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Brain histamine holds a key position in the regulation of behavioral states, biological rhythms, body weight, energy metabolism, thermoregulation, fluid balance, stress and reproduction in female animals. However, it is not clear whether central histamine exerts any effect on hypothalamic-pituitary-testicular in male rats and if so, the involvement of type of central histamine receptors. The current study was designed to determine the effect of centrally administrated histamine on plasma gonadotropin hormone-releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone level, and sperm parameters, and to show the mediation of the central histaminergic H1, H2 and H3/H4 receptors on histamine-evoked hormonal and sperm parameters’ effects. Studies were performed in male Sprague-Dawley rats. A total of 50 or 100 nmol doses of histamine were injected intracerebroventricularly (icv). 100 nmol dose of histamine significantly caused increases in plasma GnRH, LH, FSH and testosterone levels of animals, but not 50 nmol dose of histamine. Moreover, central pretreatment with chlorpheniramine, histaminergic H1 receptor antagonist (100 nmol), ranitidine and histaminergic H2 receptor antagonist (100 nmol) completely prevented histamine evoked increase in plasma GnRH, LH, FSH and testosterone levels, while thioperamide, histaminergic H3/H4 receptor antagonist (100 nmol) pretreatment failed to reverse sex hormones responses to histamine. Both central histamine treatment alone and central histamine treatment after central histaminergic receptors antagonists’ pretreatments did not alter any sperm parameters in rats. In conclusion, our findings show that centrally administered histamine increases plasma GnRH, LH, FSH and testosterone levels of conscious male rats without change any sperm parameters. Moreover, according to our findings, central histaminergic H1, and H2 receptors mediate these histamine-induced effects.

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.

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(2 alpha), 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(2 alpha), dimethylamine partially blocked the cardiorespiratory and blood gas changes induced by AA. In conclusion, these data plainly report that central PGD, PGE or PGF(2 alpha) might mediate, at least partly, centrally administered AA-evoked cardiorespiratory and blood gas responses.

Phoenixin (PNX) and nesfatin-1 are localised in the hypothalamus and the pituitary gland. Moreover, the most of the PNX-expressing neurons in the hypothalamus also co-express nesfatin-1. These outcomes may suggest that there is an interaction between PNX and nesfatin-1, at least in terms of neuroendocrine-mediated regulations. Hence, the study was planned to find out the effects of centrally delivered PNX and nesfatin-1 on male sex hormones or to show the interactive association of intracerebroventricularly (ICV) injected PNX+nesfatin-1 combination on the release of male hormones. PNX and nesfatin-1, single or together, were delivered ICV to different male Wistar Albino rat groups. Both PNX and nesfatin-1 induced a significant enhancement in plasma FSH, LH and testosterone without inducing any alteration in plasma GnRH in the rats. The central combinatorial treatment of both the neuropeptides produced a more potent rise in male plasma hormone levels than treating with single neuropeptide. In summary, our preliminary data show that centrally delivered PNX and nesfatin-1 can affect plasma male hormone levels. Moreover, that the combinatorial treatment with both the neuropeptides in male rats leading to a more potent effect on the plasma male hormone levels might suggest that both these neuropeptides act synergistically in terms of regulation of male HPGA.

Nesfatin-1, a peptide whose receptor is yet to be identified, has been shown to be involved in the modulation of feeding, stress, and metabolic responses. Recently, increasing evidence has supported a modulatory role of nesfatin-1 in cardiovascular activity. We have previously reported that nesfatin-1 causes an increase in blood pressure in normotensive and hypotensive rats by increasing plasma catecholamine, vasopressin, and renin levels. Recent reports suggest that nesfatin-1 may activate the central cholinergic system. However, there is no evidence showing an interaction between central nesfatin-1 and the cholinergic system. Therefore, this study aimed to determine whether the central cholinergic system may have a functional role in the nesfatin-1-induced cardiovascular effect observed in normotensive rats. Intracerebroventricular injection of nesfatin-1 caused short-term increases in mean arterial pressure and heart rate responses including bradycardic/tachycardic phases in normotensive animals. Central injection of nesfatin-1 increased the acetylcholine and choline levels in the posterior hypothalamus, as shown in microdialysis studies. Central pretreatment with the cholinergic muscarinic receptor antagonist atropine and/or nicotinic receptor antagonist mecamylamine blocked nesfatin-1-induced cardiovascular effects. In conclusion, the results show that centrally administered nesfatin-1 produces a pressor effect on blood pressure and heart rate responses including bradycardic/tachycardic phases in normotensive rats. Moreover, according to our findings, the central cholinergic system can modulate nesfatin-1-evoked cardiovascular activity.

Histamine, acting centrally as a neurotransmitter, evokes a reversal of hemorrhagic hypotension in rats due to the activation of the sympathetic and the renin–angiotensin systems as well as the release of arginine vasopressin and proopiomelanocortin-derived peptides. We demonstrated previously that central nicotinic cholinergic receptors are involved in the pressor effect of histamine. The aim of the present study was to examine influences of centrally administrated histamine on acetylcholine (ACh) release at the posterior hypothalamus—a region characterized by location of histaminergic and cholinergic neurons involved in the regulation of the sympathetic activity in the cardiovascular system—in hemorrhage-hypotensive anesthetized rats. Hemodynamic and microdialysis studies were carried out in Sprague–Dawley rats. Hemorrhagic hypotension was induced by withdrawal of a volume of 1.5 ml blood/100 g body weight over a period of 10 min. Acute hemorrhage led to a severe and long-lasting decrease in mean arterial pressure (MAP), heart rate (HR), and an increase in extracellular posterior hypothalamic ACh and choline (Ch) levels by 56% and 59%, respectively. Intracerebroventricularly (i.c.v.) administered histamine (50, 100, and 200 nmol) dose- and time-dependently increased MAP and HR and caused an additional rise in extracellular posterior hypothalamic ACh and Ch levels at the most by 102%, as compared to the control saline-treated group. Histamine H1 receptor antagonist chlorpheniramine (50 nmol; i.c.v.) completely blocked histamine-evoked hemodynamic and extracellular posterior hypothalamic ACh and Ch changes, whereas H2 and H3/H4 receptor blockers ranitidine (50 nmol; i.c.v.) and thioperamide (50 nmol; i.c.v.) had no effect. In conclusion, centrally administered histamine, acting via H1 receptors, increases ACh release at the posterior hypothalamus and causes a pressor and tachycardic response in hemorrhage-hypotensive anesthetized rats.

CDP-choline is an endogenous metabolite in phosphatidylcholine biosynthesis. Exogenous administration of CDP-choline has been shown to affect brain metabolism and to exhibit cardiovascular, neuroendocrine neuroprotective actions. On the other hand, little is known regarding its respiratory actions and/or central mechanism of its respiratory effect. Therefore the current study was designed to investigate the possible effects of centrally injected CDP-choline on respiratory system and the mediation of the central cholinergic receptors and phospholipase to thromboxane signaling pathway on CDP-choline-induced respiratory effects in anaesthetized rats. Intracerebroventricularly (i.c.v.) administration of CDP-choline induced dose- and time-dependent increased respiratory rates, tidal volume and minute ventilation of male anaesthetized Spraque Dawley rats. I.c.v. pretreatment with atropine failed to alter the hyperventilation responses to CDP-choline whereas mecamylamine, cholinergic nicotinic receptor antagonist, mepacrine, phospholipase A 2 inhibitor, and neomycin phospholipase C inhibitor, blocked completely the hyperventilation induced by CDP-choline. In addition, central pretreatment with furegrelate, thromboxane A 2 synthesis inhibitor, also partially blocked CDP-choline-evoked hyperventilation effects. These data show that centrally administered CDP-choline induces hyperventilation which is mediated by activation of central nicotinic receptors and phospholipase to thromboxane signaling pathway.

The purpose of the current study is to investigate the functional connections between the central histaminergic and cholinergic systems at NTS level in hypotensive condition. Experiments were carried out in male Wistar Albino rats. The hypotension was achieved by withdrawing a total volume of 1.5 ml blood/100 g bodyweight over a period of 10 min. A microdialysis study was performed in NTS area to measure extracellular ACh and Ch levels. The hemorrhage produced a severe and long-lasting decrease in mean arterial blood pressure (MAP) and increase in extracellular ACh and Ch levels in NTS. Administration of histamine intracerebroventricularly (i.c.v.) or into the NTS reversed the hemorrhagic hypotension by increasing MAP and heart rate. I.c.v. injection of histamine also caused the additional increase in extracellular ACh and Ch levels. Moreover, central histamine injection augmented intracytoplasmic AChE immunoreactivity in NTS. These changes were completely blocked by histaminergic H1 receptor antagonist chlorpheniramine, but histaminergic H2 receptor blocker ranitidine and histaminergic H3/H4 receptor antagonist thioperamide failed to produce these effects. In conclusion, these findings are interpreted that brain histaminergic H1 receptor activation by central histamine injection may promote cholinergic stimulation in the NTS and subsequently reverses the hypotension.

This study investigated the cardiovascular effects of nesfatin-1 in normotensive rats and animals subjected to hypotensive hemorrhage. Hemorrhagic hypotension was induced by withdrawal 2 mL blood/100 g body weight over a period of 10 min. Acute hemorrhage led to a severe and long-lasting decrease in mean arterial pressure (MAP) and heart rate (HR). Intracerebroventricularly (i.c.v.) administered nesfatin-1 (100 pmol) increased MAP in both normotensive and hemorrhaged rats. Nesfatin-1 also caused bradycardia in normotensive and tachycardia in hemorrhaged rats. Centrally injected nesfatin-1 (100 pmol, i.c.v.) also increased plasma catecholamine, vasopressin and renin concentrations in control animals and potentiated the rise in all three cardiovascular mediators produced by hemorrhage. These findings indicate that centrally administered nesfatin-1 causes a pressor response in conscious normotensive and hemorrhaged rats and suggest that enhanced sympathetic activity and elevated vasopressin and renin concentrations mediate the cardiovascular effects of the peptide.

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.

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 A 2 . Recently we demonstrated that centrally or peripherally administrated melittin caused pressor effect and central thromboxane A 2 (TXA 2 ) 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, H 2 receptor antagonist ranitidine (50nmol; i.c.v.) almost completely and H 3 /H 4 receptor antagonist thioperamide (50nmol; i.c.v.) partly blocked melittin-evoked cardiovascular effects, whereas H 1 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.