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We previously reported that intracerebroventricularly (ICV) injected arachidonic acid (AA) could produce pressor and bradycardic responses on the cardiovascular system and hyperventilation effect on the respiratory system by activating cyclooxygenase (COX). We also demonstrated that centrally injected AA-induced cardiovascular and respiratory responses were mediated by COX-metabolites, such as thromboxane A 2 (TXA 2 ), prostaglandin (PG) D, PGE, and PGF 2α . Brain tissue is also able to express the lipoxygenase (LOX) enzyme and LOX-induced AA-metabolites. The current study was designed to investigate the possible mediation of the central LOX pathway in AA-induced cardiorespiratory effects in anesthetized rats. Central pretreatment with different doses of a non-selective LOX inhibitor, nordihydroguaiaretic acid (NDGA) (500 and 1000 μg; ICV) partially blocked the AA (0.5 μmol; ICV)-evoked pressor and bradycardic cardiovascular responses in male anesthetized Sprague Dawley rats. Pretreatment with different doses of NDGA (500 and 1000 μg; ICV) also reduced AA-induced hyperventilation responses, with an increase in tidal volume, respiratory rate and minute ventilation, in the rats. Moreover, AA-induced increasing pO 2 and decreasing pCO 2 responses were diminished by central NDGA pretreatment. In summary, our findings show that the central LOX pathway might mediate, at least in part, centrally administered AA-evoked cardiorespiratory and blood gases responses., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Nesfatin-1 is a multifunctional neuropeptide having crucial autonomic roles. It is well known that nesfatin-1 collaborates with other central neuromodulatory systems, such as central corticotropin-releasing hormone, melanocortin, oxytocin, and cholinergic systems to show its autonomic effects. Central arachidonic acid cascade plays an important role to provide the homeostasis by exhibiting similar autonomic effects to nesfatin-1. Based on these similarities, the current study was designed to show the effects of intracerebroventricularly (ICV) injected nesfatin-1 on the hypothalamic arachidonic acid (AA) cascade. Immunochemistry and western blot approaches demonstrated that ICV administration of nesfatin-1 provokes an increase in the hypothalamic cyclooxygenase (COX) -1, -2 and lipoxygenase (LOX) protein expression. Moreover, the microdialysis study demonstrated that centrally injected nesfatin-1 increased the posterior hypothalamic extracellular AA products. In conclusion, these findings report that while nesfatin-1 is generating its autonomic effects, it also might be using central prostaglandins and leukotrienes by activating central COX and LOX pathways., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Arachidonic acid (AA), which is released from synaptic membrane phospholipid by neuroreceptor-initiated activation of phospholipase A 2 , is abundant in the brain and works as a neurotransmitter and/or neuromodulator in the central nervous system. Recently we reported that centrally injected AA generated pressor and hyperventilation effects by activating thromboxane A 2 (TXA 2 ) signaling pathway. The present study was designed to investigate the mediation of other metabolites of AA such as prostaglandin (PG) D, PGE and PGF 2α alongside TXA 2 in the AA-evoked cardiorespiratory effects in anaesthetized rats. Intracerebroventricular (i.c.v.) administration of AA caused pressor, bradycardic and hyperventilation responses by increasing pO 2 and decreasing pCO 2 in adult male anaesthetized Sprague Dawley rats. Pretreatment (i.c.v) with different doses of DP/EP prostanoid receptor antagonist, AH6809 or FP prostanoid receptor antagonist, PGF 2α dimethylamine partially blocked the cardiorespiratory and blood gas changes induced by AA. In conclusion, these data plainly report that central PGD, PGE or PGF 2α might mediate, at least partly, centrally administered AA-evoked cardiorespiratory and blood gas responses., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Arachidonic acid (AA) is a polyunsaturated fatty acid that is present in the phospholipids of the cell membranes of the body and is abundant in the brain. Exogenously administered AA has been shown to affect brain metabolism and to exhibit cardiovascular and neuroendocrine actions. However, little is known regarding its respiratory actions and/or central mechanism of its respiratory effects. Therefore, the present study was designed to investigate the possible effects of centrally injected AA on respiratory system and the mediation of the central cyclooxygenase (COX) to thromboxane A2 (TXA2) signaling pathway on AA-induced respiratory effects in anaesthetized rats. Intracerebroventricular (i.c.v.) administration of AA induced dose- and time-dependent increase in tidal volume, respiratory rates and respiratory minute ventilation and also caused an increase in partial oxygen pressure (pO2) and decrease in partial carbon dioxide pressure (pCO2) in male anaesthetized Spraque Dawley rats. I.c.v. pretreatment with ibuprofen, a non-selective COX inhibitor, completely blocked the hyperventilation and blood gases changes induced by AA. In addition, central pretreatment with different doses of furegrelate, a TXA2 synthesis inhibitor, also partially prevented AA-evoked hyperventilation and blood gases effects. These data explicitly show that centrally administered AA induces hyperventilation with increasing pO2 and decreasing pCO2 levels which are mediated by the activation of central COX to TXA2 signaling pathway., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The current study was designed to determine the effect of centrally administrated arachidonic acid (AA) on plasma gonadotropin hormone-releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone level, and sperm parameters, and to show the mediation of the central cyclooxygenase (COX) to thromboxane A2 (TXA2) signaling pathway in AA-induced hormonal and sperm parameter effects. Studies were performed in male Sprague-Dawley rats. A total of 150 or 300 μl/5 μl doses of AA were injected intracerebroventricularly (icv). AA significantly caused dose- and time-dependent increases in plasma FSH, LH and testosterone levels of animals, but not plasma GnRH level. AA also significantly increased sperm motility of the rats without change sperm number. Pretreated with ibuprofen, a nonselective COX inhibitor (250 μg/5 μl; icv), and furegrelate, a TXA2 synthesis inhibitor (250 μg/5 μl; icv), prevented AA-evoked increase in plasma FSH, LH and testosterone levels, and sperm motility. In conclusion, our findings show that centrally administered AA increases plasma FSH, LH and testosterone levels and sperm motility of conscious male rats. Moreover, according to our findings, central COX-TXA2 signaling pathway mediates these AA-induced effects., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The aim of this study was to explain the involvement of the central histaminergic system in arachidonic acid (AA)-induced cardiovascular effects in normotensive rats using hemodynamic, immunohistochemistry, and microdialysis studies. Intracerebroventricularly (i.c.v.) administered AA (0.25, 0.5, and 1.0 μmol) induced dose- and time-dependent increases in mean arterial pressure and decreased heart rate in conscious normotensive Sprague-Dawley rats. Central injection of AA (0.5 μmol) also increased posterior hypothalamic extracellular histamine levels and produced strong COX-1 but not COX-2 immunoreactivity in the posterior hypothalamus of rats. Moreover, the cardiovascular effects and COX-1 immunoreactivity in the posterior hypothalamus induced by AA (0.5 μmol; i.c.v.) were almost completely blocked by the H2 receptor antagonist ranitidine (50 and 100 nmol; i.c.v.) and partially blocked by the H1 receptor blocker chlorpheniramine (100 nmol; i.c.v.) and the H3-H4 receptor antagonist thioperamide (50 and 100 nmol; i.c.v.). In conclusion, these results indicate that centrally administered AA induces pressor and bradycardic responses in conscious rats. Moreover, we suggest that AA may activate histaminergic neurons and increase extracellular histamine levels, particularly in the posterior hypothalamus. Acting as a neurotransmitter, histamine is potentially involved in AA-induced cardiovascular effects under normotensive conditions.

The aim of the current study was to elucidate the underlying central mechanism(s) of the cardiovascular effects evoked by centrally injected melittin and arachidonic acid (AA) in hemorrhaged hypotensive condition, specifically, from central AA release from the cell membrane under the influence of phospholipase A(2) (PLA(2)) to central thromboxane A(2) (TXA(2)) signaling via the cyclooxygenase (COX) pathway. As the main control of the study, melittin (3 μg) or AA (150 μg) was injected intracerebroventricularly (i.c.v.) after the hemorrhage procedure, which was performed by withdrawing a total volume of 2.2 ml of blood/100g body weight over a period of 10 min. Both treatments generated a pressor response and abolished the hypotension-induced hemorrhage. Pretreatment with the PLA(2) inhibitor mepacrine (500 μg; i.c.v.) completely blocked the pressor response to melittin in the hemorrhagic hypotensive state. Pretreatments with the nonselective COX inhibitor indomethacin (200 μg; i.c.v.) or the TXA(2) synthesis inhibitor furegrelate (250 or 500 μg; i.c.v.) were made to test the role of central COX activity and, subsequently, the TXA(2) signaling pathway in the melittin- or AA-mediated reversal of hemorrhagic hypotension. Indomethacin completely prevented the pressor response to melittin and AA in the hemorrhaged, hypotensive state, but furegrelate did so only partially. In conclusion, these findings suggest that central COX activity and, subsequently, the central TXA(2) signaling pathway, are, at least in part, involved in the melittin- or AA-induced reversal effect during hemorrhagic shock., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The aim of the current study was to determine the central cyclooxygenase (COX) pathway and central thromboxane signaling in the cardiovascular effects evoked by arachidonic acid (AA). As a main control for the study, different doses of AA (75, 150, or 300 µg) were administered intracerebroventricularly (i.c.v.). Centrally injected AA dose- and time-dependently increased mean arterial pressure and decreased heart rate in conscious normotensive Sprague-Dawley rats. The maximal cardiovascular effects of AA were observed at min 10 of the injection and lasted almost 30 min. To investigate the central mechanism of the AA-induced cardiovascular effect in conscious normotensive animals, pretreatment with nonselective COX inhibitor indomethacin (200 µg; i.c.v.), thromboxane A2 (TXA2) synthesis inhibitor furegrelate (250 or 500 µg; i.c.v.), or TXA2 receptor antagonist SQ-29548 (8 or 16 µg; i.c.v.) was carried out 15 min before AA (150 µg; i.c.v.) injection. While indomethacin completely prevented the pressor and bradycardic responses to AA, furegrelate and SQ-29548 attenuated these effects in part in awake normotensive rats. In conclusion, these findings suggest that the pressor and bradycardic cardiovascular effects of centrally injected AA are dependent on COX activity being totally central and the TXA2 signaling pathway being subsequently central, at least in part.

1. The aims of the present study were to determine the cardiovascular effects of arachidonic acid (AA) and to investigate the peripheral mechanisms mediating these effects in haemorrhage-induced hypotensive rats. 2. Acute haemorrhage was induced by withdrawing a total volume of 2.2 mL blood/100 g bodyweight over a period of 10 min. Rats were then injected with 75-300 microg, i.c.v., AA and cardiovascular changes were monitored over the next 60 min. Plasma catecholamine and vasopressin levels, as well as plasma renin activity (PRA), were measured 10 min after injection of 150 microg AA in haemorrhage-induced hypotensive awake rats. In addition, rats were pretreated with saline (1 mL/kg, i.v.), the vasopressin V(1) receptor antagonist [beta-mercapto-beta,beta-cyclopentamethylenepropionyl(1),O-Me-Tyr(2),Arg(8)]-vasopressin (10 microg/kg, i.v.), the alpha(1)-adrenoceptor antagonist prazosin (500 microg/kg, i.v.), the non-specific angiotensin II receptor antagonist saralasin (250 microg/kg, i.v.) or a combination of these three antagonists 5 min before injection of AA (150 microg, i.c.v.). The effects of these antagonists on responses to AA were determined. 3. Arachidonic acid caused dose- and time-dependent increases in mean arterial pressure and heart rate and reversed hypotension in haemorrhaged rats. Haemorrhage itself produced an increase in plasma catecholamine and vasopressin levels, as well as PRA; injection of AA produced further increases in these parameters, ranging from 39-123%, under hypotensive conditions. Under hypotensive conditions, pretreatment of rats with all three receptor antagonists produced similar partial blockade of the pressor response to AA, but not the increase in heart rate. Moreover, combined administration of all three receptor antagonists prior to the i.c.v. injection of 150 microg AA completely abolished the pressor response to AA in haemorrhage-induced hypotensive rats. 4. These results indicate that centrally administered AA reverses hypotension by increasing blood pressure and heart rate in the hypotensive setting. The observed increases in plasma catecholamine and vasopressin levels, as well as PRA, mediate the pressor response to AA in haemorrhage-induced hypotensive rats.

In the current study, we aimed to determine the cardiovascular effects of arachidonic acid and peripheral mechanisms mediated these effects in normotensive conscious rats. Studies were performed in male Sprague Dawley rats. Arachidonic acid was injected intracerebroventricularly (i.c.v.) at the doses of 75, 150 or 300 microg and it caused dose- and time-dependent increase in mean arterial pressure and decrease in heart rate in normal conditions. Maximal effects were observed 10 min after 150 and 300 microg dose of arachidonic acid and lasted within 30 min. In order to evaluate the role of main peripheral hormonal mechanisms in those cardiovascular effects, plasma adrenaline, noradrenaline, vasopressin levels and renin activity were measured after arachidonic acid (150 microg; i.c.v.) injection. Centrally injected arachidonic acid increased plasma levels of all these hormones and renin activity. Intravenous pretreatments with prazosin (0.5 mg/kg), an alpha1 adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl1, O-Me-Tyr2-Arg8]-vasopressin (10 microg/kg), a vasopressin V1 receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, partially blocked the pressor response to arachidonic acid (150 microg; i.c.v.) while combined administration of these three antagonists completely abolished the effect. Moreover, both individual and combined antagonist pretreatments fully blocked the bradycardic effect of arachidonic acid. In conclusion, our findings show that centrally administered arachidonic acid increases mean arterial pressure and decreases heart rate in normotensive conscious rats and the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity appear to mediate the cardiovascular effects of the drug.

Abstract: Melittin is a polypeptide component of bee venom that leads to an increase in arachidonic acid release and subsequently in prostaglandin synthesis by activating phospholipase A2. Recently we demonstrated that centrally or peripherally administrated melittin caused pressor effect and central thromboxane A2 (TXA2) and cholinergic system mediated these effects of melittin. Also centrally injected histamine leads to pressor and bradycardic response by activating central histamine receptors in normotensive rats and central cholinergic system involved the effects of histamine. The present study demonstrates an involvement of the central histaminergic system in melittin-induced cardiovascular effect in normotensive rats. Experiments were carried out in male Sprague Dawley rats. Intracerebroventricularly (i.c.v.) injected melittin (0.5, 1 and 2nmol) caused dose- and time-dependent increases in mean arterial pressure (MAP) and decrease in heart rate (HR) as we reported previously. Moreover, H2 receptor antagonist ranitidine (50nmol; i.c.v.) almost completely and H3/H4 receptor antagonist thioperamide (50nmol; i.c.v.) partly blocked melittin-evoked cardiovascular effects, whereas H1 receptor blocker chlorpheniramine (50nmol; i.c.v.) had no effect. Also centrally injected melittin was accompanied by 28% increase in extracellular histamine concentration in the posterior hypothalamus, as shown in microdialysis studies. In conclusion, results show that centrally administered melittin causes pressor and bradycardic response in conscious rats. Moreover, according to our findings, there is an involvement of the central histaminergic system in melittin-induced cardiovascular effects. [Copyright &y& Elsevier]

Abstract: The aim of the current study was to elucidate the underlying central mechanism(s) of the cardiovascular effects evoked by centrally injected melittin and arachidonic acid (AA) in hemorrhaged hypotensive condition, specifically, from central AA release from the cell membrane under the influence of phospholipase A2 (PLA2) to central thromboxane A2 (TXA2) signaling via the cyclooxygenase (COX) pathway. As the main control of the study, melittin (3μg) or AA (150μg) was injected intracerebroventricularly (i.c.v.) after the hemorrhage procedure, which was performed by withdrawing a total volume of 2.2ml of blood/100g body weight over a period of 10min. Both treatments generated a pressor response and abolished the hypotension-induced hemorrhage. Pretreatment with the PLA2 inhibitor mepacrine (500μg; i.c.v.) completely blocked the pressor response to melittin in the hemorrhagic hypotensive state. Pretreatments with the nonselective COX inhibitor indomethacin (200μg; i.c.v.) or the TXA2 synthesis inhibitor furegrelate (250 or 500μg; i.c.v.) were made to test the role of central COX activity and, subsequently, the TXA2 signaling pathway in the melittin- or AA-mediated reversal of hemorrhagic hypotension. Indomethacin completely prevented the pressor response to melittin and AA in the hemorrhaged, hypotensive state, but furegrelate did so only partially. In conclusion, these findings suggest that central COX activity and, subsequently, the central TXA2 signaling pathway, are, at least in part, involved in the melittin- or AA-induced reversal effect during hemorrhagic shock. [Copyright &y& Elsevier]

• ICV injected orexin produces pressor and tachycardic cardiovascular effects. • ICV injection of orexin causes an increase in the posterior hypothalamic extracellular total prostaglandin level. • Central cyclooxygenase pathway mediates orexin-evoked cardiovascular effects. • Central lipoxygenase pathway mediates orexin-evoked cardiovascular effects. Previously it was reported that central orexin (OX) and arachidonic acid (AA) signaling pathways played an active role in the control of the cardiovascular system. It was also reported that they have exhibited their cardiovascular control role by using similar central or peripheral mechanisms. However, there has been no study demonstrating the interaction between OX and AA signaling pathways in terms of cardiovascular control. The current study was designed to investigate the possible mediation of the central cyclooxygenase (COX) and lipoxygenase (LOX) pathways in OX-induced cardiovascular effects in the rats. Intracerebroventricular injection of OX increased blood pressure and heart rate in a dose-dependent manner in normotensive male Sprague Dawley rats. Moreover, the microdialysis study revealed that intracerebroventricular injected OX caused a time-dependent increase in the extracellular total prostaglandin concentrations in the posterior hypothalamus. Interestingly, central pretreatment with a non-selective COX inhibitor, ibuprofen, or a non-selective LOX inhibitor, nordihydroguaiaretic acid, partially reversed pressor and tachycardic cardiovascular responses evoked by central administration of OX. In summary, our findings show that the central treatment with OX causes pressor and tachycardic cardiovascular responses along with an increase in posterior hypothalamic extracellular total prostaglandin concentrations. Furthermore, our results also demonstrate that central COX and LOX pathways mediate, at least in part, centrally administered OX-evoked pressor and tachycardic responses, as well. [ABSTRACT FROM AUTHOR]