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The need for a better co-ordinated interdisciplinary approach to cancer is widely recognised. An analysis of strengths and weaknesses has emphasised the importance of a better understanding of the behavioural and social factors which determine the success of preventative and screening programmes and those which will enhace the quality of care and support available to patients and their families. The european commission provided funds to establish a consultation to formulate a strategy for the development of research in the behavioural, social and related sciences relevant to cancer. The key objectives were to inform research organisations of the steps necessary to enhance research capacity in these areas and identify the most productive directions for research in the forseeable future. The expert group identified 11 areas in which research might be expected to improve cancer control and treatment.

Removal of drinking water at the start of the dark period reduced food intake in freely feeding rats within 45 min. Both first and later meals were smaller during 7.5 h of water deprivation, but meal frequency did not change. Ingestion of a normal-sized meal (3 g) rapidly increased plasma tonicity when drinking water was withheld, but intravenous infusions of hypertonic NaCl causing similar increases in plasma tonicity did not reduce feeding. Feeding during 6 h of water deprivation was restored by slowly infusing the volume of water normally drunk into the stomach, jejunum, or cecum, but not in the vena cava or hepatic portal vein. The infusions did not alter water or electrolyte excretion or affect food intake in rats allowed to drink. We conclude that the inhibition of feeding seen during water deprivation is mediated by a sensor that is located in the gastrointestinal tract or perhaps in the mesenteric veins draining the gut, but not the hepatic portal vein or the liver. In the absence of drinking water, signals from this sensor provoke the early termination of a meal.

Little is known about the role of the renin–angiotensin system in anuran amphibians, although they appear to possess the functional components of such a system. We investigated the role of angiotensin (ANG) in arterial blood pressure regulation in the conscious toad Bufo marinus using the angiotensin-converting enzyme blocker captopril. We found that conversion of endogenous ANG I to ANG II made a significant contribution to mean arterial pressure in undisturbed animals. The vascular tone contributed by ANG II was not mediated via alpha adrenergic mechanisms because increases in pressure in response to ANG infusion were unaffected by the presence of the alpha antagonist phentolamine. Angiotensin-induced vasoconstriction was shown to be an important mechanism in arterial blood pressure regulation in the face of an acute hypotensive perturbation of pressure brought about by sodium nitroprusside. Blockade of the conversion of ANG I to ANG II significantly delayed the recovery of mean arterial pressure after sodium nitroprusside-induced hypotension. This suggests that the renin–angiotensin system may play an important role in the initial responses to hypotension in anurans, whether brought about by haemorrhage or dehydration.

We investigated the effects of endotoxins on water balance, rectal temperature, and food intake in male Long-Evans rats with femoral venous catheters. Extracts of Escherichia coli or Salmonella minnesota , in doses ranging from 125 to 500 μg/kg IV, stimulated drinking and reduced urinary water loss for several hours. The net gain of 5 ml water 2 h after the lowest dose of E. coli endotoxin was sufficient to reduce plasma osmolality and sodium concentration 2 to 3%. Drinking occurred during the period of hypothermia that frequently precedes the onset of endotoxin-induced fever, so cannot be attributed to increased body temperature. Doses of endotoxin causing drinking inhibited both spontaneous and deprivation-induced feeding. The cause of the drinking is not known, but may involve mechanisms other than the known dehydrational signals controlling thirst.

Several lines of evidence suggest that angiotensin II plays a physiological role in the control of thirst. Establishing that, however, has been surprisingly difficult, given our current knowledge about the renin–angiotensin systems in the circulation and the brain and the variety of techniques available to measure and manipulate them. A major problem is that stimulating or blocking the renin–angiotensin system affects several physiological variables simultaneously. Since several of these variables also influence the controls of water intake directly or indirectly, the interpretation of the effect on drinking becomes more difficult. To illustrate the problem and recent developments, this paper describes some of the interactions between the effects of angiotensin II on arterial pressure and thirst, and it shows how they have contributed to the controversy over the physiological role of the peptide.Key words: renin–angiotensin system, thirst, arterial pressure.

The effect of water deprivation for 19 h on renal Na excretion of conscious adrenalectomized (ADX) sheep maintained on a constant intravenous infusion of aldosterone and cortisol (ADX-constant steroid sheep) was investigated. Both ADX and normal sheep showed large increases in renal Na excretion when they were deprived of water. ADX-constant steroid sheep also exhibited a normal postprandial natriuresis 3–6 h after feeding, whether or not water was available to drink. In another experiment, sheep deprived of water for 41 h were then allowed to drink water. Both normal and ADX-constant steroid sheep exhibited a large reduction of renal Na excretion in the 6 h after rehydration. Changes in plasma Na and K concentration and osmolality were similar in normal and ADX-constant steroid sheep during periods of dehydration and rehydration. These results show that change in aldosterone secretion is not a major factor in causing either dehydration-induced or postprandial natriuresis. Neither is it a major cause of rehydration-induced renal Na retention.

This study investigated the effect of intracerebroventricular administration of the angiotensin AT1 receptor antagonist losartan on the natriuresis, pressor effect, and arginine vasopressin (AVP) secretion caused by intracerebroventricular infusion of either ANG II, hypertonic saline, or carbachol. Losartan (1 mg/h) or artificial cerebrospinal fluid (CSF) was infused into the lateral ventricle before, during, and after infusions of either ANG II at 10 μg/h for 1 h, 0.75 mol/l NaCl at 50 μl/min for 20 min, or carbachol at 1.66 μg/min for 15 min. Intracerebroventricular infusions of ANG II, 0.75 mol/l NaCl, or carbachol caused increases in renal Na+ and K+ excretion, arterial pressure, and plasma AVP levels. Increases in arterial pressure, Na+ excretion, and plasma AVP concentration ([AVP]) in response to intracerebroventricular ANG II or intracerebroventricular 0.75 mol/l NaCl were either abolished or attenuated by intracerebroventricular infusion of losartan but not by intracerebroventricular infusion of artificial CSF or intravenous losartan. Intracerebroventricular losartan did not reduce the increase in plasma [AVP] or arterial pressure in response to intracerebroventricular carbachol, but it did attenuate the natriuretic response to intracerebroventricular carbachol. We conclude that an intracerebroventricular dose of losartan (1 mg/h) that inhibits responses to intracerebroventricular ANG II also inhibits vasopressin secretion, natriuresis, and the pressor response to intracerebroventricular hypertonic saline. These results suggest that common neural pathways are involved in the responses induced by intracerebroventricular administration of ANG II and intracerebroventricular hypertonic NaCl. We propose that intracerebroventricular infusion of hypertonic saline activates angiotensinergic pathways in the central nervous system subserving the regulation of fluid and electrolyte balance and arterial pressure in sheep.

We investigated the contribution of brain angiotensinergic mechanisms to postprandial drinking in sheep. Sheep in fluid balance were given 0.8 kg chaff for 30 min, and water intake was measured for the next hour. Intracerebroventricular infusion of the AT1 type angiotensin II (ANG II) receptor blocker losartan (1 mg/h) reduced postprandial drinking by approximately 70% (n = 7, P < 0.01) but did not affect food intake. The same losartan dose given intravenously had little or no effect on prandial drinking. Feeding increased Na+ concentrations in plasma and cerebrospinal fluid (CSF; n = 5, P < 0.05). Intracerebroventricular losartan (1 mg/h) inhibited the drinking responses to intracarotid infusion of ANG II (0.8 microg/min for 30 min, n = 4, P < 0.01) and to intracerebroventricular infusion of 0.5 M NaCl (1 ml/h for 1 h, n = 5, P < 0.05) but had no effect on drinking responses to intravenous infusion of 4 M NaCl (1.3 ml/min for 30 min). These findings indicate that a brain ANG II-dependent mechanism is involved in postprandial drinking in sheep. They suggest also that the mechanism by which increasing CSF Na+ causes thirst involves brain ANG II and is different from the mechanism subserving the drinking response to changes in blood Na+.

We have investigated the development and maintenance of schedule-induced polydipsia (SIP) when ingested water (and food) was allowed to drain from the stomach. Fourteen male Long-Evans rats were prepared with permanent gastric cannulas and, after recovery, their body weight was reduced to 80%. Water intake was measured, with cannulas open or closed, during 42 daily 1-h sessions in which 45-mg food pellets were delivered one per minute. Allowing ingested material to drain from the stomach impaired the development of SIP and reduced the polydipsia in rats in which SIP had already been established. In contrast, opening the gastric fistulas increased drinking in these rats when all the food pellets were provided at once or after water deprivation. The opposite effects of gastric drainage on dehydration and schedule-induced drinking is consistent with the view that SIP is not a fluid-regulating phenomenon. It is not clear, however, how these unexpected findings fit current hypotheses to explain SIP that are based on oral, neural excitatory, or emotional mechanisms.

Intravenous injections of endotoxins from Escherichia coli or Salmonella minnesota stimulate drinking and reduce urinary excretion of water and solutes in rats. E. coli endotoxin (0.15 or 0.45 mg/kg i.v.) stimulated drinking without increasing plasma osmolality or sodium concentration, hematocrit, blood hemoglobin, or plasma protein concentration and without decreasing arterial pressure. Similarly, a dipsogenic dose of S. minnesota endotoxin (0.25 mg/kg i.v.) did not reduce arterial or venous pressures or change heart rate. Blocking the renin-angiotensin system with captopril or blocking histamine receptors with pyrilamine and cimetidine did not reduce drinking or urinary fluid retention caused by E. coli endotoxin. Injections of 10 or 450 ng E. coli endotoxin into a lateral cerebral ventricle increased body temperature but not water intake. In contrast to its stimulatory effect in water-replete rats, E. coli endotoxin (0.45 mg/kg i.v.) inhibited drinking in 24-h water-deprived rats. Thus we find no evidence to support the hypothesis that endotoxin causes thirst by changing known physiological signals of cellular or extracellular dehydration. The mechanism remains unknown.

Rats with bladder and venous cannulas were deprived of water from midnight (00:00) to 10:00. Water deprivation reduced food intake within 2 h, reducing the amount of water sequestered in the gut and the solute load to the tissues. There was little change in either urinary water loss or osmolality, but water-deprived rats excreted more Na+, K+, and Cl− than food-matched controls. The change in solute balance helped preserve osmolality and cell volume at the expense of extracellular fluid volume. When water was returned, rats quickly drank enough to restore the intracellular but not the extracellular fluid deficit. Plasma osmolality and sodium concentration fell below predeprivation values. Urine osmolality and excretion of Na+, K+, and Cl− fell rapidly after drinking. Drinking continued at a slower rate for at least 4 h, but urine flow also increased so water balance stabilized. The changes in intake and electrolyte excretion during water deprivation and rehydration illustrate the important role of changes in solute balance in fluid homeostasis.Key words: water deprivation, thirst, drinking, water balance, sodium balance.

Diazoxide, a potent vasodilator and antidiuretic, was used to examine the relationship between hypotension and thirst in conscious rats with indwelling arterial and venous catheters. Bolus iv. injections (5-50 mg/kg) caused prompt, long-lasting, and dose-dependent reductions in mean arterial pressure (MAP) and stimulated drinking. Water intake and degree of hypotension were closely correlated when MAP was 10-65 mmHg below normal. At the time of drinking there were no significant changes in central venous pressure, plasma osmolality, or Na+ or K+ concentration. Plasma glucose increased approximately 35%, and blood volume increased approximately 10% (based on hematocrit changes and dilution of Evans blue). Captopril (100 mg/kg sc to block the renin-angiotensin system) enhanced the depressor response to diazoxide but abolished the dipsogenic response over the same range of arterial pressures tested in controls. Angiotensin II iv infusion restored drinking in captopril-treated animals. The combination of captopril and diazoxide did not block drinking to iv infusions of hypertonic saline or water deprivation. These results confirm that hypotension potently stimulates thirst and support the hypothesis that angiotensin II mediates the dipsogenic response in rats.

Rats with bladder and venous cannulas were deprived of water from midnight (00:00) to 10:00. Water deprivation reduced food intake within 2 h, reducing the amount of water sequestered in the gut and the solute load to the tissues. There was little change in either urinary water loss or osmolality, but water-deprived rats excreted more Na+, K+, and Cl− than food-matched controls. The change in solute balance helped preserve osmolality and cell volume at the expense of extracellular fluid volume. When water was returned, rats quickly drank enough to restore the intracellular but not the extracellular fluid deficit. Plasma osmolality and sodium concentration fell below predeprivation values. Urine osmolality and excretion of Na+, K+, and Cl− fell rapidly after drinking. Drinking continued at a slower rate for at least 4 h, but urine flow also increased so water balance stabilized. The changes in intake and electrolyte excretion during water deprivation and rehydration illustrate the important role of changes...

This paper explores the relationship between an individual's scenario about his own future and his characterizing behaviors within the institutional setting. Statements made by 87 persons about their own futures (5 years ahead) are examined, coded (in terms of the person's ease of projecting himself into the future situation), and related with measures of the person's overall performance and activism within the organizational system. The relationships (and nonrelationships) found indicate that there are behaviorally important differences in individual styles of cognizing one's own future. Two different orientations toward futurity seem to be evidenced from these results and those previously reported by the author in Human Relations. The first is a facility to project oneself ahead and to picture one's own future, which is associated with active participation in the ongoing organizationalprocesses. The second is a motivation to generate multiple images of alternatives to the prevailing system, which is associated with organizational activism and innovative behavior.

The author examines the reasons for researching into society's interest in the future and considers several indicators. Two main types of indicators emerge—which relate either to professional or to popular interest in the future. From a content analysis of periodical literature over the past 75 years the author is able to plot the increasing interest in the future and the cycles imposed on that trend. These findings raise a number of questions : eg what are the reasons for the variations and, in particular, for the recent decline in interest in the early 1970s. The author forecasts that interest in the future will revive again over the next decade.

1. Angiotensin II is as potent a stimulus to drink in pigeons as it is in mammals. There are striking similarities in the action of this peptide in pigeons and mammals. 2. Angiotensin II injected intracranially, I.V. or I.P. consistently caused short-latency and vigorous drinking in pigeons but no other behaviour. Drinking was completed rapidly and intakes were very large, sometimes in excess of 10% of the bird's body weight. 3. The latency to drink and the amount drunk were dose dependent for all routes of injection. Angiotensin II was most effective when injected directly into the brain. As little as 10(-4) mol angiotensin II injected into the cerebral ventricles caused birds to drink. 4. The rapid cessation of drinking after intracranial injection of angiotensin II was not caused by rapid loss of activity of the peptide in the brain but by the actual ingestion of the water. 5. The brain sites most sensitive to the dipsogenic action of angiotensin II in the pigeon were the dorsal and ventral third ventricle, the tissue adjacent and anterior to these sites, and the lateral ventricles. The lateral hypothalamic area was only slightly less sensitive. Negative sites for drinking were found in the lateral forebrain and the hind brain. These findings are similar to those in mammals. 6. Pigeons drank during I.V. infusion of as little as 16 X 10(-12) mol angiotensin II kg-1 min-1. This was near the threshold for increasing arterial pressure in pigeons and is near the threshold for drinking in rats and dogs. 7. The Asn1, Asp1, Val5 and Ile5 analogues of angiotensin II were equipotent as stimuli to drink but a wide range of other peptides and drugs injected into the brain failed to increase water intake. An exception was eledoisin which was, comparing molecule with molecule, only 10-100 times less potent than angiotensin II in the pigeon. 8. Injections of angiotensin II into brain sites which caused drinking failed to alter heart rate or arterial pressure in pigeons. 9. This and other recent studies demonstrate the wide phylogenetic distribution of the dipsogenic action of angiotensin II and support the idea that the control of water intake is an important physiological function of the renin-angiotensin system in vertebrates.

We have investigated the effects on water intake of subcutaneous (S.C.) injections of low (0.5 mg/kg) and high (100 mg/kg) doses of captopril, an inhibitor of angiotensin-converting enzyme (CE). Low doses block the synthesis of angiotensin II only in the circulation whereas high doses block CE in both the blood and the brain. The low dose of captopril enhanced drinking in response to three hypotensive drugs, isoprenaline (0.1 mg/kg, S.C.), phentolamine (5 mg/kg, S.C.) and serotonin (2 mg/kg, S.C.), whereas the high dose of captopril abolished drinking in response to these stimuli. The low dose of captopril also enhanced drinking in response to histamine (0.25-5.0 mg/kg, intraperitoneal, I.P.), but in this case the high dose of captopril only partially reduced the drinking response. The low dose of captopril enhanced drinking after 24 h water deprivation but high doses had no significant effect on deprivation-induced thirst. Hypovolaemia was produced either by injecting polyethylene glycol (30% w/v, 10 ml/kg) S.C. or by replenishing the cellular deficit in water-deprived rats with 10 ml water (by gavage). The low dose of captopril enhanced the drinking response to hypovolaemia but the high dose had no significant effect. Neither the high nor the low dose of captopril significantly affected drinking in response to cellular dehydration caused by injecting 2 M-NaCl (2 ml) I.P. or by replenishing the extracellular deficit in water-deprived rats (10 ml balanced salt solution by gavage). Nephrectomy (but not ligation of the ureters) or injections of propranolol (5 mg/kg, S.C.) to prevent renin secretion prevented the enhancement of deprivation-or serotonin-induced thirst by the low dose of captopril. The low dose of captopril did not enhance drinking in response to I.V. injections of renin (1 Goldblatt unit), or intracerebroventricular (I.C.V.) injections of angiotensin I or II. The high dose of captopril blocked drinking in response to I.V. injections of renin or I.C.V. injections of angiotensin I but did not reduce drinking in response to angiotensin II, I.C.V. These results are consistent with the hypothesis that blocking CE only in the circulation enhances drinking in response to hypotension or hypovolaemia because angiotensin I, accumulating in high concentration in the blood, enters the brain and is converted intracerebrally to angiotensin II. These findings suggest that the enhancement of drinking caused by low doses of captopril s.c. is a sensitive indicator of whether the renin- angiotensin system participates at all in the regulatory response to a particular stimulus to drink.(ABSTRACT TRUNCATED AT 400 WORDS)

To investigate the relationship between angiotensin II (ANG II) and mean arterial pressure (MAP) in the control of drinking in rats, we infused ANG II intravenously at constant rates (either 50 or 100 ng.kg-1.min-1 for 90 min) and varied MAP by intravenous injections of diazoxide (5-20 mg/kg). Rats were pretreated with captopril to block the endogenous synthesis of ANG II. When given alone, low and high doses of ANG II increased MAP approximately 30 and 50 mmHg, respectively. The low but not the high dose significantly increased water intake above control levels. Both doses caused such a large diuresis and natriuresis that the net effect was fluid loss. Reducing MAP toward normal greatly increased the drinking response to the high but not the low dose of ANG II and reduced the urinary solute and water loss to both doses. These results support the hypothesis that water intake and net fluid gain are inhibited when MAP is above normal. When MAP was reduced below normal in rats given constant infusions of ANG II the amount of water drunk and net fluid gain was proportional to the dose of ANG II but not the dose of diazoxide, the degree of hypotension, or urinary losses. This is consistent with previous reports that ANG II is essential for the drinking response to hypotension. Furthermore, it demonstrates that ANG II is not merely permissive but probably the signal controlling water intake when arterial pressure is reduced below normal.

The paper explores some of the attributes of organizational activists, in terms of their personality types, their characteristic behaviors, and their imaging styles when personally confronting their own futures. It was found that activists prefer intangible imagery to the tangible sensible world; are intuitives rather than sensers; are internally rather than externally oriented; are somewhat compulsive; are self-generative in terms of their identity; and are diversity generators rather than diversity regulators. The study provides a significant bridge between (a) Lewin 's little-recognized formulation of the life-space notion in terms of 'degrees of reality/irreality'; (b) the intuitivesensing dimension of Jung's theory of psychological types; and (c) the internal-external dichotomy of Rotter and others. The overall aim of the paper is to contribute to the integration of the conceptual foundations of the social sciences, in order to create an eventual theory of social change. A redefinition of planning and change is presented, in terms of the interaction between the two kinds of reality discussed in the paper: Reality-], the finite sensible material reality, and Reality-2, the limitless world of symbols and imagery.

We have investigated the extent to which captopril's short-term (1 h) effects on salt and water intake in the rat are caused by effects on taste. In single-bottle tests a low dose of captopril (0.5 mg/kg s.c.), which blocks the synthesis of angiotensin II in the blood but not the brain, increased equally the intakes of water, 0.05, 0.15, 0.30 and 0.45 M NaCl, 0.3 M KCl, 10 mM HCl, 0.14 mM quinine hydrochloride and 0.1 mM saccharin solutions without changing the animals' preference for or aversion to each with respect to water. In two-choice tests this dose increased water but not 0.15 or 0.45 M NaCl intake. A large dose of captopril (100 mg/kg s.c.), to block the synthesis of angiotensin II also in the brain, did not enhance water or NaCl intake. Neither dose affected NaCl or water intake by rats drinking in response to 2 M NaCl, 5 ml/kg i.p. We conclude that during the first hour following injection captopril has no major effect on taste perception or preference in the rat and does not stimulate sodium appetite in the sodium-replete rat. Our results support the hypothesis that low doses of captopril increase fluid intake by enhancing the synthesis of angiotensin II in the brain.

1. 1. A number of neuropeptides have been found to affect fluid intake when injected directly into the brain of various vertebrate species. These inlcude: angiotensin II and its peptide precursors; the tachykinins Substance P, eledoisin and physalaemin; the opioid peptides met- and leu-enkephalin and β-endorphin; bombesin; neurotensin; and vasopressin. 2. 2. Some of these stimulate drinking, some inhibit water intake, and the tachykinins have opposite effects on thirst depending on the species tested. 3. 3. Very little is known about the site or mechamism of action of most of these peptides or if their effects on thirst are physiological. 4. 4. The exception is angiotensin II, a peptide hormone that is synthesized in the blood in response to hypovalaemia or hypotension and is involved in many aspects of the regulation of blood volume and pressure. Angiotensin II injected intravenously or intracranially stimulates drinking in all reptiles, birds and mammals tested. 5. 5. In addition to its role as a hormone, angiotensin II may also function as a neurotransmitter or neuromodulator, since all of the enzymes and precursors necessary for its synthesis have been found in the central nervous system.

1. The pigeon drank as vigorously in response to intracranial injection of synthetic renin substrate and angiotensin I as to angiotensin II. 2. Mammalian renin injected into the brain caused the water-replete pigeon to drink but it was a less effective dipsogen than in the mammal. As in the mammal, renin-induced drinking was slower in onset and continued for longer than angiotensin-induced drinking. 3. The converting enzyme inhibitor SQ 20881 attenuated drinking in response to intracranial renin, synthetic renin substrate and angiotensin I but enhanced intracranial angiotensin II-induced drinking. Therefore drinking induced by the intracranial injection of precursors of angiotensin II is mediated through local generation of angiotensin II. 4. I.V. injection of angiotensin I was as effective as angiotensin II in causing the pigeon to drink, but synthetic renin substrate was less effective. I.V. doses of angiotensin I and II had to be about 100 times greater than the intracranial doses in order to produce similar intakes. 5. Angiotensin I and II were equally effective pressor agents by I.V. injection in the pigeon but synthetic renin substrate was much less effective. I.V. SQ 20881 inhibited the pressor response to I.V. synthetic renin substrate or angiotensin I but enhanced the angiotensin II-induced response. 6. Aliphatic position 8-substituted analogues of angiotensin II which are competitive antagonists of angiotensin II-induced drinking and pressor responses in the mammal in antagonist:agonist mole ratios as low as 10:1, failed to reduce drinking in response to intracranial synthetic renin substrate or angiotensin II, although not themselves agonists, nor did they prevent the pressor to infusion of angiotensin II even with antagonist:agonist mole ratios as high as 10,000:1. 7. Shortening the angiotensin octapeptide from the N-terminus caused a progressive reduction in intracranial dipsogenic activity. Activity was completely abolished by removing the C-terminal phenylalanine. 8. These results demonstrate that in pigeons, as in mammals, it is angiotensin II which is the biologically active peptide in the control of drinking behaviour and blood pressure by the renin-angiotensin system. Precursors of angiotensin II can be converted to the octapeptide in the avian brain as well as in the circulation. The angiotensin receptors for drinking and blood pressure responses are similar to each other in the pigeon and they are very similar but not identical with the angiotensin receptors for the dipsogenic, pressor and myotropic actions of angiotensin II in mammals.

1. We investigated the role of the renin—angiotensin system in isoprenaline-induced drinking in the rat. Captopril, an inhibitor of angiotensin-converting enzyme, was used to block the synthesis of angiotensin II either in the circulation alone or in the brain as well. 2. Subcutaneous injections of isoprenaline (0·1 mg/kg) alone caused nine rats to drink 8·4 ± 0·9 ml water in 3 h. 3. Pre-treatment with doses of captopril (0·1-1·0 mg/kg, s.c.), which inhibit conversion of angiotensin I to II in the circulation but not in the brain, dose-dependently enhanced the drinking response to isoprenaline. Captopril alone did not cause drinking. 4. Higher doses of captopril (5·0-100 mg/kg, s.c.), which inhibit conversion of angiotensin I to II in the brain as well as in the blood, caused dose-dependent inhibition of drinking elicited by isoprenaline. 5. The highest dose of captopril tested (100 mg/kg, s.c.) completely blocked the drinking response to isoprenaline (0·1 or 0·33 mg/kg, s.c.) for at least 45 min. This inhibition was not caused by general debility of the rats; animals deprived of water (12 h) and treated with both captopril and isoprenaline drank as much as water-deprived controls. 6. We found no evidence that blocking the renin—angiotensin system inhibits drinking because it exacerbates isoprenaline-induced hypotension. After injection of isoprenaline the mean arterial pressure of nephrectomized rats or rats pre-treated with the high dose (100 mg/kg, s.c.) of captopril (which blocked drinking) was only slightly lower (5-10 mmHg) than that of rats pre-treated with the low dose (0·5 mg/kg, s.c.) of captopril (which enhanced drinking). 7. Water deprivation, which caused rats treated with isoprenaline and captopril to drink, did not increase arterial pressure. Pitressin increased the arterial pressure of rats treated with isoprenaline and captopril but did not cause drinking. We conclude that the renin—angiotensin system has a direct and essential role in the drinking response to isoprenaline.

Effects of central losartan on plasma renin and centrally mediated natriuresis. Because intracerebroventricular (ICV) infusion of hypertonic saline or angiotensin II (Ang II) both induce water drinking, vasopressin secretion, natriuresis and increased arterial pressure, the possibility that common neural pathways mediate responses to ICV Ang II and hypertonic saline has been investigated. This was done by testing the effect of ICV infusion of the Ang II antagonist losartan on the natriuretic and pressor responses to ICV hypertonic NaCl in sheep. The effect of ICV losartan on plasma renin concentration (PRC) was also investigated. Infusion of losartan (1 mg/hr) into a lateral ventricle prevented both natriuretic and pressor responses to infusion of 0.6 mol/liter NaCl into a lateral ventricle at 1 ml/hr. In another experiment, ICV losartan at 1 mg/hr caused a pronounced increase in the PRC of Na-depleted sheep, while ICV Ang II at 3 µg/hr decreased PRC. The results suggest that: (i) a central angiotensinergic pathway may mediate osmoregulatory responses to centrally administered hypertonic saline, and (ii) a central angiotensinergic pathway may have a tonic inhibitory influence on renin secretion in Na-depleted animals.

We investigated whether the pressor response to intravenous angiotensin II (ANG II) suppresses drinking. All experiments were done on conscious water-replete rats (200-400 g) with chronic vascular cannulas. Two rates of ANG II infusion (16.7 and 100 ng/min for 90 min) were tested; captopril (0.33 mg/min) was infused simultaneously to prevent endogenous production of ANG II. Both doses of ANG II increased mean arterial pressure (MAP) by 40-50 mmHg for the duration of the infusions, but water intakes were small. The drinking response was increased as much as fivefold, however, when the pressor response was reduced by injecting either isoproterenol (0.01 or 0.1 mg/kg, sc), diazoxide (20, 30, or 75 mg/kg, sc), or minoxidil (10 mg/kg, ip) 15 min after starting the ANG II infusion. The closer MAP was returned to normal, the greater was the drinking response. Since lowering MAP also reduced urinary water losses, net fluid intake increased even more dramatically. It is unlikely that the vasodilators directly stimulated thirst in the experiments because the dose of captopril used completely blocked drinking to these agents given alone. A situation of high circulating levels of ANG II but with MAP near or below normal more closely resembles physiological conditions of dehydration. Our results demonstrate that intravenous ANG II is a very potent dipsogen under these conditions.

Stimuli such as hypovolemia or hypotension which increase the secretion of renin from the kidneys increase thirst in man and other vertebrates1. However, intravenous infusions of renin or angiotensin II (Ang II) at doses which produce circulating concentrations similar to those observed in hypovolemia and hypotension cause relatively little drinking2,3,4. This could be interpreted to mean that the role of Ang II in the control of drinking to these stimuli is minor. The conditions are not comparable, however. Intravenous infusions of Ang II cause large increases in arterial pressure in the water-replete animal whereas under physiological conditions these same concentrations of Ang II would occur when blood pressure was at or below normal.

Captopril (30 mg/kg daily by gavage), an orally active inhibitor of angiotensin-converting enzyme, reduced the intake of 0.15 M NaCl in rats treated with desoxycorticosterone acetate (2.5 mg/day S.C.). However, this is probably not a specific effect on salt appetite as captopril (30 or 60 mg/kg daily) did not reduce the intake of less palatable 0.5 M NaCl in desoxycorticosterone acetate-treated rats (1 or 2.5 mg daily). In contrast, captopril given alone (30 or 60 mg/kg daily) consistently caused a 3- to 5-fold increase in intake of 0.5 M NaCl that usually began on the 1st day and persisted until treatment stopped (1-3 weeks). Sodium intake and sodium excretion increased concomitantly, but the stimulation of salt appetite occurred even in the absence of sodium depletion. Also, the effect on salt appetite was specific; captopril did not increase the intake of 0.5 M KCl or 0.03 M sucrose. This potent and specific stimulation of sodium intake by oral treatment with an inhibitor of the renin-angiotensin system may be caused by a paradoxical increase in the synthesis of angiotensin II in the brain.

Rats with lesions of the zona incerta (ZI) dorsal to the lateral hypothalamus drink as much water as controls following intracellular or extracellular dehydration but restrict their daily water intake to minimal requirements for fluid balance, suggesting a specific impairment in secondary drinking. Following water deprivation, however, rats with ZI lesions responded to changes in palatability of the water as if they were experiencing slightly greater difficulty or aversiveness in drinking than controls. The cause appears to be an impairment in the ability to lick fluids from a spout. When water was available ad libitum or when water or liquid diet were provided after water or food deprivation, rats with ZI damage were unable to obtain as much fluid per lick as controls. It is concluded that lesions in this region of the brain impair the motor act of drinking and that the subsequent reduction in the efficiency of drinking is the cause of the attenuation of excessive water intake.

Growth hormone release inhibiting hormone (GHRIH) was administered by constant infusion over 75 minutes to eight acromegalic patients at different doses. 100 to 1,000 mug were equally effective in reducing circulating growth hormone (GH) levels; 25 mug lowered GH levels in only five patients, and at this dose the extent of the fall was smaller than from doses of 100 mug or more. 10 mug was ineffective. Injection of single doses of 500 mug by intravenous, subcutaneous, and intramuscular routes caused only small and transient reductions in GH levels, though the effect was improved by injecting the hormone intramuscularly in 2 ml of 16% gelatin. Injection of a suspension of 4 mg GHRIH in 1 ml of arachis oil lowered growth hormone levels for between three and four hours.In four acromegalic patients an oral 50-g glucose tolerance test was performed during a continuous infusion of either saline or 1,000 mug GHRIH. The "paradoxical" rise in growth hormone seen in these patients during the saline infusion was suppressed by GHRIH. The blood glucose responses were, moreover, modified by GHRIH in that the peak was delayed and occurred at the end of the infusion in each case. A "normal" glucose tolerance curve was converted to a "diabetic" type of response in two patients. This effect could be accounted for by the inhibition of insulin secretion known to occur with large doses of GHRIH.We speculate that acromegaly may be primarily a hypothalmic disease due to deficiency of GHRIH resulting in excessive secretion of growth hormone from the pituitary and adenoma formation due to inappropriate and prolonged stimulation of the pituitary.

In rats with permanent brain cannulas intracerebroventricular (i.c.v.) injections of 2 microgram captopril nearly abolished drinking responses elicited by i.c.v. injections of 1 mUnit hog renin, 10 pmol synthetic renin substrate or 10 pmol angiotensin I but did not reduce drinking elicited by 10 pmol angiotensin II. Inhibition of the response to precursors of angiotensin II was long-lasting (at least 2 h) and dose-dependent (20 ng-2 microgram captopril). Captopril was 3-5 times more potent than SQ 20,881 i.c.v. Subcutaneous injections of captopril in doses 0.1 to 1.0 mg/kg reduced pressor responses to intravenous injections of angiotensin I without attenuating drinking elicited by i.c.v. injections of angiotensin precursors. Higher doses of captopril, however, given subcutaneously (5-50 mg/kg) or by gavage (10 mg/kg) did not reduce drinking to i.c.v. injections of renin or angiotensin I (but not angiotensin II). We conclude that captopril inhibits angiotensin-converting enzyme activity in the brain even when given subcutaneously or by gavage in doses commonly used in the rat.

Increasing pressure is being placed on the scientific community to evaluate research activities. Scientific meetings consume a small but important fraction of the research budget. Audit of a well established series of scientific meetings showed that they met their immediate objectives in that they were international and multidisciplinary and provided a forum in which all participants actively contributed to discussion. The meetings had a positive outcome for the participants, leading in many cases to the subsequent exchange of research material (60% of participants) and to the establishment of collaborative research projects (31%). The impact of the meetings on the scientific community at large was assessed by citation analysis, which showed that the proceedings were cited early, often, and over a substantial period.

THE only peptide known which rapidly and consistently elicits a specific behavioural response when injected into the brain is angiotensin II, which in picomole doses causes reptiles, birds and mammals to seek out and drink water1. But, there is evidence to suggest that other peptides such as substance P may also participate in the control of brain function and behaviour. Substance P is distributed throughout the mammalian peripheral and central nervous system, particularly in myenteric plexus, sensory afferent pathways, hypothalamus and substantia nigra2. In the human brain regional concentrations as high as 0.5 × 10−9 mol per g wet tissue have been reported3. Substance P is a member of a family of peptides with similar pharmacological properties and which also includes eledoisin, an undecapeptide obtained from the salivary glands of certain Mediterranean cephalopods4. These peptides share a similar amino acid sequence at the C-terminal end (Fig. 1). Both eledoisin and substance P stimulate nerve cell activity in vertebrates and invertebrates and may act as regulators of neural activity5, but no specific behavioural effect of these peptides has yet been reported. We report here that eledoisin and substance P elicit vigorous drinking when injected into the brain of conscious pigeons.