Cardiovascular and renal effects of intracerebroventricular angiotensin II in conscious sheep.

Effects on systemic and pulmonary haemodynamics, renal electrolyte excretion, and plasma concentration of vasopressin, catecholamines, electrolytes and proteins in response to intracerebroventricular infusions of [Val5]-angiotensin II (ANG II) at 1, 2 and 4 pmol kg-1 min-1 in isotonic saline for 30 min were studied in conscious sheep (n = 6). Vehicle control infusions were performed in four of the animals. All three doses of ANG II were expected to increase CFS concentration of the peptide above physiological levels. All ANG II infusions were noticed to be dipsogenic, but the animals were not allowed to drink freely until at the end of the experiments (at 120 min post-infusion). The systemic arterial blood pressure increased significantly only in response to 2 and 4 pmol kg-1 min-1, concomitant with an increase of the systemic vascular resistance, whereas the cardiac output and heart rate remained unchanged. The central venous pressure increased only after administration of the highest ANG II dose, while pulmonary artery, and capillary wedge pressures were unaffected during all experiments. The plasma protein and K concentration fell in response to ANG II administration. Also here, the effects were significant only at 2 and 4 pmol kg-1 min-1. The plasma levels of vasopressin, noradrenaline, adrenaline and dopamine did not change significantly in response to any of the infusions. The renal Na excretion increased by 100-400%, but not in a strictly dose-dependent manner. Much smaller and more variable effects were seen on the renal K excretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypertension and thirst outlasting renal vasoconstriction as effects of a brief elevation of systemic angiotensin II in sheep

The influence of 10 min intracarotid (i.e.) and intravenous (i.v.) infusions of angiotensin II (Ang II; 20 pmol kg^-1 min^-1) on carotid blood pressure (cBP) and renal blood flow (RBF) was studied in unanaesthetized ewes without and with pre-treatment with the α₁-and β-adrenoceptor blocker labetalol. RBF was also monitored during 30 min intracerebroventricular (ICV) infusions of Ang II at 2 pmol kg^-1 min^-1. The i.e. infusions of Ang II induced about 50 mmHg rise in cBP. A steep decline occurred during 5 min post-infusion, followed by a much slower reduction with the cBP remaining above control level at 40 min post-infusion. The pressure elevation induced by i.v. Ang II was less pronounced but exhibited a similar pattern. Labetalol significantly reduced the pressor response to i.e. as well as i.v. Ang II. The i.e. and i.v. infusions of Ang II conspicuously reduced the RBF regardless of whether the ewes were labetalol-treated or not. At 5 min after the infusions RBF had returned to control level. The ICV infusions did not influence the RBF. Ang II i.e. elicited thirst in 50% of the ewes with the urge to drink remaining at 40 min post-infusion. The dipsogenic response was not reduced by labetalol pre-treatment. The results imply that no cerebral component contributes to the reduction in RBF induced by systemic Ang II. However, a centrally mediated action seems to be the cause of the long-lasting post-infusion cBP elevation and dipsogenic response. It suggests that, once bound at brain sites, Ang II may have a sustained action, alternatively may initiate cerebral processes of long duration.     

Atrial natriuretic peptide attenuates pressor but enhances natriuretic responses to angiotensin II in pregnant conscious goats

This study was designed to examine the actions of ANP in acute, ANGII-mediated hypertension during pregnancy. Effects on blood pressure, blood volume, and renal Na and K excretion were evaluated in conscious goats (n= 6). ANP (2 μrg min^-1), ANGII (0.5 μg min^-1), or ANGII + ANP (doses the same as for each peptide alone) was infused intravenously for 60 min. The pressor response to ANGII was reduced in pregnant goats. This reduction was seen in systolic, but not in diastolic pressure. ANP decreased pressure by 5–10 mmHg both in pregnancy and in non-pregnancy. When ANGII + ANP was infused, blood pressure initially rose as with ANGII but then declined. ANP suppressed only the elevated systolic pressure. Plasma protein concentration and haematocrit was reduced by ANGII but increased by ANP alone or together with ANGII, thereby implying fluid shift into the vasculature by ANGII and opposite movement by ANP. ANGII increased renal Na excretion to 1500 μmol min^-1in non-pregnancy, but only to half of that in pregnancy. ANP alone caused small natriuresis, but enhanced ANGII-induced natriuresis to near 3000 μmol min^-1in both non-pregnant and pregnant goats. In summary, ANP further attenuated the blunted blood-pressure rise due to ANGII in pregnant goats, and reduced plasma volume, but enhanced renal Na excretion as in non-pregnant goats. This implies that with the present combination ANP and ANGII caused a near maximal natriuretic response that was not modified by the systemic cardiovascular changes occurring in pregnant goats.     

Intracerebroventricular angiotensin II increases tolerance to blood loss in conscious sheep

Intracerebroventricular (i.c.v.) infusion of hypertonic NaCl improves the tolerance to haemorrhage in sheep. Since i.c.v. angiotensin II (ANG II) shares many of the effects of hypertonic NaCl on fluid balance control and blood pressure, we aimed to determine whether i.c.v. ANG II would also be effective in that regard. Six adult conscious ewes were bled from the jugular vein until the mean arterial pressure suddenly dropped to between 45 and 50 mmHg, during an i.c.v. infusion of ANG II (2 pmol kg^-1 min^-1) which commenced 30 min prior to start of blood removal and continued until end of retransfusion about 80 min after haemorrhage. A corresponding haemorrhage in the same animals during an i.c.v. infusion of 0.9% NaCl served as controls. Significantly more blood had to be withdrawn to induce hypotension when ANG II was given i.c.v. (22.3±1.8 vs. 12.6±1.2 mL kg^-1). The degree of hypotension and the recovery rate of the blood pressure did not differ between the experiments. The increased tolerance to blood loss by ANG II i.c.v. was accompanied by a reinforced elevation of the systemic vascular resistance and a larger decline of the cardiac output. The plasma norepinephrine concentration was significantly increased immediately after haemorrhage during i.c.v. ANG II, but not in control experiments. The overall vasopressin response to the hypotensive blood loss was not affected by ANG II, but high plasma levels were obtained already during the non-hypotensive stage of haemorrhage. The i.c.v. infusion of ANG II caused a significant lowering of the plasma protein concentration before start of bleeding and accentuated the haemodilution caused by the haemorrhage. We conclude that central administration of ANG II increases the tolerance to haemorrhage in sheep but with concomitant haemodynamic changes which appear unfavourable regarding cardiac load and tissue perfusion.     

Effects on renal sodium and potassium excretion of vasopressin and oxytocin in conscious dogs

Renal effects of arginine vasopressin and oxytocin were studied in conscious dogs, made water-diuretic by a waterload equivalent to 2% of body weight. Body water and content of sodium were maintained by separate servo-controlled infusions. Peptides were infused for 60 min at rates of 50 pg kg^-1 min^-1 (arginine vasopressin) or 1 ng kg^-1 min^-1 (oxytocin), either separately or combined. Infusions increased plasma arginine vasopressin to 1.9 ± 0.2 (arginine vasopressin alone) and 1.8 ± 0.3 pg kg^-1 (arginine vasopressin plus oxytocin and plasma oxytocin to 72 ± 5 (oxytocin alone) and 77 ± 8 pg ml^-1 (oxytocin plus arginine vasopressin). Arginine vasopressin or arginine vasopressin plus oxytocin increased urine osmolality similarly by a factor of 13, decreased urine flow to between 5 and 7% of control and decreased free water clearance. Oxytocin reduced urine flow and free water clearance and increased urine osmolality by a factor of 2. Oxytocin and arginine vasopressin separately increased excretion of sodium from 4 ± 2 to 15 ± 6 μmol min^-1 and from 7 ± 4 to 25 ± 13 μmol min^-1, respectively. Arginine vasopressin plus oxytocin led to a pronounced natriuresis (13 ± 4 to 101 ± 27 μmol min^-1). Arginine vasopressin and arginine vasopressin plus oxytocin increased the excretion of potassium by a factor of 2.5. Oxytocin and arginine vasopressin plus oxytocin increased urinary Na⁺/K⁺ ratio by a factor of 3.7. It is concluded, that oxytocin at plasma concentrations of 70–80 pg ml^-1 has modest antidiuretic and natriuretic effects and that the combined action of arginine vasopressin oxytocin may elicit supra-additive natriuretic effects.     

Systemic and centrally mediated angiotensin II effects in the horse

The primary aim of the study was to evaluate the potential value of intravenous (i. v.) infusion of angiotensin II (AII) for phonocardiographic differential diagnosis of equine valvular insufficiency. Ten-minute AII infusions at 4.5–33 pmol kg^-1 min^-1 induced clear-cut dose-dependent rises in systemic arterial blood pressure (aBP), whereas the pulmonary aBP remained largely unaffected. It implies that i. v.infusion of All at about 10 pmol kg^-1 min^-1 could be a valuable tool for the acoustic differentiation between mitral and tricuspid valvular dysfunction in the horse. The infusion at, and above 9 pmol kg^-1 min^-1 caused increased heart rate. This chronotrophic effect was not strictly dose-dependent and exhibited significant tachyphylaxis. Angiotensin II administration at, or above 9 pmol kg^-1 min^-1 was needed to induce an urge to drink, suggesting that angiotensin-induced thirst does not appear in the euhydrated horse until the octapeptide reaches supraphysiological blood concentration. Determinations of plasma aldosterone concentration (PA) revealed comparatively high morning control values (269 ± 46 pmol^-1).Three consecutive AII infusions with 10-min intervals and at increasing dosages caused a cumulative, almost fourfold elevation of PA.The PA pattern indicated that AII-induced hypersecretion of aldosterone continued for several minutes after the end of the infusions, but also showed that the metabolic clearance of the hormone took precedency of the secretion within 20 min post-infusion. In two of the horses a fall in PA occurred during a fourth, final infusion, indicating that in these instances the previous AII administration had impoverished the store of aldosterone available for release from the adrenal cortex.     

Natriuresis in conscious dogs caused by increased carotid [Na+] during angiotensin II and aldosterone blockade

The renal response to a selective increase in the Na⁺ concentration of the blood perfusing the central nervous system was investigated in conscious dogs treated with the converting enzyme inhibitor enalaprilat and the aldosterone antagonist canrenoate. In split-infusion experiments the plasma [Na⁺] of carotid blood was increased (approx. 6 mM) by bilateral infusion of hypertonic NaCl. Concomitantly distilled water was infused into the v. cava making the sum of the infusions isotonic. In control experiments isotonic saline was infused at identical rates into all three catheters. Na⁺ excretion increased markedly in both series, 103 ± 14 to 678± 84 μmol min^-1 during split-infusion and 90 ± 14 to 496 ± 74 μmol min^-1 during the isotonic volume expansion. Peak rate of excretion, peak fractional sodium excretion, and cumulative sodium excretion were all significantly higher (P < 0.05) during split-infusion than during control experiments. Plasma vasopressin increased only during split-infusion (0.68 ± 0.11 to 2.4 ± 0.8 pg ml^-1) while the increases in plasma atrial natriuretic peptide were similar in the two series. Urinary excretion of urodilatin (ANP95-126) increased significantly more during split-infusion (46 ±11 to 152 ±28 fmol min^-1) than during the isotonic volume expansion (45 ± 14 to 84 ± 16 fmol min^-1) (P < 0.05). It is concluded that the natriuretic mechanisms activated by a selective increase in the Na⁺ concentration of carotid blood and associated with increased excretion of urodilatin cannot be eliminated by blockade of the renin-angiotensin-aldosterone system.     

Inefficiency of intracerebroventricular ANP to alter haemodynamic,plasma vasopressin and renin responses to haemorrhage in sheep

Whether intracerebroventricular (i.e.v.) infusion of atrial natriuretic peptide (human-ANP, 1–28) 25 pmol min^-1 influences the tolerance to blood loss and haemorrhage induced cardiovascular, vasopressin and renin responses were studied in five conscious sheep. The i.e. v. infusion was started 60 min prior to a slow (0.7 ml kg^-1 min^-1) venous haemorrhage, was run concurrently with bleeding, and for 90 min thereafter. Venous blood was removed until the mean systemic arterial pressure suddenly fell to about 50 mmHg. There were no statistically significant differences in either the bleeding volume necessary to induce the sudden decrease in blood pressure, or in cardiovascular parameters measured by venous heart thermodilution catheterization, compared with control experiments with i.e.v. infusion of artificial CSF. The plasma protein and vasopressin concentrations and renin activity were unaffected by the i.c.v. infusion of ANP as were the changes in these parameters occurring during the subsequent haemorrhage. The same negative findings were obtained with a three times higher dose of ANP(l-28) (75 pmol min^-1), tested in three of the animals. Thus the i.c.v. infusion of ANP(l-28), in amounts expected to elevate the CSF concentration far above basal levels does apparently not influence normal blood pressure regulation or alter haemodynamic, vasopressin and renin responses to haemorrhage in conscious sheep.     

Calciuresis elicited by spontaneous rehydration in dehydrated sheep

Cardiovascular and renal responses to a step-up infusion of endothelin-1 (ET-1) (1, 5, and 15 ng kg^-1 min^-1) were investigated in conscious dogs. In addition, the disappearance of ET-l in arterial and central venous plasma after an infusion of 10 ng kg^-1 min^-1 was quantified, and the effects of vasopressin (AVP, 10 ng kg^-1 min^-1) and angiotensin II (AII, 2, 5, and 10 ng kg^-1 min^-1) on plasma ET-1 were investigated. The step-up infusion of ET-1 increased the plasma level from 3.6 ± 0.3 to 243 ± 23 pg ml^-1. Concomitantly, arterial blood pressure increased and heart rate (HR) decreased dose-dependently. Diuresis, sodium, and potassium excretion did not change significantly. However, free water clearance increased during the infusion. Clearance of creatinine and excretion of urea decreased (39 ± 4 to 29 ± 3 ml min^-1 and 87 ± 16 to 71 ± 14 μmol min^-1, respectively). Decay curves for ET-1 in venous and arterial plasma were identical, and initial t_½ was 1.1 ± 0.1 min. Vasopressin increased arterial blood pressure (107 ± 4 to 136 ± 3 mmHg) beyond the infusion period and increased plasma ET-1 (85%). An equipressor dose of AII tended to decrease plasma ET-1. It is concluded that the lung is apparently not important in the removal of ET-1, that the disappearance of ET-1 follows a complex pattern, and vasopressin – in contrast to angiotensin II – is able to increase the plasma concentration of ET-1. The latter may suggest that ET-1 is involved in the prolonged pressor action of AVP observed.     

The relation between carotid solute concentration and renal water excretion in conscious dogs

Verney's hypothesis of cerebral osmoreceptors controlling the renal excretion of water via vasopressin was reinvestigated in conscious trained dogs provided with bilateral skin loops containing the common carotid arteries. In multiple experiments in two dogs, bilateral intracarotid injections (0.25 ml.(kg b. wt.)^-1 per artery in 10 s) of a hyperosmotic solution of sodium chloride (0.257 mol/l) during transient water diuresis failed to produce an antidiuretic response, although it is estimated that the injections elevated the osmolality of the carotid blood by 12–15%. In another 5 dogs, bilateral intracarotid infusions of hyperosmotic saline (45 μmol. (kg b. wt. min)^-1 per artery for 10 min) during sustained water diuresis resulted in a 3% increase in jugular venous osmolality and an antidiuretic response without detectable changes in heart rate or mean arterial pressure. Equal intravenous hyperosmotic or intracarotid isosmotic infusions were not associated with antidiuretic responses. Analysis of the concomitant concentrations of vasopressin in plasma fell short of supporting the hypothesis that the antidiuretic response to intracarotid hyperosmotic infusions was exclusively or mainly due to liberation of vasopressin. although the renal response could be mimicked by exogenous vasopressin. It is concluded that the present results—although discordant with several of Verney's results and assumptions—nevertheless support the concept of a cerebral solute receptor influencing the rate of renal water excretion.     

Comparison of PGE2, 6-keto PGF1α and renin release from dog kidneys

Several renal cell types synthesize prostaglandin E₂ (PGE₂) and prostacyclin (PGI₂). To examine whether the release of these prostaglandins varies in proportion, prostaglandin synthesis was stimulated in anaesthetized dogs by renal arterial constriction, ureteral occlusion, intrarenal angiotensin II infusion and infusion of arachidonic acid, the precursor of PG synthesis. PGI₂ was measured as its stable hydrolysed product, 6-keto PGF_1α. The two former procedures raised PGE₂ release to 13 ± 2 pmol min^-1, 6-keto PGF_1α release to 5 ± 2 pmol min^-1 and renin release to 23 ± 5 μg AI min^-1, Angiotensin II infusion, reducing the renal blood flow by 30%, increased PGE₂ and 6-keto PGF_1α release only half as much as ureteral and renal arterial constriction, and exerted no significant effect on renin release. By increasing the infusion rate of angiotensin II up to 10 times, the renal blood flow remained unaltered in four dogs and fell to 50% of control in two dogs, but PGE₂ and 6-keto PGF_1α release did not increase further in any of the experiments. Arachidonic acid, infused at 40 and 160 μg kg^-1 min^-1, increased prostaglandin release in proportion to the infusion rate. At the highest infusion rate, PGE₂ release averaged 166± 37 pmol min^-1 and 6-keto PGF_1α release 98 ± 28 pmol min^-1. All procedures increased PGE₂ and 6-keto PGF_1α release in a fixed proportion of about 2.5:1, whereas renin release increased only during autoregulatory vasodilation.     

Lactation affects pressor,volumetric and natriuretic responses to angiotensin II in goats

Demands on cardiovascular function and fluid turnover increase during lactation and pregnancy in the goat, but the hormonal status is different. This study is aimed at investigating the effects of hypertensive angiotensin II (ANGII) in lactating goats. The results were compared with those of pregnancy and control conditions. ANGII (0.5 pg min^-1) was infused intravenously for 60 min (n = 6). The rise in blood pressure in response to ANGII was attenuated during lactation as in pregnancy (P < 0.001 vs control period). ANGII caused reflex bradycardia. Plasma protein concentration decreased by 7.5% during infusions in lactating goats (pregnancy: 9%; control period: 4.5%). Renal Na excretion increased by 260% (lactation), by 400% (pregnancy; n.s. vs. lactation), and by 800% (control period; P < 0.01 vs. lactation). The glomerular filtration rate was unchanged during ANGII infusions in lactating animals, but increased in the other periods. Effective renal plasma flow decreased. ANGII raised aldosterone from < 34.5 pmol 1^--¹ to 539 ± 80 pmol l^-1 (lactation) and to 428 ± 41 pmol l^-1 (control; P < 0.05 vs. lactation), and from 72 ± 9 to 651 ± 103 pmol l^-1 (pregnancy; P < 0.01 vs. lactation). Plasma progesterone was undetectable during lactation, but varied from 0 to 17 nmol l^-1 during control conditions and was 16 ± 1 nmol l^-1 during pregnancy. Oestradiol 17β was 181± 22 pmol l^-1 in pregnant goats, and undetectable in lactating animals. In conclusion, lactation affects ANGII-induced changes in cardiovascular and fluid regulation, but in this period the effects were not related to progesterone or oestradiol 17 β.     

Effects on intravascular pressures of vasopressin and angiotensin II in dogs

The effects of 30-min intravenous infusions of 8-arginine vasopressin (AVP) and angiotensin-(1,8)-octapeptide (ANG II) to conscious dogs were studied by measurements of systolic (SABP), mean (MABP), and diastolic arterial blood pressures, central venous pressure (CVP), heart rate (HR), and plasma concentrations of vasopressin (pAVP). Infusion of AVP at six rates (0.4-12.8 ng X min-1 X kg-1) raised mean pAVP by 5-490 pg/ml and increased CVP by 2-10 cmH2O. HR decreased and arterial pressures increased with infusion rates of 1.6-12.8 ng X min-1 X kg-1. However, the increase in SABP was only transient. ANG II increased all arterial pressures; however, it barely changed CVP and did not change HR or pAVP. It is concluded that 1) AVP can elevate MABP without changes in SABP, 2) the effects of AVP on arterial pressures are buffered within 5-15 min, 3) CVP can be increased by doses of AVP that do not affect arterial pressures, and 4) the pressor activity is independent of the presence of ANG II. The results confirm that the cardiovascular response to vasopressin is qualitatively different from that elicited by ANG II.     

Influence of Prostaglandin E1 on Cerebral Mechanisms Involved in the Control of Fluid Balance

The effects of infusions of PGE₁ (30 ng/kg min^-1) into the lateral cerebral ventricle were studied in the conscious, hydrated goat. The infusions caused release of antidiuretic hormone and increased renal sodium excretion. When PGE₁ was infused together with hypertonic NaCl these effects became markedly enhanced and the infusion also induced drinking and a rise in the arterial blood pressure. Much weaker effects were obtained by the infusion of the hypertonic NaCl alone. This sodium-PGE₁ interaction is discussed in relation to previously observed, central sodium-angiotensin II interaction. A more pronounced drinking effect was obtained in response to the intraventricular infusion of PGE₁+ angiotensin II, than to the infusion of either substance separately. The PGE₁ administered into the lateral cerebral ventricle did not induce any febrile response.     

Effect of atrial natriuretic factor on renal prostaglandin E2 release in the anaesthetized dog

Experiments were undertaken in two groups of barbiturate anaesthetized dogs to examine whether atrial natriuretic factor (ANF) exerts an effect on renal release of prostaglandin E₂ (PGE₂). In the first group, intravenous infusion of ANF (50 ng min^-1kg^-1body wt) reduced basal PGE₂ release from 4.4 ± 0.8 pmol min^-1to 1.8 ± 0.7 pmol min^-1. In the second group, intrarenal infusion of an α-adrenoceptor agonist, phenylephrine (2.5–6.75 μg min^-1), raised PGE₂ release from 2.7 ± 0.5 pmol min^-1to 7.5 ± 1.3 pmol min^-1. During continuous α₁-adrenergic stimulation, intravenous infusion of ANF (100 ng min^-1kg^-1body wt) reduced PGE₂ release to 3.5 ± 1.0 pmol min^-1. These results demonstrate that ANF reduces basal and α₁-adrenergic stimulated renal PGE₂ release.     

Effects of angiotensin ll on blood flow in rat submandibular gland

The effect of angiotensin II (Ang II) was studied on blood flow in the submandibular gland and tongue in male rats. Blood flow changes were determined with laser Doppler flowmetry and Ang II was infused into the common carotid artery before and after i.v. doses (18 nmol kg^-l) of the angiotensin II antagonist saralasin. Angiotensin II (10–60 pmol min^-l) dose-dependently increased blood pressure and tongue blood flow, whereas glandular blood flow decreased at all of the doses used. After saralasin administration the angiotensin II effects on blood pressure, tongue and glandular blood flow were significantly diminished (glandular blood flow reduction was diminished from 29%-3%, P < 0.005, n = 9). However, the responsiveness of these 3 parameters to local infusions with noradrenaline (0.75–3.0 pmol min^-1) was unaffected by saralasin. The dose of saralasin used in the present study did not affect any of the parameters on it's own. Our results show that vascular receptors sensitive to angiotensin II operate in the submandibular gland but not in the tongue.     

Systemic and renal hemodynamic effects of the AT1 receptor antagonist, ZD 7155, and the AT2 receptor antagonist, PD 123319, in conscious lambs

Experiments were carried out to investigate age- and dose-dependent effects of the selective AT₁ receptor antagonist, ZD 7155, and the selective AT₂ receptor antagonist, PD 123319, on systemic and renal hemodynamics in conscious, chronically instrumented lambs aged ∼1 and ∼6 weeks of postnatal life. Mean arterial pressure (MAP), mean venous pressure (MVP), and renal blood flow (RBF) were measured for 10 min before and for 120 min after ZD 7155, PD 123319, or vehicle. In both age groups, administration of ZD 7155 decreased renal vascular resistance (RVR) and increased RBF within 5 min. These responses lasted less than 90 min but were not dose-dependent. MAP decreased by 30 min after administration of ZD 7155 in both age groups at doses ≥400 μg kg⁻¹; the remaining decreased for up to 120 min, depending upon the dose. Pressor responses to angiotensin II (ANG II) were abolished within 5 min of administration of all doses of ZD 7155, at both 1- and 6 weeks. PD 123319 had no detectable effects on systemic or renal hemodynamics or on the pressor responses to ANG II. Therefore, under physiological conditions in conscious newborn animals, ANG II modulates both resting blood pressure and RVR through activation of AT₁ but not AT₂ receptors.     

Cerebral sodium/angiotensin interaction studied by RIA-determination of urinary arginine vasopressin in the hydrated goat

Radioimmunoassay determination of urinary arginine vasopressin (AVP) was employed to study quantitatively cerebral Na⁺/angiotensin II (A II) interaction in the hydrated goat. The solutions infused for 30 min at 0.02 ml/min into the lateral cerebral ventricle were: a) Hypertonic (0.25 M) NaCl, b) A II (0.3 ng/kg min) in isotonic (0.15 M) NaCl, and c) A II (dose as in b) in 0.25 M NaCl. The mean amounts of AVP detected in the urine in response to the various infusions were: a) 2.8 ng, b) 3.6 ng, and c) 13.3 ng. Thus, the A II/NaCl stimulation induced a detected renal excretion of AVP that was two times as large as the sum of the effects recorded in response to the separate stimuli. Infusion c) invariably induced a pronounced, long-lasting inhibition of the water diuresis, intense thirst, and natriuresis. The corresponding effects of infusions a) and b) were much weaker and, as regards thirst and natriuresis, inconsistent. The determinations of renal AVP excretion provide additional, and rather direct evidence for the concept of a synergistic action of elevated cerebrospinal fluid [Na⁺] and A II as concerns cerebral control of fluid balance. With regard to this kind of interaction, the observed dipsogenic and natriuretic effects mainly confirm earlier observations.     

Effect of substance P on CCK- or VIP-induced choleresis in anesthetized dogs

10 anesthetized dogs were provided with acute common bile duct fistulas and the gallbladder was excluded. Hepatic bile output and biliary content of sodium, potassium and amylase were studied. 6 caval infusions were administered of CCK, 0.3 Ivy U-kg^-1 min^-1, with a superimposed infusion of SP, 20 ng kg^-1 min^-1. 7 caval infusions were given of VIP, 50 ng-kg^-1 min^-1, with a superimposed infusion of SP, 20 ng·kg^-1 min^-1. CCK increased bile output and biliary content of sodium, potassium and amylase by 78–110%. The corresponding increase induced by VIP was 55–85%. Biliary pH was not influenced. SP abolished the effects of both CCK and VIP. It is suggested that all peptides studied influenced canalicular bile secretion by changing the electrolyte excretion.     

Reducing brain sodium concentration prevents post-prandial and dehydration-induced natriuresis in sheep

Renal Na excretion during the 24 h following feeding was studied in sheep. A pronounced natriuresis occured 3.5-5.5 h after feeding. Na excretion then fell to low levels in animals allowed to drink water, but was significantly elevated above this level in water-deprived sheep for most of the remaining period. Both the post-prandial and dehydration-induced natriuresis were prevented by intracerebroventricular (icv) infusions of low Na concentration 0.3 mol 1^-1 mannitol at 1 ml h^_1, and a water diuresis also occurred. These effects were not caused by icv infusion of artificial cerebrospinal fluid (Na concentration = 150 mmol l^-1). As a result, there was a much greater increase in plasma Na concentration and osmolality in the sheep given icv mannitol. Intravenous infusion of vasopressin prevented the water diuresis induced by icv mannitol, but the inhibition of natriuresis was still observed and plasma Na concentration increased by 8 mmol l^-1 over 24 h compared with an increase of 3 mmol l^-1 in dehydrated sheep infused icv with artificial cerebrospinal fluid. The results show that the ambient Na concentration in the brain plays an important role in the normal homeostatic regulation of Na balance by the kidney in sheep.