Intracerebroventricular infusion but not bolus injection of vasopressin increases the cerebrospinal fluid pressure in awake rabbits

The effect of intracerebroventricular infusion or injection of arginine vasopressin (AVP) was examined in awake rabbits with permanent ventricular cannulae. Intracerebroventricular infusion of artificial cerebrospinal fluid (CSF) 43 μl min^–1 containing AVP concentrations exceeding 0.4 ng ml^–1, equivalent to an AVP infusion rate of 17.2 pg min^–1, caused a dose-dependent increase in intracranial pressure (ICP) of 3 to 5 mmHg after 30-50 min of AVP infusion. Intracerebroventricular bolus injection of equivalent doses of AVP did not provoke changes in ICP. At the end of the experiments cisternal CSF concentrations of AVP were higher after infusion of AVP than after injection of the same amount of AVP. The mean arterial blood pressure increased slightly in the group of animals infused with AVP at rates above 17.2 pg min^–1. It is concluded that intracerebroventricular infusion of AVP increases ICP in awake rabbits but the mechanism responsible for the elevation of ICP remains speculative.     

Intracerebroventricular infusion but not bolus injection of vasopressin increases the cerebrospinal fluid pressure in awake rabbits

The effect of intracerebroventricular infusion or injection of arginine vasopressin (AVP) was examined in awake rabbits with permanent ventricular cannulae. Intracerebroventricular infusion of artificial cerebrospinal fluid (CSF) 43 microliters min-1 containing AVP concentrations exceeding 0.4 ng ml-1, equivalent to an AVP infusion rate of 17.2 pg min-1, caused a dose-dependent increase in intracranial pressure (ICP) of 3 to 5 mmHg after 30-50 min of AVP infusion. Intracerebroventricular bolus injection of equivalent doses of AVP did not provoke changes in ICP. At the end of the experiments cisternal CSF concentrations of AVP were higher after infusion of AVP than after injection of the same amount of AVP. The mean arterial blood pressure increased slightly in the group of animals infused with AVP at rates above 17.2 pg min-1. It is concluded that intracerebroventricular infusion of AVP increases ICP in awake rabbits but the mechanism responsible for the elevation of ICP remains speculative.     

Cerebrospinal fluid neurohypophysial peptides in benign intracranial hypertension.

The cerebrospinal fluid (CSF) concentrations of arginine vasopressin (AVP) and oxytocin (OT) were investigated both in patients with benign intracranial hypertension and in age and sex matched controls. Twenty eight lumbar punctures were performed on 15 patients with benign intracranial hypertension as part of their routine investigation and therapy. All patients had raised intracranial pressure (27.4, SE 1.7 cm.CSF). CSF AVP levels were significantly elevated in benign intracranial hypertension (2.1, SE 0.3 pmol/l) compared with controls (0.7, SE 0.1 pmol/l, p less than 0.001) but CSF OT concentrations were similar in both groups. CSF osmolality and plasma AVP and osmolality were identical in patients and controls. There was no correlation between CSF AVP concentration and intracranial pressure. The selective elevation of AVP in CSF may be of importance in the pathogenesis of raised intracranial pressure in benign intracranial hypertension.     

Central and peripheral release of vasopressin and oxytocin in the conscious rat after osmotic stimulation

Vasopressin (AVP) and oxytocin (OXT) were measured by radioimmunoassay in push-pull perfusates and tissue samples of various brain areas, plasma and cerebrospinal fluid (CSF) of male rats in response to osmotic stimulation. Hypertonic saline caused a significant rise in plasma AVP and OXT and different changes in peptide contents, in the septum and hippocampus at 30 and 60 min after intraperitoneal injection. Push-pull perfusion (20 microliters artificial CSF/min, 30-min periods) of the septum and dorsal hippocampus of conscious, unrestrained animals revealed a significant, stimulus-evoked release of both AVP and OXT. This release was: (1) not always reflected by corresponding changes in the regional peptide content; (2) simultaneous with the peripheral release from the posterior pituitary; and (3) probably the result of synaptic/parasynaptic events as suggested by use of agents in the artificial CSF which either inhibit or facilitate the release from intact fibre terminals.     

Vasopressin in the cerebrospinal fluid of febrile children with or without seizures

Immaturity in water and electrolyte balance in the brain has been considered to increase the susceptibility of young animals and children to febrile convulsions (FCs). Arginine-vasopressin (AVP) is involved in the regulation of several centrally mediated events such as modulation of fever and the ease with which water permeates into and out of the brain. To evaluate the possible role of AVP in the control of water balance and susceptibility to convulsions during fever we measured the AVP concentration in the cerebrospinal fluid (CSF) and plasma of febrile children with or without convulsions. The febrile population consisted of 47 children, of whom 29 experienced seizures during fever. Seven children with epileptic symptoms and 18 children without seizures were included as nonfebrile controls. The CSF AVP concentration in febrile children without seizures and in nonfebrile convulsive children was significantly lower (0.60 ± 0.07 pmol / 1, mean ± SEM,P < 0.01 and 0.65 ± 0.19 pmol/l,P < 0.05, respectively) than in nonfebrile children without convulsions (0.83 ± 0.06 pmol/1). However, the levels of CSF AVP were not significantly different in children with FCs (0.71 ± 0.06 pmol/1) compared with other groups. CSF AVP correlated with the CSF osmolality (r = 0.33, P = 0.02). No statistical differences in plasma AVP levels between the groups could be found. The present data provide support for the hypothesis of synchronous regulation of osmolality and AVP concentration in CSF. During fever the concentration of CSF AVP was lower in nonconvulsive children compared with nonfebrile nonconvulsive children. CSF AVP levels were not affected in febrile children by convulsions.     

Cerebrospinal fluid pressure during cerebroventricular infusion of angiotensin and vasopressin

Rationale exists for suspecting that angiotensin (Ang) and arginine vasopressin (AVP) given by the intracerebroventricular (IVT) route can affect cerebrospinal fluid (CSF) pressure. This hypothesis was tested in conscious, unrestrained adult male Sprague-Dawley rats with IVT and left carotid arterial catheters. The rats were infused (IVT) for 30 min with artificial CSF followed by 30 additional minutes with CSF, Ang, (0.6 micrograms/h) AVP (5 or 50 ng/h), or AVP (5 or 50 ng/h) + Ang, (0.6 micrograms/h). Angiotensin evoked a central hypertensive effect (+ 16 mm Hg) and increased CSF pressure from 10 to 16 cm H2O (P less than 0.05). Neither dose of AVP affected blood or CSF pressures. The AVP (5 ng/h) prevented Ang-induced changes in blood and CSF pressures and AVP (50 ng/h) blocked only the Ang-induced rise in CSF pressure. These results raise the possibility that angiotensin and vasopressin participate in the regulation of CSF pressure.     

Mechanism of delayed intracranial hypertension after cerebroventricular infusions in conscious rats

Prior studies showed that cerebroventricular infusions of artificial cerebrospinal fluid, 8 μl/min for 10 min, followed by a 10 min rest and a 24 h infusion of 0.5 μl/min, raised cerebrospinal fluid pressure (CSFp) of conscious, unrestrained rats after about 2 h. Here, we report that the 10 min infusion alone evoked a delayed, prolonged rise in CSFp. Pressure during the infusion itself rose and recovered quickly, as is usually reported. Pressure/volume tests, used to calculate resistance to outflow (R_o) and compliance (C), revealed that infusions increasedR_o and decreasedC, after a delay (P < 0.05). The rise in CSFp after infusion was blocked by pretreatment with acetazolamide + ouabain (P < 0.05), but the delayed changes in R_o andC were unaffected. We suggest that the 10 min infusion of a sterile, balanced salt solution has a primary effect that increasesR_o; as CSF synthesis continues, C is exhausted and the delayed rise in CSFp ensues. This non-traumatic method of raising CSFp may be a useful method to study intracranial fluid dynamics.     

Vasopressin reduces release from vasopressin-neurons and oxytocin-neurons by acting on V2-like receptors

The effects of arginine vasopressin (AVP), and of the V2-AVP receptor agonist 1-deamino[8-D-arginine] vasopressin (DDAVP) on release from the vasopressin-neurons and oxytocin-neurons of Long-Evans rats were evaluated using specific radioimmunoassays for rat neurophysins. AVP (1 microgram, 1 nmol) or DDAVP (25 ng, 25 pmol) was administered i.p. to animals 1 h before they received an i.v. infusion of 18% saline at 10 microliters/100 g b. wt./min for 60 min. Both AVP and DDAVP decreased the responsiveness (slope) but not the sensitivity threshold of vasopressin-neurons to acute changes in plasma osmolality. Since the amounts of the peptides giving comparable decreases in responsiveness were directly related to their antidiuretic potencies, it is most probable that this influence is mediated through V2-like receptors. However, while ruling out a significant contribution of V1-type receptors, the data do not exclude involvement of other vasopressin receptors (e.g. V3-type receptors). Both AVP and DDAVP also appeared to have an inhibitory effect on release from oxytocin-neurons, but in this case they significantly altered sensitivity threshold but not responsiveness to acute changes in plasma osmolality. Because AVP produced a shift in sensitivity threshold larger than that by DDAVP when the peptides were used in amounts related to their antidiuretic potencies, our results suggest that the feedback influence of AVP on oxytocin-neurons is largely, although not entirely, exercised through V2-like receptors.     

Contribution of N-methyl-d-aspartate receptors in the anteroventral third ventricular region to vasopressin secretion,but not to cardiovascular responses provoked by hyperosmolality and prostaglandin E2 in conscious rats

The aim of this study is to pursue roles of N-methyl-d-aspartate (NMDA) receptors in the anteroventral third ventricular region (AV3V; a pivotal area for autonomic functions) in controlling vasopressin (AVP) release and cardiovascular system. In conscious rats, we examined effects of AV3V infusion of MK-801 (a selective antagonist for NMDA receptor) on plasma AVP, osmolality, electrolytes, arterial pressure and heart rate, in the absence or presence of NMDA, hyperosmotic or prostaglandin (PG) E2 stimulus. The AV3V infusion of NMDA caused significant increases in plasma AVP, osmolality and sodium, hematocrit, arterial pressure and heart rate after 5 or 15min. When NMDA was administered into the cerebral ventricle, relatively smaller elevations were observed only in plasma AVP and arterial pressure. The effects of AV3V infusion of NMDA were nearly completely prevented by MK-801 applied to the same region before 15min. The application of MK-801 was also potent to block rises of plasma AVP elicited by AV3V injection of PGE2 or i.v. infusion of hypertonic saline. However, it inhibited neither increases of arterial pressure and heart rate due to the PGE2 treatment nor those of arterial pressure, plasma osmolality and sodium in response to the osmotic load. Histological analysis on the AV3V infusion sites of NMDA, MK-801 and PGE2 indicated that they had been located in the structures such as the median and medial preoptic nuclei, periventricular nucleus and medial preoptic area. These results suggest that stimulation of AV3V NMDA receptors in the basal state may facilitate AVP secretion and cause pressor and tachycardiac actions, and that these receptors may be involved in both the hyperosmolality- and PGE2-induced hormone release, but not in the cardiovascular responses to these stimuli.     

Differential effects of V2 vasopressin agonist and antagonists on blood pressure regulation in normotensive (WKY) and spontaneously hypertensive (SHR) rats.

The effects of arginine vasopressin analogs with V2 agonistic and antagonistic properties on blood pressure (BP) and heart rate (HR) were compared in conscious, spontaneously hypertensive (SHR) and normotensive (WKY) rats under resting conditions and after administration of phenylephrine (Phe) and sodium nitroprusside (SN). In WKY rats, resting BP and HR were not significantly affected during intravenous (i.v.) infusion of dVDAVP, (V2 agonist; 200 pg/kg/min), d(CH2)5 (D-Ile2,Abu4]AVP (V2 antagonist 1; weak V1 antagonist; V2/V1 ratio = 29; 0.6 microgram/kg/min), d(CH2)5[D-Ile2,Ile4,AlaNH2]AVP (V2 antagonist 2; very weak V1 antagonist; V2/V1 ratio = 83; 0.6 microgram/kg/min) and combined infusion of V2 agonist and V2 antagonist 2. Under resting conditions BP and HR were not affected in WKY by any of the treatments. In SHR rats BP and HR were significantly decreased by V2 antagonist 2 infused alone or in combination with V2 agonist. In WKY but not in SHR V2 agonist without and with prior V2 receptors blockade significantly augmented bradycardia associated with a maximum increase of the systolic blood pressure after Phe administration. Significant differences were found between SHR and WKY in SN-induced changes of HR and BP after administration of V2 agonist and antagonists. The results suggest that circulating vasopressin may modify the baroreflex by interaction with receptors which are stimulated by V2 agonist but are different from the classical V2 receptors. The study supports evidence for differential effects of vasopressin analogs on blood pressure and blood pressure-heart rate relations in WKY and SHR.     

Occlusion of rostroventral 3rd ventricle abolishes drinking but not AVP release in response to central osmotic stimulation

Dogs were implanted with a device for chronic cannulation of the anterior part of the 3rd ventricle (A3V). Intracerebroventricular (i.c.v.) infusion of artificial cerebrospinal fluid (CSF) containing 0.35 M NaCl into the A3V of 7 normally hydrated dogs induced thirst (average water intake 11.8 +/- 2.0 ml.kg-1 b. wt.) and significantly increased arginine-vasopressin (AVP) concentration in the blood plasma from 3.4 +/- 0.3 to 8.2 +/- 1.2 pg.ml-1. When repeating the i.c.v. hypertonic infusion at intervals of one week or more in two dogs, its dipsogenic effect vanished within 3-5 months. X-ray analysis revealed an occlusion of the rostroventral part of the A3V. Subsequent controls on 3 other dogs confirmed that the dipsogenic response to i.c.v. osmotic stimulation was abolished in association with similar partial occlusions of the A3V. However, this stimulus still produced a significant increase of plasma AVP from 3.7 +/- 0.5 to 5.7 +/- 0.7 pg.ml-1 in the 5 dogs. Control of drinking in these dogs was otherwise unimpaired as indicated by their normal plasma osmolalities. Histological examination revealed that the loss of the dipsogenic response to i.c.v. infusion of 0.35 M NaCl was in each case associated with fibrinous occlusion of the A3V between its rostral wall and the mass intermedia, preventing the passage of the infusate to the supraoptic and infundibular recesses.     

Lack of relationship between resistance to cerebrospinal fluid outflow and intracranial pressure in normal pressure hydrocephalus

OBJECTIVE: To explore whether calculation of resistance to cerebrospinal fluid (CSF) outflow (Rout) by the lumbar constant rate infusion test in a reliable way predicts the intracranial pressure (ICP) profile in normal pressure hydrocephalus (NPH). METHODS: A prospective study was undertaken including 16 cases with clinical signs of normal pressure hydrocephalus that were investigated with both continuous ICP monitoring and the lumbar constant rate infusion test. Intracranial pressure monitoring was performed for about 24 h, and supplied with a simultaneous lumbar constant rate infusion test at the end of the monitoring period. The pressure recordings were analysed using the Sensometrics Pressure Analyser. Various characteristics of the pressure curves were compared. RESULTS: The continuous ICP recordings were considered as normal (mean ICP<11.5 mmHg) in all 16 cases. The lumbar infusion test showed an apparently abnormal resistance to CSF outflow (Rout) (> or =12.0 mmHg/ml/min) in 12 of 16 cases. There was no relationship between lumbar Rout and mean ICP during sleep. We could not find any relationship between lumbar Rout and number of nightly ICP elevations of 1525 mmHg lasting 0.5 or 1 min. Neither resistance to CSF outflow (Rout) nor mean ICP during sleep was related to the ventricular size. CONCLUSIONS: The results of this prospective study revealed no significant relationship between resistance to CSF outflow (Rout) and the ICP profile in NPH cases. The results also suggest that caution should be made when predicting the ICP profile on the basis of measuring the lumbar CSF pressure for a few minutes duration.     

Effects of intravenous infusion of substance P on arginine vasopressin and oxytocin secretion in normal men.

In order to establish possible stimulatory effects of increasing plasma concentrations of substance P (SP) on the arginine vasopressin (AVP) and/or oxytocin (OT) secretion, successively increasing doses of SP(0.5, 1 and 1.5 pmol/kg-1/min-1; each dose for 20 min) were infused in 7 normal men. Plasma AVP and OT levels were measured before infusion and every 20 min, just before increasing the infusion dose of SP. During tests, SP infusion did not produce untoward side effects or changes in blood osmolality and/or pressure. Plasma OT levels did not change during SP infusion. Plasma AVP concentrations were not modified by the infusion of the lowest dose of SP, whereas they were significantly increased in a dose response fashion when higher amounts of SP were given. These findings demonstrate for the first time in humans that the systemic administration of SP exerts stimulatory effects on AVP, but not on OT secretion.     

Assessment of intracranial pressure volume relationships in childhood: the lumbar infusion test versus intracranial pressure monitoring

OBJECT: This study was undertaken to compare the results of two tests that are widely used to assess intracranial pressure-volume relationships in children: the lumbar steady state infusion test providing information about the resistance to cerebrospinal fluid (CSF) outflow (Rout), and continuous intracranial pressure (ICP) monitoring. METHODS: The study included 28 children aged 5-91 months, on whom both tests were performed. The median duration between the tests was 1 month. With the child in general narcosis, the lumbar CSF pressure was recorded before and during infusion of artificial CSF, and the Rout was calculated on the basis of the opening (Po) and plateau (Pp) pressures (Rout=Pp-Po/infusion rate). ICP was recorded every 5 s using a computer-based system. CONCLUSIONS: We found no significant correlation between Rout and mean ICP asleep. There were no significant relationships between abnormal mean ICPs during sleep (defined as either 10 or 15 mmHg) and abnormally high Rout values (defined as either 10 or 12 mmHg/ml/min), and no significant relationships between abnormally high Rout values (10 or 12 mmHg ml(-1) min(-1)) and the presence of abnormal ICP elevations (defined as either 20 or 25 mmHg and lasting 5 min). Therefore the calculation of Rout by the infusion test performed on children under general anesthesia gave no reliable prediction of abnormal ICP.     

Pursuit of roles for metabotropic glutamate receptors in the anteroventral third ventricular region in regulating vasopressin secretion and cardiovascular function in conscious rats

This study aimed to evaluate the roles of metabotropic glutamate receptors (mGluRs) in the anteroventral third ventricular region (AV3V; a pivotal area for osmotic responses and PGE2 actions) in regulating AVP secretion and cardiovascular function. In conscious and unrestrained rats, we examined the effects of AV3V infusion of t-ACPD (an agonist for mGluRs) and 8-bromo (Br)-cAMP (an agonist for cAMP associated with mGluR action) on plasma and cardiovascular variables, and the effects of MCPG (an antagonist for mGluRs) on the responses to t-ACPD, PGE2, and hyperosmolality. AV3V infusion of t-ACPD or 8-Br-cAMP produced dose-dependent rises in plasma AVP, arterial pressure and heart rate after 5 or 15 min, without altering plasma osmolality, sodium, potassium or chloride. t-ACPD administration into the cerebral ventricle had no effects on the variables. The plasma AVP and arterial pressure responses to AV3V t-ACPD infusion were blocked by preadministration of MCPG 15 min before the infusion. MCPG treatment was also potent at inhibiting the augmentation of plasma AVP elicited by AV3V infusion of PGE2, although its pressor and tachycardiac actions were not influenced. MCPG application, however, had no effect on either the increases in plasma AVP or arterial pressure in response to the enhanced plasma osmolality induced by i.v. infusion of hypertonic saline or their stable levels during isotonic saline infusion. Histological analysis showed that the AV3V drug infusion sites were located in structures such as the median or medial preoptic nucleus and periventricular nucleus. These results suggest that AV3V mGluRs may act to potentiate AVP release and cardiovascular function when stimulated in the basal state, and may participate in the hormone secretion prompted by AV3V PGE2, despite probable negligible contributions to the mechanisms responsible for the PGE2 cardiovascular effects or the phenomenon provoked by osmotic load.     

A study on the mechanism by which sodium nitroprusside,a nitric oxide donor,applied to the anteroventral third ventricular region provokes facilitation of vasopressin secretion in conscious rats

We reported previously that sodium nitroprusside (SNP) applied to the anteroventral third ventricular region (AV3V), a pivotal area for autonomic functions, facilitates vasopressin (AVP) secretion in conscious rats. The aim of this study was to pursue the problems of whether nitric oxide (NO) generated from the agent may be responsible for the phenomenon, and whether it may be mediated by cyclic guanosine monophosphate (cGMP), the biosynthesis of which could reportedly be activated by NO. The infusion of SNP into the AV3V of conscious rats produced dose-related increases in plasma AVP, the maximal responses of which appeared at 5 min. Blood pressure and heart rate tended to rise at 15 min. The plasma osmolality, sodium, potassium or chloride did not show marked alteration following the SNP administration. Although the SNP solution was hypertonic and hypernatremic, AV3V application of hypertonic saline with a relatively higher osmolality and an equal sodium level was significantly less effective in augmenting plasma AVP. When injected into the lateral ventricle, SNP did not change plasma AVP and reduced arterial pressure, different from the results provoked by the AV3V application. The rise in plasma AVP in response to the AV3V application of SNP was diminished by preadministration of hemoglobin, a scavenger of NO, that did not affect the responses of the other variables. In contrast, pretreatment with methylene blue, an agent capable of antagonizing the potency of NO to activate guanylate cyclase, did not attenuate but potentiated the responses of both plasma AVP and arterial pressure to the AV3V infusion of SNP. Hemoglobin or methylene blue given alone into the AV3V did not affect any of the variables monitored. On the other hand, the AV3V injection of 8-bromo cGMP, a stable analogue of cGMP, was not potent for causing a significant rise in plasma AVP, in contrast to the notable AVP-enhancing effect of 8-bromo cAMP. Arterial pressure and heart rate were elevated by both of these agents, whereas the remaining variables were not altered. Histological inspection indicated that the infusion sites of the drugs in the AV3V had included areas such as the organum vasculosum of the lamina terminalis, median preoptic nucleus, medial preoptic nucleus and periventricular nucleus. On the basis of these results, we concluded that the AVP secretion prompted by the AV3V application of SNP may be attributable to NO, whereas its well-known ability to stimulate guanylate cyclase activity may hardly contribute to this phenomenon.     

Cerebrospinal fluid and plasma concentrations of oxytocin and vasopressin during parturition and vaginocervical stimulation in the sheep

Simultaneous blood and cerebrospinal fluid (CSF) samples were taken from conscious sheep before, during and after parturition. Concentrations of plasma and CSF oxytocin were significantly elevated during contractions and particularly at birth. Mean prepartum CSF concentrations of oxytocin were around 55% of those found in plasma but postpartum they were up to 2-fold higher than those in plasma. Plasma concentrations of oxytocin were only significantly elevated, compared to prepartum levels, for 15 min postpartum whereas those in CSF were increased for the whole of the 120 min postpartum sampling period. Plasma, but not CSF, concentrations of arginine-vasopressin (AVP) were significantly raised during contractions and birth, and for 15 min postpartum. During the prepartum period CSF AVP concentrations were 67% of those found in plasma whereas at birth plasma levels were 10-fold higher than in CSF. In a separate experiment it was shown that 5 min of mechanical vaginocervical stimulation also stimulated significant increases in CSF and plasma oxytocin concentrations and in plasma vasopressin. Results support previous work suggesting an important role for central oxytocin release in the postpartum induction of maternal behavior and demonstrate that elevated concentrations of oxytocin in the CSF are present for a greater period than in blood. Elevated plasma AVP concentrations during contractions, birth or vaginocervical stimulation may be stimulated by stress associated with these stimuli.     

Cerebrospinal fluid outflow resistance in sheep: impact of blocking cerebrospinal fluid transport through the cribriform plate

Recent studies in sheep suggest that a significant proportion of global cerebrospinal fluid (CSF) drainage (50% or greater) occurs through the cribriform plate into nasal mucosal lymphatics. If this is true, obstructing CSF clearance through the cribriform plate should have an impact on the ability of the intracranial pressure regulating systems to compensate for volume infusions. To test this concept, bolus infusions of artificial CSF were administered into one lateral ventricle in sheep and the intracranial pressure monitored from the contralateral side. Peak intracranial pressures (ICP) were measured and CSF outflow resistances were calculated from the pressure patterns observed in response to bolus infusions administered before and after the cribriform plate was sealed in the same animal. To obstruct the cribriform plate, a portion of nasal bone was removed to expose the nasal mucosa. The olfactory mucosa, a portion of the nasal mucosa and all soft tissue on the extracranial surface of the cribriform plate were scraped away with a curette and the bone surface sealed with bone wax. Obstruction of CSF transport through the cribriform plate increased the peak ICP after infusion (P = 0.016) and augmented the time required for ICP to return to baseline. CSF outflow resistance was elevated approximately 2.7 times (P = 0.006). When the cribriform plate was left intact (sham surgery), no significant changes in peak ICP or CSF outflow resistance were observed. We conclude that the cribriform plate represents an important site for CSF clearance. Obstruction of this pathway reduces volumetric CSF transport significantly.     

ACTH-Suppressive and Vasodilator Actions of Adrenomedullin in Conscious Sheep

Adrenomedullin (ADM) is a 52 amino-acid peptide which is a potent vasodilator in rats, and suppresses basal and CRF-induced ACTH release from cultured pituitary cells. The present study examines the hemodynamic and hormonal actions of human ADM (1–52) infusion in conscious, chronically instrumented sheep. Five sheep were infused intravenously (IV) or intracerebroventricularly (ICV) with ADM at 100 pg/h for 60 min, and mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral conductance (TPC), coronary blood flow (CF), coronary conductance (CC), peak aortic flow (Fmax), and left ventricular dF/dt were monitored by a computer-based data collection system every 2 min. Plasma concentrations of adrenocorticotropin (ACTH), arginine vasopressin (AVP) and renin were measured after 60 min of infusion. IV ADM produced a small fall in MAP of 3 ± 1 mmHg, associated with a reflex increase in HR of 14 ± 3 b/min. CO increased by 1.3 ± 0.3 1/min, whereas SV remained unchanged. TPC was markedly increased by 20 ± 3 ml/min/mmHg. Changes in CF were also seen with an increase of 10 ± 2ml/min, and CC increased in parallel by 0.15 ± 0.02 ml/min/mmHg. Fmax and dF/dt showed small increases of 2.1 ± 0.5 Vmin and 85 ± 20 1/min/sec respectively. Plasma concentrations of ACTH and cortisol were reduced by 58% and 55% respectively, whereas plasma renin concentration increased by 106%. There was no change in plasma levels of AVP. ICV infusion of ADM had no effect on any parameter measured. These data suggest that systemic ADM produces a sustained vasodilator action to lower blood pressure in sheep, and this is the first study to report the ACTH-suppressor action of ADM in conscious animals. ADM may therefore be an important hormone involved in the regulation of pituitary/adrenal function, in addition to its cardiovascular and fluid regulatory actions in mammals.     

Opening the blood-brain barrier to zinc

Sheep with guide tubes implanted over the brain lateral ventricles, in order to facilitate episodic sampling of cerebrospinal fluid (CSF), were used to determine the effects of increasing cranial blood osmolality or electroconvulsive shock (ECS) on the permeability of the blood-brain barrier (BBB) to zinc. Zinc acetate solution (1 mg Zn/ml) was infused intravenously (i.v.) at 1.0 ml/min for 30 min and then continuously at 0.125 ml/min. This infusion increased plasma total zinc concentration (pZn) approximately 10-fold without altering CSF zinc concentration (CSFZn). After 1.5-3.5 h, 4 M NaCl was infused at 5-10 ml/min for 10 min into one carotid artery with the other carotid artery occluded, or the animals were anaesthetized and given an ECS (140 V, 2 s). Paired samples of blood and CSF were collected before and after these treatments. Results were: (i) CSFZn was approximately one tenth of pZn; (ii) zinc administered i.v. was almost completely excluded from the CSF; (iii) increased cranial blood osmolality or ECS increased CSFZn in all experiments, but the time course and extent of the rise were variable. CSFZn reached the concentrations of zinc in normal sheep plasma in some experiments; (iv) CSFZn subsequently fell towards the low values of zinc in normal CSF; (v) the animals suffered no evident ill-effects from either procedure. The procedures may, therefore, be used for reversible opening of the BBB to particles such as zinc in conscious or anaesthetized sheep with no troublesome sequelae.