Involvement of the histaminergic system in the resuscitating effect of centrally acting leptin in haemorrhagic shock in rats.

Leptin, acting centrally as a neuromodulator, induces the activation of the sympathetic nervous system, which may lead to a pressor action in normotensive animals. In haemorrhagic shock, leptin administered intracerebroventricularly (icv.) evokes the resuscitating effect, with long-lasting rises in mean arterial pressure (MAP) and heart rate (HR), subsequent increase in peripheral blood flows, and a 100% survival at 2 h. Since leptin is able to activate histaminergic neurons, and centrally acting histamine also induces the resuscitating effect with the activation of the sympathetic nervous system, in the present study, we investigated an involvement of the histaminergic system in leptin-evoked cardiovascular effects in haemorrhagic shock. The model of irreversible haemorrhagic shock, with MAP decreased to and stabilised at 20 - 25 mmHg, has been used. Leptin (20 µg) given icv. at 5 min of critical hypotension evoked 181.5% increase in extracellular hypothalamic histamine concentration during the first 10 min after injection. Rises in MAP, HR and renal, mesenteric and hindquarters blood flows induced by leptin were inhibited by icv. pre-treatment with histamine H1 receptor antagonist chlorpheniramine (50 nmol). In contrast, there was no effect of H2, H3 and H4 receptor antagonists ranitidine (25 nmol), VUF 5681 (25 nmol) and JNJ 10191584 (25 nmol), respectively. In conclusion, the histaminergic system is involved in centrally-acting leptin-induced resuscitating effect in haemorrhagic shock in rats.

Protective effect of CDP-choline on ischemia-reperfusion-induced myocardial tissue injury in rats.

BACKGROUND: CDP-choline exerts tissue protective effect in several ischemic conditions. Recently we have reported that the drug prevents cardiac arrhythmias and improves survival rate in short-term myocardial ischemia reperfusion in rats. AIM: In the current study, we determined the effect of intravenously administered CDP-choline on myocardial tissue injury induced by 30-min ischemia followed by 3-h reperfusion in anesthetized rats. METHODS: Myocardial ischemia was produced by ligature of the left main coronary artery. CDP-choline (100-500 mg/kg) was intravenously injected in the middle of the ischemic period. Cardiovascular parameters were recorded through the experimental period. At the end of the reperfusion period, the hearts of the animals were removed and stained for the investigation of tissue necrosis and apoptosis. The infarct size was evaluated as the ratio of the infarct area to the risk area. Apoptotic activation was assessed by TUNEL assay. Also the blood samples of rats were collected for the measurement of M30-M65, ADMA, homocysteine, and lactate levels. RESULTS: Ischemia/reperfusion caused serious injury in myocardium, increased blood ADMA and lactate levels without influencing other parameters. CDP-choline significantly reduced the infarct size and the number of apoptotic cells in the risk area. Blood pressure increased after CDP-choline injection; however, it returned back to the basal levels before the onset of reperfusion. CDP-choline failed to alter any other measured parameters. CONCLUSION: The present results demonstrate that intravenously administered CDP-choline is able to protect myocardium from injury induced by long-term coronary occlusion-reperfusion in rats. The inhibition of apoptosis by the drug may contribute to its protective effect. But neither the increase in blood pressure in response to CDP-choline injection nor changes in plasma ADMA concentration appear to mediate the attenuation of the myocardial injury.

Involvement of the histaminergic system in cytidine 5'-diphosphocholine-induced reversal of critical haemorrhagic hypotension in rats.

Cytidine 5'-diphosphocholine (CDP-choline) is an endogenously synthesized mononucleotide which exerts a variety of physiological effects by altering central cholinergic transmission. Administered intracerebroventricularly (i.c.v.) or intravenously, it reverses haemorrhagic hypotension in rats, apparently by the activation of central cholinergic receptors. The study was undertaken to investigate the involvement of the central histaminergic system in CDP-choline-mediated reversal of haemorrhagic hypotension. Experiments were carried out in male ketamine/xylazine-anaesthetised Wistar rats subjected to haemorrhagic hypotension of 20-26 mmHg. CDP-choline (2 micromol; i.c.v.) administered at 5 min of critical hypotension produced a long-lasting pressor effect with increases in mean arterial pressure (MAP), heart rate (HR), and renal, hindquarters and mesenteric blood flows, resulting in a 100% survival at 2 h. The action was accompanied by approximately a 26% increase in extracellular histamine concentration at the posterior hypothalamus, as measured by microdialysis. Cardiovascular effects mediated by CDP-choline were almost completely blocked by pretreatment with H(1) receptor antagonist chlorpheniramine (50 nmol; i.c.v.), but not with H(2) receptor blocker ranitidine (25 nmol; icv) or H(3)/H(4) receptor antagonist thioperamide (50 nmol; i.c.v.). In conclusion, the present results show that he central histaminergic system, through the activation of H(1) histaminergic receptors, is involved in CDP-choline-induced resuscitating effect in haemorrhage-shocked rats.

Involvement of the cholinergic system in the central histamine-induced reversal of critical haemorrhagic hypotension in rats.

Histamine, acting centrally as a neurotransmitter, evokes a reversal of haemorrhagic shock 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. In the present study, we demonstrate influences of cholinergic receptor antagonists on the central histamine-induced resuscitating action. Experiments were carried out in male anaesthetised Wistar rats subjected to a haemorrhagic hypotension of 20-25 mmHg, resulting in the death of all control animals within 30 min. Histamine (100 nmol) administered intracerebroventricularly (icv) at 5 min of critical hypotension produced a long-lasting pressor effect with increases in heart rate and peripheral blood flows, and a 100% survival at 2 h. Mean arterial pressure and blood flow changes were almost completely blocked by nicotinic receptor antagonist mecamylamine (246.3 nmol; icv) and partially inhibited by muscarinic receptor blocker atropine sulphate (14.8 nmol; icv). Cholinergic receptor antagonists given alone in the control saline-treated groups did not affect cardiovascular parameters in the post-bleeding period. In conclusion, there are interactions between the histaminergic and cholinergic systems, with an involvement of both nicotinic and muscarinic receptors, in the central cardiovascular regulation in haemorrhagic hypotension in rats.

Reversal of Haemorrhagic Shock in Rats by Tetrahydroaminoacridine.

The cardiovascular effects of tetrahydroaminoacridine (tacrine; THA) were investigated in haemorrhaged rats. Intracerebroventricular (i.c.v.) injection of THA (10, 25 and 50 microg) restored blood pressure in a dose- and time-dependent manner. Atropine (10 microg, i.c.v.), a muscarinic receptor antagonist, attenuated the pressor response to THA (25 microg, i.c.v.), while mecamylamine (50 microg, i.c.v.), a nicotinic receptor antagonist, caused only a slight blockade in the pressor effect of THA. Simultaneous pretreatment with atropine and mecamylamine almost abolished the blood pressure effect of i.c.v. THA (25 microg). Haemorrhage increased plasma levels of adrenaline, noradrenaline, vasopressin and plasma renin activity. THA (25 microg, i.c.v.) administration caused additional increases in vasopressin and adrenaline levels but not of renin activity and noradrenaline levels. The reversal of hypotension by THA was greatly attenuated by administration of either prazosin, an alpha(1)-adrenoceptor antagonist (0.5 mg/kg, i.v.) or by the vasopressin V(1) receptor antagonist [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl(1), O-Me-Tyr(2)-Arg(8)]-vasopressin (10 microg/kg, i.v.). Pretreatment of rats with both prazosin and the vasopressin antagonist simultaneously completely inhibited the pressor response. Intravenous administration of THA (1, 1.5 and 3 mg/kg) also reversed hypotension in rats. Atropine (10 microg, i.c.v.) greatly attenuated the pressor response to THA (1.5 mg/kg, i.v.), while mecamylamine (50 microg, i.c.v.) failed to change the pressor effect of THA. In anaesthetised haemorrhaged rats, THA (1.5 mg/kg, i.v.) increased blood pressure and survival time of the animals. These results show that centrally and peripherally injected THA reverses haemorrhagic hypotension and increases survival time in rats. Activation of central muscarinic and nicotinic receptors is involved in the pressor response to i.c.v. THA. The pressor effect of i.v. THA is solely mediated by central muscarinic receptors. Moreover, the increase in plasma adrenaline and vasopressin levels appears to be involved in the pressor effect of THA.

Cardiovascular effects of centrally injected tetrahydroaminoacridine in conscious normotensive rats.

In freely moving rats, intracerebroventricularly (i.c.v.) injected tetrahydroaminoacridine (10, 25, 50 microg) increased blood pressure and decreased heart rate in a dose- and time-dependent manner. Intravenous (i.v.) tetrahydroaminoacridine (1 and 3 mg/kg) also increased blood pressure. Atropine sulphate (10 microg; i.c.v.) pretreatment greatly attenuated the blood pressure response to i.c.v. tetrahydroaminoacridine while mecamylamine (50 microg; i.c.v.) failed to change the pressor effect. Neither atropine sulphate nor mecamylamine pretreatment affected the bradycardia induced by tetrahydroaminoacridine. However, the bradycardic response was completely blocked by atropine methylnitrate (2 mg/kg; i.p.) pretreatment. The pressor response to i.c.v. tetrahydroaminoacridine was associated with a several-fold increase in plasma levels of vasopressin, adrenaline and noradrenaline, but not of plasma renin. Pretreatment with prazosin (0.5 mg/kg; i.v.) attenuated the pressor effect without changing the bradycardia. Vasopressin V1 receptor antagonist [beta-mercapto-beta,beta-cyclopentamethylenepropionyl1,O-Me-Tyr2-A rg8]vasopressin (10 microg/kg; i.v.) pretreatment also partially inhibited the pressor response to i.c.v. tetrahydroaminoacridine and abolished the bradycardia. Tetrahydroaminoacridine's cardiovascular effects were completely blocked when rats were pretreated with prazosin plus vasopressin antagonist. The data show that tetrahydroaminoacridine increases blood pressure in normotensive freely moving rats by activating central muscarinic cholinergic transmission. Increases in plasma catecholamines and vasopressin are both involved in this response. The tetrahydroaminoacridine-induced reduction in heart rate appears to be due to the increase in vagal tone and plasma vasopressin.

Choline administration reverses hypotension in spinal cord transected rats: the involvement of vasopressin.

Intracerebroventricular (i.c.v.) choline (50-150 microg) increased blood pressure and decreased heart rate in spinal cord transected, hypotensive rats. Choline administered intraperitoneally (60 mg/kg), also, increased blood pressure, but to a lesser extent. The pressor response to i.c.v. choline was associated with an increase in plasma vasopressin. Mecamylamine pretreatment (50 microg; i.c.v.) blocked the pressor, bradycardic and vasopressin responses to choline (150 microg). Atropine pretreatment (10 microg; i.c.v.) abolished the bradycardia but failed to alter pressor and vasopressin responses. Hemicholinium-3 [HC-3 (20 microg; i.c.v.)] pretreatment attenuated both bradycardia and pressor responses to choline. The vasopressin V1 receptor antagonist, (beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2, Arg8)-vasopressin (10 microg/kg) administered intravenously 5 min after choline abolished the pressor response and attenuated the bradycardia-induced by choline. These data show that choline restores hypotension effectively by activating central nicotinic receptors via presynaptic mechanisms, in spinal shock. Choline-induced bradycardia is mediated by central nicotinic and muscarinic receptors. Increase in plasma vasopressin is involved in cardiovascular effects of choline.

The effects of ejaculation on serum prostate-specific antigen (PSA).

To determine the effects of ejaculation on serum PSA, we measured serum levels just before masturbation and 24 hours and 5 days later in a study group (n=25) aged between 23 and 25 years. In the study group, 16 cases showed a decrease (mean 22.37%, range 10-50%) in serum PSA levels 24 hours after ejaculation, while 6 had higher levels (mean 38.33%, range 21-67%) and 3 had no changes. No relation was found between seminal plasma levels or total amounts expelled of this marker and the difference in serum levels due to ejaculation. In the control group free of ejaculation in the same period determinations of serum PSA levels revealed no significant changes between days 0, 1 and 5. As compared with the control group, the changes in the study group were found to be statistically insignificant. These results may indicate that ejaculation has an insignificant effect on serum PSA levels.

Cardiovascular effects of central choline during endotoxin shock in the rat.

The cardiovascular effects of intracerebroventricular (i.c.v.) administration of choline were studied in endotoxin-treated rats. Intravenous (i.v.) endotoxin (20 mg/kg) caused a moderate hypotension and tachycardia within 10 min of treatment. Choline (50, 100, and 150 microg; i.c.v.) increased blood pressure and decreased heart rate in this condition in a dose-dependent manner. Mecamylamine (50 microg; i.c.v.) pretreatment prevented the pressor and bradycardic responses to choline, whereas atropine (10 microg; i.c.v.) failed to alter both responses. Atropine pretreatment, alone, inhibited endotoxin-induced hypotension. The pressor responses to choline in endotoxin-treated rats were attenuated by pretreatment with hemicholinium-3 (20 microg; i.c.v.), a high-affinity neuronal choline-uptake inhibitor. Plasma vasopressin levels of endotoxin-treated rats were severalfold higher than those of control animals, and choline (50-150 microg; i.c.v.) produced further increases in plasma vasopressin in this condition. Mecamylamine abolished vasopressin response to endotoxin as well as to choline. The vasopressin receptor antagonist, (beta-mercapto-beta,beta-cyclopentamethylene-propionyl(1)-O-Me-Tyr2,Arg8 )-vasopressin (10 microg/kg; i.v.) administered 5 min after choline decreased blood pressure from the increased level to the precholine levels but did not alter bradycardia. These results indicate that, in rats treated with endotoxin, choline increases blood pressure and decreases heart rate by a presynaptic mechanism leading to the activation of central nicotinic cholinergic pathways. An increase in plasma vasopressin levels seems to be involved in the pressor, but not in the bradycardic response, to choline.

Centrally administered choline increases plasma prolactin levels in conscious rats.

Intracerebroventricular (i.c.v.) administration of choline, a precursor of acetylcholine (ACh) increased plasma prolactin levels in a time and dose-dependent manner in conscious rats. Pretreatment of rats with the cholinergic muscarinic antagonist, atropine (10 microg, i.c.v.), blocked the increase in plasma prolactin level. The increase was not influenced by pretreatment with the cholinergic nicotinic antagonist, mecamylamine (50 microg, i.c.v.). Pretreatment with hemicholinium-3 (HC-3; 20 microg, i.c.v.), a high affinity choline uptake inhibitor, attenuated the choline-induced increase of plasma prolactin levels. These results show that choline increases plasma prolactin levels by activating muscarinic receptors via presynaptic mechanisms.

Intracerebroventricular choline reverses hypotension induced by acute chemical sympathectomy.

1. The effect of centrally administered choline on blood pressure was investigated in rats made hypotensive by chemical sympathectomy. Chemical sympathectomy was produced by intravenous (i.v.) injection of 50 mg kg-1 of 6-hydroxydopamine (6-OHDA). Intracerebroventricular (i.c.v.) administration of choline (50-150 micrograms) 2 h after 6-OHDA treatment increased blood pressure and reversed the hypotension in a dose-dependent manner without affecting the heart rate. The pressor response was associated with an increase in plasma vasopressin levels. 2. Pretreatment of rats with the nicotinic receptor antagonist, mecamylamine (50 micrograms, i.c.v.), but not the muscarinic receptor antagonist atropine (10 micrograms, i.c.v.), blocked both the pressor and vasopressin responses to choline (150 micrograms). Pretreatment of rats with hemicholinium-3 (HC-3), a high affinity choline uptake inhibitor, greatly attenuated the pressor response to i.c.v. choline (150 micrograms). 3. The vasopressin V1 receptor antagonist, beta-mercapto-beta,beta-cyclopentamethylenepropionyl-O-Me-Try,Arg) - vasopressin (10 micrograms kg-1; i.v.) given 5 min after i.c.v. choline, decreased the blood pressure but failed to return it to the pre-choline levels. Prazosine (0.5 mg kg-1; i.p.), an antagonist of alpha-adrenoceptors, also decreased blood pressure. Administration of both antagonists together eliminated the pressor response to choline, and the blood pressure was reduced further to below the pre-choline levels. 4. It is concluded that i.c.v. choline can increase blood pressure in rats made hypotensive by acute chemical sympathectomy through the activation of central nicotinic receptors by presynaptic mechanisms. An elevation in plasma levels of both vasopressin and catecholamines (possibly released from the adrenal medulla) is involved in the pressor response to choline.

Central choline reverses hypotension caused by alpha-adrenoceptor or ganglion blockade in rats: the role of vasopressin.

The effect of intracerebrovenricularly (i.c.v.) injected choline on blood pressure was investigated in rats made hypotensive by blocking peripheral alpha-adrenoceptors or autonomic ganglionic transmission. Choline (50-150 micrograms; i.c.v.) increased blood pressure in a dose-dependent manner and 150 micrograms of choline restored blood pressure to the resting level. The pressor response to choline was associated with an increase in plasma vasopressin levels. Pretreatment with mecamylamine (50 micrograms; i.c.v.), but not atropine (10 micrograms; i.c.v.), blocked both the pressor and vasopressin responses to i.c.v. choline. The vasopressin receptor antagonist, [beta-mercapto-beta,beta-cyclopenta-methylene-propionyl1,O-Me-T ry2,Arg8] vasopressin (10 micrograms/kg; i.v.), given 5 min after i.c.v. choline (150 micrograms), abolished the pressor effect of choline and blood pressure returned to the pre-choline levels. It is concluded that the precursor of acetylcholine, choline, can increase blood pressure and reverse hypotension in alpha-adrenoceptor or ganglionic transmission blocked rats, by increasing plasma vasopressin.

Effect of intracerebroventricularly injected choline on plasma ACTH and beta-endorphin levels in conscious rats.

In the present study, we examined the effect of intracerebroventricularly injected choline on plasma ACTH (adrenocorticotrophin) and beta-endorphin levels in conscious rats. The intracerebroventricularly injection of choline (50-150 micrograms) elevated plasma ACTH levels in a dose-dependent manner. Plasma beta-endorphin levels were also significantly increased. Pretreatment of rats with mecamylamine (50 micrograms; intracerebroventricularly), the nicotinic receptor antagonist, completely inhibited the ACTH and beta-endorphin response to choline (150 micrograms; intracerebroventricularly). An antagonist of the muscarinic receptor, atropine (10 micrograms; intracerebroventricularly), failed to alter these effects. Pretreatment of rats with hemicholinium-3 (20 micrograms; intracerebroventricularly), a drug which inhibits the uptake of choline into cholinergic neurons, abolished the choline-induced increases in both plasma ACTH and beta-endorphin levels. These results indicate that choline can increase plasma concentrations of ACTH and beta-endorphin through the activation of central nicotinic acetylcholine receptors.

Choline's phosphorylation in rat striatal slices is regulated by the activity of cholinergic neurons.

The mechanism by which populations of brain cells regulate the flux of choline (Ch) into membrane or neurotransmitter biosynthesis was investigated using electrically stimulated superfused slices of rat corpus striatum. [Me-14C]Ch placed in the superfusion medium for 30 min during a 1-h stimulation period was incorporated into tissue [14C] phosphorylcholine (PCh) and [14C]phosphatidylcholine (PtdCh). Stimulation also caused a profound inhibition of PCh synthesis and a 10-fold increase in [14C]ACh release into the medium; it failed to affect tissue [14C]ACh levels. This effect was not explained by changes in ATP levels nor in the kinetic properties of Ch kinase (E.C. 2.7.1.32) or Ch acetyltransferase (ChAT) (E.C.2.3.1.7). To investigate the mechanism of these effects, Ch uptake studies were performed with and without hemicholinium-3 (HC3), a selective inhibitor of high affinity Ch uptake. A two-compartment model accurately fit the observed data and yielded a K(m) for Ch uptake of 5 microM into cholinergic structures and 72 microM into all other cells. Using this model it was estimated that cholinergic neurons account for 60% of observed uptake of Ch at physiologic Ch concentrations, even though they represent fewer than 1% of the total cells in the slice. The model also predicts that an increase in Ch uptake within cholinergic neurons, reported to be associated with depolarization [4,27,32], would significantly inhibit Ch uptake into all other cells, and would account for the observed decrease in PCh synthesis.

Intracerebroventricular injection of choline increases plasma oxytocin levels in conscious rats.

In the present study, we examined the effect of intracerebroventricularly (i.c.v.) injected choline on both basal and stimulated oxytocin release in conscious rats. I.c.v. injection of choline (50-150 micrograms) caused time- and dose-dependent increases in plasma oxytocin levels under normal conditions. The increase in plasma oxytocin levels in response to i.c.v. choline (150 micrograms) was greatly attenuated by the pretreatment of rats with atropine (10 micrograms; i.c.v.), muscarinic receptor antagonist. Mecamylamine (50 micrograms; i.c.v.), a nicotinic receptor antagonist, failed to suppress the effect of 150 micrograms choline on oxytocin levels. Pretreatment of rats with 20 micrograms of hemicholinium-3 (HC-3), a specific inhibitor of choline uptake into nerve terminals, greatly attenuated the increase in plasma oxytocin levels in response to i.c.v. choline injection. Osmotic stimuli induced by either oral administration of 1 ml hypertonic saline (3 M) following 24-h dehydration of rats (type 1) or an i.c.v. injection of hypertonic saline (1 M) (type 2) increased plasma oxytocin levels significantly, but hemorrhage did not alter basal oxytocin concentrations. The i.c.v. injection of choline (50, 150 micrograms) under these conditions caused an additional and significant increase in plasma oxytocin concentrations beyond that produced by choline in normal conditions. These data show that choline can increase plasma oxytocin concentrations through the stimulation of central cholinergic muscarinic receptors by presynaptic mechanisms and enhance the stimulated oxytocin release.

Restoration of blood pressure by choline treatment in rats made hypotensive by haemorrhage.

1. Intracerebroventricular (i.c.v.) injection of choline (25-150 micrograms) increased blood pressure in rats made acutely hypotensive by haemorrhage. Intraperitoneal administration of choline (60 mg kg-1) also increased blood pressure, but to a lesser extent. Following i.c.v. injection of 25 micrograms or 50 micrograms of choline, heart rate did not change, while 100 micrograms or 150 micrograms i.c.v. choline produced a slight and short lasting bradycardia. Choline (150 micrograms) failed to alter the circulating residual volume of blood in haemorrhaged rats. 2. The pressor response to i.c.v. choline (50 micrograms) in haemorrhaged rats was abolished by pretreatment with mecamylamine (50 micrograms, i.c.v.) but not atropine (10 micrograms, i.c.v.). The pressor response to choline was blocked by pretreatment with hemicholinium-3 (20 micrograms, i.c.v.). 3. The pressor response to i.c.v. choline (150 micrograms) was associated with a several fold increase in plasma levels of vasopressin and adrenaline but not of noradrenaline and plasma renin. 4. The pressor response to i.c.v. choline (150 micrograms) was not altered by bilateral adrenalectomy, but was attenuated by systemic administration of either phentolamine (10 mg kg-1) or the vasopressin antagonist [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2,Arg8]-vasopressin (10 micrograms kg-1). 5. It is concluded that the precursor of acetylcholine, choline, can increase and restore blood pressure in acutely haemorrhaged rats by increasing central cholinergic neurotransmission. Nicotinic receptor activation and an increase in plasma vasopressin and adrenaline level appear to be involved in this effect of choline.

Evidence that 5'-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels.

We examined the effects of orally administered 5'-cytidinediphosphocholine (CDP-choline) on arterial plasma choline and cytidine levels and on brain phospholipid composition in rats. Animals receiving a single oral dose of 100, 250, or 500 mg/kg showed peak plasma choline levels 6-8 h after drug administration (from 12 +/- 1 to 17 +/- 2, 19 +/- 2, and 24 +/- 2 microM, respectively). The area under the plasma choline curve at > 14 microM, i.e., at a concentration that induces a net influx of choline into the brain, was significantly correlated with CDP-choline dose. In rats receiving 500 mg/kg this area was 2.3 times that of animals consuming 250 mg/kg, which in turn was 1.8 times that of rats receiving 100 mg/kg. Plasma cytidine concentrations increased 5.4, 6.5, and 15.1 times baseline levels, respectively, 8 h after each of the three doses. When the oral CDP-choline treatment was prolonged for 42 and 90 days, brain phosphatidylcholine concentrations increased significantly (by 22-25%; p < 0.05) in rats consuming 500 mg/kg/day. Brain phosphatidylethanolamine and phosphatidylserine concentrations also increased significantly under some experimental conditions; levels of other phospholipids were unchanged.

Effect of cytidine on membrane phospholipid synthesis in rat striatal slices.

Using rat striatal slices, we examined the effect of cytidine on the conversion of [3H]choline to [3H]-phosphatidylcholine ([3H]PC), and on net syntheses of PC, phosphatidylethanolamine (PE), and phosphatidylserine, when media did or did not also contain choline, ethanolamine, or serine. Incubation of striatal slices with cytidine (50-500 microM) caused dose-dependent increases in intracellular cytidine and cytidine triphosphate (CTP) levels and in the rate of incorporation of [3H] choline into membrane [3H]PC. In pulse-chase experiments, cytidine (200 microM) also increased significantly the conversion of [3H]choline to [3H]PC during the chase period. When slices were incubated with this concentration of cytidine for 1 h, small (7%) but significant elevations were observed in the absolute contents (nmol/mg of protein) of membrane PC and PE (p < 0.05), but not phosphatidylserine, the synthesis of which is independent of cytidine-containing CTP. Concurrent exposure to cytidine (200 microM) and choline (10 microM) caused an additional significant increase (p < 0.05) in tissue PC levels beyond that produced by cytidine alone. Exposure to choline alone at a higher concentration (40 microM) increased the levels of all three membrane phospholipids (p < 0.01); the addition of cytidine, however, did not cause further increases. Concurrent exposure to cytidine (200 microM) and ethanolamine (20 microM) also caused significantly greater elevations (p < 0.05) in tissue PE levels than those caused by cytidine alone. In contrast, the addition of serine (500 microM) did not enhance cytidine's effects on any membrane phospholipid. Exposure to serine alone, however, like exposure to sufficient choline, increased levels of all three membrane phospholipids significantly (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intracerebroventricular injected choline on cardiovascular functions and sympathoadrenal activity.

Intracerebroventricular (i.c.v.) injection of choline (50-150 micrograms) increased blood pressure (SP) and decreased heart rate (HR) in freely moving rats. Intracerebroventricular pretreatment of rats with mecamylamine (50 micrograms) blocked the reduction in HR and reduced the increase in SP induced by i.c.v. choline (150 micrograms). Central muscarinic blockade with atropine (10 micrograms, i.c.v.) reduced the pressor response to i.c.v. choline (150 micrograms) by about 70%, without influencing the decrease in HR. The decrease in HR induced by i.c.v. choline was prevented by intraarterial (i.a.) treatment of atropine methylnitrate (2 mg/kg). Intracerebroventricular choline (150 micrograms) produced a fivefold increase in catecholamine concentrations in adrenal venous plasma. Bilateral adrenalectomy reduced, but did not block, choline's effect on SP. Intracerebroventricular choline (150 micrograms) showed an ability to increase and restore SP in rats subjected to spinal cord transection or pretreatment with hexamethonium (15 mg/kg, i.a.) or with phentolamine (10 mg/kg, i.a.). Intracerebroventricular choline (150 micrograms) increased plasma vasopressin (VP) levels from 2.2 +/- 0.4 to 25.6 +/- 2.5 pg/ml. Pretreatment of rats with a VP antagonist reduced the pressor response to i.c.v. choline. It is concluded that (a) the reduction in HR results from a central nicotinic receptor-mediated increase in vagal tone, (b) the increase in SP appears to be due to activation of both nicotinic and muscarinic central cholinergic receptors, and that (c) the central activation of the adrenal medulla and the increase in plasma levels of VP are involved in the pressor response to i.c.v. choline.