum depression of MSR(approximately 66%) was seen at 10 min and it was 25 min for PSR (approximately 75%). The time to produce 50% depression of MSR and PSR was 6.7+/- 1.5 and 10.8 +/- 2.6 min, respectively. Pretreatment of the cords with 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX, 0.1 microM), an AMPA receptor antagonist, blocked the venom-induced depression of MSR but not PSR. The results indicate that venom-induced depression of MSR is mediated via AMPA receptors.