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Enhancement of memory processing in an inhibitory avoidance and radial maze task by post-training infusion of bombesin into the nucleus tractus solitarius.

Bombesin is a peptide known to modulate memory storage when given either systemically or intraventricularly immediately after training. Two experiments were conducted to determine whether the nucleus of the solitary tract (NTS) mediates the effects of bombesin on memory. In the first experiment male Sprague-Dawley rats were trained in an inhibitory avoidance task (0.35 mA, 0.5 s footshock) and bombesin or vehicle was infused unilaterally into the NTS through implanted cannulae immediately after training. Retention was assessed either 2 or 7 days later. Doses of 25 or 50 ng of bombesin significantly enhanced retention on the 2 day test (P < 0.05 and 0.01 compared with vehicle controls, respectively). There were no differences between the drug and control groups on the 7 day retention test. In the second experiment, bombesin (25, 50, or 250 ng) or vehicle was infused unilaterally into the NTS immediately after the animals were trained in a win-shift radial arm maze task. On retention tests given 18 h later, groups that received 25 ng or 50 ng of bombesin made a significantly greater percentage of correct choices on the retention test than did the vehicle-treated controls (P < 0.02 and P < 0.05, respectively). The findings indicating that bombesin influences retention by activating the NTS is consistent with recent evidence suggesting that the NTS is involved in regulating memory storage.

Analysis of Variance↗

Independent receptors for pressor and drinking responses to central injections of angiotensin II and carbachol.

Angiotensin II and carbachol when injected in the brain ventricles of the rat produce similar responses of an increase in blood pressure and drinking behavior. The question of whether these effects are produced by independent receptors or via a cholinergic circuit is debatable for the drinking behavior and evidence is lacking for the blood pressure effect. We have used a chronic rat preparation for recording blood pressure and drinking at the same time during intraventricular injections (i.v.t.) of both angiotensin and carbachol and i.v.t. or intravenous infusions of appropriate antagonists. The results show that drinking and blood pressure response to angiotensin II can be blocked by P113 (500 ng 1.v.t.) an angiotensin antagonist; they are not blocked by atropine (10 mug i.v.t.) a cholinergic antagonist; carbachol effects, however, are not blocked by P113, but are totally blocked by atropine (10 mug i.v.t.), At high doses of atropine there is inhibition of both agents but this probably represents a general inhibition. The hormone and cholinomimetic administered together interact and both are inhibited by adrenergic stimulation. We conclude from these experiments that angiotensin and carbachol act upon independent receptors in the brain to produce blood pressure and drinking responses but at some point they share common, central effector pathways.

Angiotensin II↗

Cellular and molecular neurosurgery: pathways from concept to reality--part II: vector systems and delivery methodologies for gene therapy of the central nervous system.

Different vector systems that have been used and/or specifically developed for central nervous system (CNS) gene transfer studies are briefly discussed along with their advantages and disadvantages with respect to potential clinical application. These include retroviruses, recombinant herpes simplex virus, adenoviruses, adenoassociated viruses, encapsulation of plasmid deoxyribonucleic acid into cationic liposomes, and neural and oliogodendroglial stem cells. Particular attention has been paid to relate the modality of a specific CNS gene therapy to the strategy for adequate delivery of genetic material to the brain for either global or localized CNS neurodegenerative chronic disorder, as well as for CNS tumors and stroke. Techniques to circumvent the "impermeable" blood-brain barrier and how to breach the more versatile blood-brain-tumor barrier to deliver the genetic material to the target CNS cells are reviewed and include the following: 1) local stereotactic CNS injection/infusion of viral vectors, administration of vector producer cells, or cell replacement; 2) local administration of genetic material into the cerebrospinal fluid ventriculocisternal system; 3) osmotic opening of the blood-brain barrier; 4) local intra-arterial infusion; and 5) administration of blood-brain-tumor barrier permeabilizers, such as a bradykinin B2 agonist RMP-7. It is concluded that gene therapy for several brain disorders holds great potential, as suggested mainly by in vitro experiments and, to some extent, by a limited number of animal experiments. However, several drawbacks currently hamper the application of gene therapy under the clinical setting. The problems associated with gene therapy that still present major obstacles are as follows: 1) inefficient transfection of host cells by viral vectors; 2) restricted delivery of genetic material across vascular barriers of the CNS and brain tumors; 3) nonselective expression of the transgene; and 4) in situ CNS regulation of the transgene expression in a therapeutically controlled manner, as imposed by the course and phenotype of the CNS disease.

Animals↗

Inhibitory effect of aprotinin on gastric acid secretion.

Aprotinin was found to inhibit the amplitude of electrically stimulated contractions of the isolated guinea pig ileum with an ID50 of 6.75 X 10(-6) M. Aprotinin inhibited pentagastrin-stimulated gastric acid secretion in the rat, cat, and pig after oral or intraventricular administration. No inhibition of gastric acid secretion was seen after intravenous infusion of aprotinin. When segments of antrum, duodenum, and ileum were incubated in vitro with increasing concentrations of aprotinin, increasing amounts of somatostatin were released from the organs. It is suggested that aprotinin's effects, which are similar to those of somatostatin, may be due to a local release of somatostatin from the D-cells in the gastrointestinal tract.

Animals↗

Differentiated metabolic stimulation of rat pituitary lobes by peripheral and central endothelin-1.

Intravenous infusion (14 nmol/min) and lateral cerebral ventricular injection (9 pmol) of endothelin-1 increased rates of glucose utilization (quantitative autoradiographic [14C]deoxyglucose method) by 75-219% in pars intermedia and distalis of the rat pituitary gland. In rats given intraventricular endothelin, glucose metabolism was also increased significantly in pars nervosa (+92%). Metabolic activation by central endothelin in pars intermedia and distalis was inhibited by intraventricular pretreatment with the dihydropyridine, nimodipine, indicating that endothelin stimulates energy metabolism and probably hormone secretion in melanotrophs and pars distalis cells via L-type calcium channels.

Animals↗

[Electrophysiologic effects of intravenous 3-hydroxy-dihydroquinidine (LNC-834) in man].

The object of this study was to determine the electrophysiological effects of 3-hydroxy-dihydroquinidine (3-OH-HQ) in man. The electrophysiological parameters were measured in 12 patients before and after intravenous infusion of 5 mg/kg of 3-OH-HQ in 15 minutes. The mean plasma concentrations obtained varied from 2.4 +/- 1.1 mg/l at the 20th minute to 0.9 +/- 0.3 mg/l at the 60th minute. In these concentrations, 3-OH-HQ did not cause hypotension or affect the heart rate and nodal conduction. It did, however, prolong infra-hisian and intraventricular conduction and ventricular repolarisation from the 20th to the 60th minute after starting the infusion. The peak effect was observed at the 20th minute (+19 +/- 3.4 ms; +14.6 +/- 3.5 ms; and +44.5 +/- 6.6 ms, respectively). The 3-OH-HQ increased the effective atrial and ventricular refractory periods at the 30th minute (+21.8 +/- 5.5 ms and +22.3 +/- 7 ms, respectively). However, the ventricular effect only was discernable at the 60th minute. These effects are quantitatively comparable to those of quinidine. Extrapolation of these results to the effects of chronic oral treatment should be reserved as the therapeutic zone of this new molecule has not yet been determined.

Aged↗

Treatment of accidental high dose intraventricular mezlocillin application by cerebrospinal fluid exchange.

An accidental high dose of intraventricular mezlocillin was given during antibiotic treatment for pneumonia in a patient admitted because of severe traumatic brain injury and occlusive hydrocephalus. Because of serial epileptic seizures not responsive to antiepileptic drug treatment, CSF exchange was performed. The CSF was drained through a ventricular catheter, while mock CSF was infused into the lumbar subarachnoid space. The patient soon recovered to her clinical status previous to intraventricular mezlocillin application. Side effects of CSF exchange were not seen. Under continued antiepileptic medication no more seizures occurred. It is concluded that high doses of intraventricular mezlocillin have proconvulsive effects. In this patient CSF exchange was a suitable means of preventing putatively permanent impairment of brain function caused by serial epileptic seizures due to intraventricular mezlocillin application.

Adult↗

Effects of increased heart rate and sympathetic tone on intraventricular electrogram morphology.

Electrogram pattern recognition by way of morphologic analysis has been proposed as a technique that may improve discrimination of ventricular tachycardia from sinus rhythm by antitachycardia devices. The potential impact that increases in heart rate and sympathetic tone could have on such techniques, however, has not been previously determined. A comparative study was undertaken to quantify possible changes in ventricular electrogram morphology using correlation waveform, area of difference, and amplitude analyses in 6 patients during atrial overdrive pacing at cycle lengths of 600 and 400 ms (group A), in 13 patients during infusions of physiologic doses of epinephrine (group B), and in 20 patients undergoing infusions of isoproterenol (group C). Four patients were in both groups A and B. A bipolar intraventricular template of cardiac depolarization during sinus rhythm at rest was compared with depolarization during subsequent passages of sinus rhythm at rest and subsequently increased heart rate. In 36 of 39 patients, waveform configuration as assessed by correlation waveform analysis remained relatively stable during atrial overdrive pacing, epinephrine infusion, and isoproterenol infusion when compared with sinus rhythm at rest. The correlation value did not fall below 0.950 in any patient. Area of difference values for the same 36 patients changed by an average of 6 and 37% during atrial overdrive pacing at cycle lengths of 600 and 400 ms intervals, respectively, by 3% during epinephrine infusion, and by 17% during isoproterenol infusion. In these same patients, there was an average change in electrogram amplitude of -1% during atrial overdrive pacing at 600 ms, 26% during pacing at 400 ms, -1% during epinephrine infusion, and 12% during isoproterenol infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

The effect of lactate infusion on myocardial metabolism and ventricular function following ischemia and cardioplegia.

Impaired myocardial fatty acid and glucose metabolism following ischemia and cardioplegia may limit the recovery of myocardial oxidative metabolism and ventricular function. Lactate, a simple three carbon compound, can be readily metabolized to pyruvate and is possibly the preferred substrate for aerobic metabolism. Therefore, increasing arterial lactate concentrations may improve myocardial metabolic recovery after ischemia and cardioplegia. Myocardial lactate metabolism and ventricular function were assessed in a canine model of 45 mins of global normothermic ischemia followed by 60 mins of cold potassium cardioplegic arrest. Thirteen dogs received a perioperative infusion of sodium lactate to elevate arterial concentrations (from 6 to 12 mmol/L) and 12 dogs received an equivalent amount of saline. The high arterial lactate concentrations were associated with an increased myocardial lactate consumption and oxidation (as assessed by 14C-labelled lactate) during reperfusion. Myocardial ATP concentrations fell during reperfusion despite improved myocardial oxidation. The recovery of ventricular function (as assessed by a compliant intraventricular balloon) was incomplete and only marginally better with the high arterial lactate concentrations. An infusion of lactate improved myocardial oxidative metabolism following ischemia and cardioplegia. However, the recovery of ventricular function was incomplete perhaps because of inadequate preservation of myocardial ATP.

Adenosine Triphosphate↗

Stability, clearance, and disposition of intraventricularly administered oligodeoxynucleotides: implications for therapeutic application within the central nervous system.

We report experiments in the rat demonstrating the feasibility of intraventricular administration of oligodeoxynucleotides (ODNs) as a regional treatment approach to disorders within the central nervous system (CNS). Although we find little intrinsic nuclease activity in cerebrospinal fluid (CSF), phosphodiester ODNs are rapidly degraded by brain-associated alpha-exonuclease activity. Phosphorothioate ODNs, however, appear resistant to degradation in the CNS and, after intraventricular administration, we find they are cleared in a manner consistent with CSF bulk flow. Continuous infusion of ODN at 1.5 nmol/hr by miniosmotic pump can maintain micromolar concentrations of intact phosphorothioate ODN in CSF for at least 1 week without obvious neurologic or systemic toxicity. After infusion, extensive brain penetration and marked cellular uptake, especially by astrocytic cells, is demonstrated.

Animals↗

Effects of isoproterenol and propranolol on pharmacologically induced depression of intraventricular conduction.

The cardiac adrenergic system is known to have practically no influence on conduction velocity in the ventricles under normal conditions. The effects of isoproterenol and propranolol were investigated on depression of intraventricular conduction induced by a class IC antiarrhythmic drug, cibenzoline, in anaesthetized, closed-chest dogs. In addition to electrocardiogram for measurement of QRS duration in sinus rhythm, conduction time was measured in the ventricular contractile tissue between an electrode advanced to the apex and a pacing electrode near the base, at 400- and 200-ms pacing periods. Effective refractory period (ERP) was measured concurrently according to the extrastimulus method. After intraventricular conduction had been slowed down by cibenzoline IV administered (loading dose of 3 mg/kg plus infusion of 0.2 mg/kg/min over 15 min), isoproterenol was infused or propranolol injected by the intravenous route also (0.5 mn/micrograms/kg/min over 5 min and 0.4 mg/kg, respectively). When conduction time has been raised by 75/150% (depending on the pacing rate), isoproterenol appears to attenuate and propranolol to aggravate substantially the impairment of conduction, whereas the reduction undergone by ERP does not differ from usual. Thus, reentrant arrhythmias might be prevented by isoproterenol and triggered by propranolol. Intraventricular conduction, when depressed, therefore, is sensitive to adrenergic drugs, probably because of the enhanced influence of polarization of the fibres in the presence of a sodium conductance impairment.

Animals↗

Mechanism of suppression of vasopressin and adrenocorticotropic hormone secretion by clonidine in anesthetized dogs.

Studies were performed in anesthetized dogs to investigate the mechanism of the suppression of vasopressin and adrenocorticotropic hormone (ACTH) secretion by clonidine. Injection of clonidine (30 micrograms/kg i.v.) produced an initial increase in arterial pressure followed by hypotension, decreased heart rate, increased right atrial pressure and decreased plasma renin activity. Plasma vasopressin concentration decreased from 14.6 +/- 3.0 to 2.2 +/- 0.4 pg/ml (P less than .01), and this was accompanied by increases in urine volume and free water clearance from 0.15 +/- 0.02 to 1.03 +/- 0.28 and -0.50 +/- 0.05 to 0.30 +/- 0.27 ml/min, respectively (P less than .01), and a decrease in urinary osmolality from 1450 +/- 124 to 372 +/- 97 mOsmol/kg of H2O (P less than .01). Plasma corticosteroid concentration, used an an index of ACTH secretion, decreased from 8.9 +/- 1.6 to 2.2 +/- 0.3 micrograms/dl (P less than .01). Plasma osmolality did not change. Pretreatment of dogs with the alpha adrenoceptor antagonist yohimbine (2 mg/kg i.p.) blocked all cardiovascular, endocrine and renal responses to clonidine. Bilateral cervical vagotomy did not block the suppression of vasopressin or corticosteroid secretion by clonidine. Intraventricular injection of yohimbine blocked the hypotension and suppression of plasma corticosteroid concentration produced by clonidine but did not block the decrease in plasma vasopressin concentration or the associated renal effects of clonidine. Intracarotid infusion of clonidine caused small decreases in plasma vasopressin and corticosteroid concentrations even though blood pressure decreased by 22 mm Hg. Intraventricular and intravertebral clonidine had no significant effect on plasma vasopressin or corticosteroid concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

Magnesium is more efficacious than phenytoin in reducing N-methyl-D-aspartate seizures in rats.

OBJECTIVE: Although magnesium sulfate is one of the most commonly used agents for seizure prophylaxis in preeclampsia, its efficacy relative to other anticonvulsants is incompletely investigated. The underlying mechanisms of eclamptic seizures are unknown, and there is currently no universally accepted animal model for eclampsia. However, one commonly used method for studying the relative efficacy of antiepileptic drugs is through their effect on N-methyl-D-aspartate-induced seizures. Our aim was to compare the anticonvulsant effects of phenytoin and magnesium sulfate in an N-methyl-D-aspartate-induced seizure model. STUDY DESIGN: Twenty-one female rats were each stereotaxically implanted with a chronic indwelling bipolar recording electrode in the hippocampus and an injection cannula in the lateral cerebral ventricle. After 7 days animals were randomly given 90 mg/kg magnesium sulfate (n = 7), 50 mg/kg phenytoin, or saline solution (n = 7) intravenously. Fifteen minutes after the infusions animals were given 20 micrograms/microliters N-methyl-D-aspartate by direct intraventricular injection, and seizure activity was assessed for 20 minutes thereafter. All data were analyzed with the Mann-Whitney test. RESULTS: When compared with saline solution controls, total duration of seizure activity in animals treated with magnesium sulfate was significantly decreased (p < 0.05) and time to onset of seizure activity was significantly increased (p < 0.05). However, rats that received phenytoin did not show significant changes in these parameters. The post-N-methyl-D-aspartate seizure mortality rate was 50% in the saline solution controls and 29% in the phenytoin group, whereas none of the rats that received magnesium sulfate died. CONCLUSION: These results suggest that magnesium sulfate is a significantly more effective prophylactic agent than phenytoin for N-methyl-D-aspartate-induced seizures.

Animals↗

Role of transmitters in mediating hypothalamic control of electrolyte excretion.

Changes in urinary volume and electrolyte excretion were monitored after the injection of cholinergic and monoaminergic drugs into the third cerebral ventricle of conscious male rats made diuretic by an intravenous infusion of 5% dextrose. A natriuretic and kaliuretic response was induced by the intraventricular injection of norephrine (NE) or carbachol, whereas dopamine (DA) had no effect. The beta-receptor stimulator isoproterenol (ISO) induced an antinatriuretic and antikaliuretic effect. Intraventricular injection of the alpha-adrenergic blocker phentolamine abolished the natriuretic response to NE and carbachol and to intraventricular hypertonic saline (HS). By contrast, the beta-adrenergic blocker propranolol induced a natriuresis and kaliuresis when injected alone and an additive effect when its injection was followed by NE or HS. Propranolol potentiated the natriuretic response to carbachol. Cholinergic blockade with atropine diminished the response to NE and blocked the natriuretic response to HS. It is suggested that sodium receptors in the ventricular wall can modify renal sodium excretion via a stimulatory pathway involving cholinergic and alpha-adrenergic receptors and can inhibit sodium excretion via a tonically active beta-receptor pathway.

Animals↗

Echocardiographic assessment of left ventricular wall motion in hypertrophic cardiomyopathy.

M-mode and two-dimensional parasternal long axis view echocardiography, and left anterior oblique cineangiography were employed to assess the left ventricular wall motion in 10 normal subjects (N) and in 25 patients with hypertrophic cardiomyopathy: 7 patients with symmetric hypertrophy (SH) and 6 patients with apical cardiomyopathy (AHCM) and no intraventricular gradient; 12 patients with hypertrophic obstructive cardiomyopathy and asymmetric septal hypertrophy with resting intraventricular gradient (6 pts) (HOCM-R) or gradient occurring only after isoproterenol infusion (6 pts) (HOCM-I). The left ventricle was divided into five portions: upper and lower septum, upper and lower posterior wall and apex. The excursion and thickness of the upper and lower portions of the septum and posterior wall were measured in all patients and compared to 10 normal subjects (N). From the superimposed end-diastolic and end-systolic echo frames and angio silhouettes a chordal and a radial-chordal method were used, respectively, to measure the motion of the left ventricular wall segments. In SH the left ventricular wall motion was qualitatively similar to N but a little reduced; the thickness was increased and no pressure gradient was present. In AHCM the lower septum, posterior wall, and apex showed significantly increased thickness and motion compared to N and compared to the upper portions of the septum and posterior wall. No gradient was present. In HOCM-R the upper septum moved towards the apex, the lower septum, upper posterior wall and lower posterior wall moved towards the left ventricular cavity. The upper posterior wall was hyperkinetic compared to N and compared to the lower posterior wall, resting gradient and SAM was present in all. In HOCM-I the upper septum moved towards the apex; the posterior wall was hyperkinetic (the excursion was a little wider in the lower posterior wall than in the upper posterior wall). No gradient was recorded at rest, but it could be provoked by isoproterenol. Echocardiography provides precise information on left ventricular wall motion in hypertrophic cardiomyopathy. Hyperkinesis of the lower left ventricular wall is related to AHCM; hyperkinesis of the upper posterior wall and the motion of the upper septum towards the apex are related to HOCM-R. Hyperkinesis of the lower posterior wall is related to HOCM-I. SAM and pressure gradients may be related to the hyperkinesis of the upper posterior wall. Finally, the septum is not an immobile structure in HOCM, since it moves mainly from the base to the apex and a less (or not at all) towards the posterior wall.

Cardiac Catheterization↗

Intraventricular glucose blocks feeding induced by 2-deoxy-D-glucose but not mercaptoacetate.

Previous results have shown that IV infusion of glucose reduces feeding induced by systemic administration of 2-deoxy-D-glucose (2-DG) or 2-mercaptoacetate (MA) in rats. Because glucose is a metabolic substrate for both central and peripheral tissues, the suppression of feeding by glucose could result from either a central or peripheral metabolic effect. In the present experiment we attempted to clarify the mechanism of glucose-induced suppression of feeding induced by 2-DG and MA by administering glucose centrally during systemic metabolic challenge. Administration of glucose into the lateral ventricle was begun immediately after systemic injection of 2-DG or MA and continued intermittently during the 2-h feeding test. We found that central glucose administration significantly reduced 2-DG- but not MA-induced feeding. These results suggest that the central effects of glucose are sufficient to suppress feeding induced by systemic 2-DG and support the hypothesis that receptors responsible for 2-DG-induced feeding are located in the brain.

Animals↗

The use of intraventricular resorption tests (IVT) in the management of hydrocephalic children.

Ventricular fluid outflow resistance was determined by steady state infusion of artificial CSF in the lateral ventricle in 35 children in whom the decision for a shunt procedure was judged to be uncertain. Such testing allows direct shunting when found indicated and unnecessary shunting can be avoided. The test was found helpful in 11 children to evaluate the need for continued shunting, assessment of indwelling shunts and establishment of a basis to remove the shunt.

Absorption↗

Central actions of adenosine on pituitary secretion of prolactin, luteinizing hormone and thyrotropin.

Pituitary hormones were measured in plasma in unanesthetized male and female rats prepared with venous and ventricular cannulae following ventricular infusions of adenosine and two adenosine receptor agonists. Adenosine (10, 100, and 200 nmol) injected intraventricularly caused dose-related rises in plasma prolactin (PRL) in males; in females, only the 100- and 200-nmol doses increased PRL. Similar doses of adenosine had little effect on plasma levels of luteinizing hormone (LH) and thyrotropin (TSH) in the same animals. The adenosine receptor agonists L-N6-phenylisopropyladenosine (L-PIA) and 5'-N-ethyl-carboxamideadenosine (NECA) potently stimulated prolactin secretion at doses of 10 and 50 nmol when administered into the lateral ventricle, and at a dose of 2.5 nmol when administered into the third ventricle. The secretion of PRL was antagonized by the adenosine receptor antagonist theophylline (25 nmol), when theophylline was coadministered with NECA and L-PIA. TSH levels were reduced slightly but significantly following the 10- and 50-nmol infusions of L-PIA into the lateral ventricle. The less potent D-isomer of PIA (D-PIA) did not significantly stimulate PRL release. Coupled with studies indicating the presence of adenosine in the basal hypothalamus, our observations indicate a potential neuroendocrine role for this purine in prolactin secretion.

Adenosine↗