Effects of high altitude and water deprivation on arginine vasopressin release in men.

High-altitude exposure changes the distribution of body water and electrolytes. Arginine vasopressin (AVP) may influence these alterations. The purpose of this study was to examine the effect of a 24-h water deprivation trial (WDT) on AVP release after differing altitude exposures. Seven healthy males (age 22 +/- 1 yr, height 176 +/- 2 cm, mass 75.3 +/- 1.8 kg) completed three WDTs: at sea level (SL), after acute altitude exposure (2 days) to 4,300 m (AA), and after prolonged altitude exposure (20 days) to 4,300 m (PA). Body mass, standing and supine blood pressures, plasma osmolality (Posm), and plasma AVP (PAVP) were measured at 0, 12, 16, and 24 h of each WDT. Urine volume was measured at each void throughout testing. Baseline Posm increased from SL to altitude (SL 291.7 +/- 0.8 mosmol/kgH2O, AA 299.6 +/- 2.2 mosmol/kgH2O, PA 302.3 +/- 1.5 mosmol/kgH2O, P < 0.05); however, baseline PAVP measurements were similar. Despite similar Posm values, the maximal PAVP response during the WDT (at 16 h) was greater at altitude than at SL (SL 1.7 +/- 0.5 pg/ml, AA 6.4 +/- 0.7 pg/ml, PA 8.7 +/- 0.9 pg/ml, P < 0.05). In conclusion, hypoxia appeared to alter AVP regulation by raising the osmotic threshold and increasing AVP responsiveness above that threshold.

Acute hormonal responses to a single bout of heavy resistance exercise in trained power lifters and untrained men.

The purpose of this study was to investigate the acute responses of both stress and fluid regulatory hormones to a single bout of resistance exercise in both trained and untrained men. Seven competitive power lifters (PL) and 12 untrained subjects (UT) performed one set of the leg press exercise to exhaustion at 80% of their respective one-repetition maximum. Blood samples were obtained twice prior to exercise (at P1 and P2), immediately postexercise (IP), and at 5 minutes postexercise (5PE). Compared to P1 and P2, plasma epinephrine, norepinephrine, dopamine, atrial peptide, osmolality, and blood lactic acid increased significantly (p < or = 0.05) at IP. Plasma epinephrine, norepinephrine, atrial peptide, and blood lactic acid concentrations remained elevated at 5PE compared to P1 and P2. Plasma renin activity and angiotensin II were significantly elevated at 5PE compared to P1, P2, and IP, and this increase was significantly greater in PL compared to UT at 5PE. These data indicate that an acute bout of resistance exercise dramatically affects secretion of stress and fluid regulatory hormones.

Natriuresis caused by increased carotid Na+ concentration after renal denervation.

The renal effects of a selective estimated 3 mM increase in the concentration of Na+ in blood perfusing the brain was investigated in conscious dogs with surgically denervated kidneys. In split-infusion experiments the concentration of Na+ in carotid plasma was increased by a bilateral carotid infusion of hypertonic NaCl combined with an infusion of distilled water into the caval vein. In control experiments the same load of NaCl and water was administered as an isotonic solution into the carotid and jugular vessels. Peak rate of Na+ excretion was significantly higher during split infusion (156 +/- 19 mumol/min) compared with control (89 +/- 14 mumol/min). Renal excretion of urodilatin increased in both series. Renal excretion of endothelin immunoreactivity increased significantly more during split infusion (20 +/- 6 pg/min) than during control (9 +/- 3 pg/min). It is concluded that the natriuretic response to minute increases in Na+ concentration of carotid plasma is intact after renal denervation. Furthermore, endothelin may be involved in the excess excretion observed.

Is urodilatin (rather than atriopeptin) the primary natriuretic peptide of the ANP family?

This article summarizes evidence supporting the hypothesis that urodilatin, rather than atriopeptin, is the member of the atrial natriuretic peptide family primarily involved in the regulation of renal sodium excretion. A number of lines of evidence imply that atriopeptin is only of trivial importance in the regulation of sodium excretion during normal living conditions. On the other hand, urodilatin, which is produced in the kidneys, has properties very similar to atriopeptin. Moreover, its excretion in the urine appears to correlate quite closely with the concomitant excretion of sodium.

Renal natriuretic peptide (urodilatin?) and atriopeptin: evolving concepts.

The discovery of the natriuretic peptide, urodilatin, in human urine, together with data from renal cell cultures, immunocytochemistry, radioimmunoassays, and other techniques, strongly indicates that distal tubules in the kidney produce a natriuretic prohormone that may be identical to the 126-residue prohormone of atrial natriuretic peptide [proANP-(1-126)] produced by cardiac atria. The 32-residue peptide, urodilatin [ANP-(95-126)], is found in urine but not in plasma; its natriuretic potency equals or exceeds that of atriopeptin [ANP-(99-126)]. It is still unclear whether urodilatin is the only, or even the primary, renal natriuretic peptide. Circumstantial evidence suggests that natriuretic peptide produced in connecting and collecting tubules may be a principal physiological ligand for more distal "ANP" receptors, but this issue is far from settled. Evidence that the kidneys produce their own natriuretic peptide may partly explain why investigations of the effects of endogenous atriopeptin on renal sodium excretion often have yielded inconsistent results. This inconsistency has led to a gradual evolution of opinion concerning the functional role of atriopeptin. Based on current data, it is postulated that atriopeptin is primarily a regulator of the cardiovascular system and that renal natriuretic peptide participates in the intrarenal regulation of sodium and chloride transport.

Effects of endothelin-1 and sarafotoxin S6b on regional hemodynamics in the conscious dog.

Endothelin, a potent vasoconstrictor, also is capable of producing transient vasodilation in some situations. We examined the changes in regional hemodynamics in response to constant infusions of endothelin-1 (ET-1) at 5, 10, or 20 ng.kg-1.min-1 for 1 h into conscious dogs. The dogs were instrumented with ultrasonic flow probes for measurement of blood flow in the ascending aorta (cardiac output) and in the coronary, mesenteric, renal, and iliac arteries. A compound structurally similar to ET-1, sarafotoxin S6b (S6b), was also infused in identical experiments to determine whether the responses to these two peptides might differ. Basal plasma levels of immunoreactive ET-1 averaged approximately 6 pg/ml. After 55 min of infusion of ET-1 at 5, 10, and 20 ng.kg-1.min-1, plasma immunoreactive ET-1 increased to approximately 55, 130, and 520 pg/ml, respectively. When given at 20 ng.kg-1.min-1, ET-1 increased total peripheral resistance and arterial pressure and decreased cardiac output and heart rate. ET-1 decreased coronary, mesenteric, and renal blood flow but did not change iliac flow. In comparison with ET-1, S6b produced relatively smaller changes in total peripheral resistance, cardiac output, heart rate, and coronary, mesenteric, and renal blood flow. Iliac resistance did not change in response to ET-1, but it increased during infusions of S6b. Similar but less pronounced responses were observed when these peptides were infused at 5 and 10 ng.kg-1.min-1. The regional variability in the hemodynamic response to ET-1 and the difference in regional responses to ET-1 and S6b are consistent with the existence of heterogenous receptor subtypes for these peptides.

Enhanced atrial peptide natriuresis during angiotensin and aldosterone blockade in dogs.

The hypothesis that the weak natriuretic effect elicited by modest amounts of atrial peptide is mediated via the inhibition of renin and aldosterone was evaluated in the conscious dog. The formation of angiotensin II (ANG II) and the effects of aldosterone (Aldo) were blocked acutely by enalaprilat and canrenoate, respectively. Infusion of alpha-human atrial natriuretic peptide (alpha-hANP) for 2 h at 25 ng.kg-1.min-1 increased plasma atrial peptide concentration 7- to 10-fold. In control experiments, i.e., experiments without ANG II-Aldo blockade, infusion of atrial peptide doubled urine volume (UV) from 0.21 +/- 0.01 to 0.43 +/- 0.09 ml/min and sodium excretion (UNaV) from 18 +/- 5 to 37 +/- 7 mueq/min; mean arterial blood pressure (AP) and atrial pressures decreased, whereas total peripheral resistance increased. The induction of ANG II-Aldo blockade elevated UNaV and UV 10- and 6-fold, respectively, and decreased AP. The subsequent 2-h infusion of atrial peptide elicited a further increase in UNaV (from 195 +/- 28 to 334 +/- 60 mueq/min); the hemodynamic changes were similar to those seen in the absence of ANG II-Aldo blockade, except that AP did not decrease significantly during the administration of atrial peptide. The data demonstrate that pharmacological inhibition of the effects of converting enzyme and Aldo does not impede the natriuretic response elicited by a 7- to 10-fold increase in circulating atrial peptide; in fact, the magnitude of the natriuresis is markedly enhanced during this blockade.

Atriopeptin alters the vasopressin and renin responses elicited by hemorrhage.

This study was designed to investigate whether an infusion of atrial peptide is capable of modulating the hormonal and hemodynamic responses elicited by acute hemorrhage. Conscious dogs were bled at a rate of 0.8 ml.kg-1.min-1 until 20 ml of blood/kg body wt had been removed. Two experiments were performed on each dog; in one experiment the animal was given alpha-human atrial natriuretic peptide (alpha-hANP) (50 ng.kg-1.min-1) dissolved in saline; in the other only the saline vehicle was given. Right and left atrial pressures decreased during hemorrhage in all experiments; the absolute decreases were greater when the animals received atriopeptin, but the differences between treatments were statistically significant only for right atrial pressure. Cardiac output decreased (P less than 0.05) and total peripheral resistance increased (P less than 0.05) during hemorrhage when atriopeptin was infused; although these variables showed similar trends when vehicle alone was infused during hemorrhage, no significant changes occurred. Infusion of atrial peptide did not affect the decrease in arterial blood pressure that occurred during hemorrhage. The increase in plasma vasopressin induced by hemorrhage was potentiated, but the increase in plasma renin activity was attenuated when alpha-hANP was infused. Hemorrhage increased circulating aldosterone levels in each experiment, but the response was less pronounced when alpha-hANP was given during the experiment. Intravenous administration of alpha-hANP modulates the hemodynamic responses elicited by hemorrhage, potentiates the rise in plasma vasopressin, and attenuates the rise in plasma renin activity induced by acute blood loss in conscious dogs.

Evidence that atriopeptin is not a physiological regulator of sodium excretion.

Although much experimental evidence is consistent with the concept that atrial natriuretic factor (atriopeptin) is an important physiological regulator of renal sodium excretion, this hypothesis remains unproven. Indeed, a rapidly expanding collection of experimental data appears to be more compatible with the opposite conclusion, namely that circulating atriopeptin exerts only a trivial effect on renal sodium excretion during normal day-to-day living conditions. In this review, the substantial evidence demonstrating that elevations of plasma atriopeptin from threefold to 13-fold produce only a slowly developing and relatively modest natriuresis is reassessed in light of recently published data indicating that the acute intake of food (the pathway by which essentially all sodium enters the body under normal living conditions) does not increase circulating atriopeptin. These considerations imply that atriopeptin does not contribute to the process that elicits a postprandial natriuresis, a process that presumably is of primary importance in the physiological regulation of sodium balance. In addition, consideration is given to a number of common physiological, experimental, and pathophysiological conditions in which circulating atriopeptin does not correlate with renal sodium excretion. This lack of correlation implies that atriopeptin is not an important regulator of sodium excretion in these situations.

Norepinephrine-induced atriopeptin release in conscious dogs is mediated by alterations in atrial pressure.

This study was designed to determine whether the increase in atriopeptin secretion induced by an intravenous infusion of norepinephrine is mediated directly by adrenergic receptor stimulation or indirectly by the associated increase in atrial pressure. Norepinephrine was infused at 0.5 microgram.kg-1.min-1 for 30 min into both sham-operated (intact) and cardiac-denervated conscious dogs. The infusion increased mean arterial pressure in all dogs. On the other hand, left atrial pressure increased from 5.0 +/- 0.7 to 9.6 +/- 1.6 mmHg (p less than 0.01) in intact dogs, but decreased from 5.5 +/- 1.0 to 2.0 +/- 0.7 (p less than 0.01) in cardiac-denervated dogs. Right atrial pressure changes followed similar trends, but were not significant in the intact group. Plasma atriopeptin increased from 73 +/- 12 to 110 +/- 18 pg/ml (p less than 0.01) as left atrial pressure increased in intact dogs and decreased from 79 +/- 15 to 54 +/- 10 pg/ml (p less than 0.01) as left atrial pressure decreased in cardiac-denervated dogs. The changes in plasma atriopeptin correlated closely with the changes in left atrial pressure (r = 0.941, p less than 0.001) and to a lesser extent with the changes in right atrial pressure (r = 0.413, p less than 0.05). These results suggest that the change in plasma atriopeptin induced by infusion of norepinephrine into conscious dogs is mediated by the concomitant change in atrial pressures.

The tenuous relationship between atriopeptin and sodium excretion.

The data reviewed here illustrate that circulating levels of atriopeptin between 3- and 12-fold above normal produce only modest and slowly developing renal responses. Left atrial distension produces a diuretic and natriuretic response that appears to be mediated by cardiac reflexes, not by the increase in circulating levels of atriopeptin. Similarly the natriuretic response to intravascular volume expansion occurs normally even if circulating atriopeptin is caused to decline during the volume expansion. Finally, plasma atriopeptin levels do not contribute to postprandial natriuresis, because circulating levels do not increase acutely in response to eating a meal containing sodium. It seems unlikely, therefore, that atriopeptin exerts a substantial effect on the regulation of sodium excretion under normal physiological conditions.

A study of serum antidiuretic hormone and atrial natriuretic peptide levels in a series of patients with intracranial disease and hyponatremia.

Patients with intracranial disease are at risk of developing clinical deterioration due to a hyponatremic syndrome associated with an inappropriate degree of natriuresis, the "syndrome of inappropriate secretion of anti-diuretic hormone (ADH)" or SIADH. To investigate the hypothesis that atrial natriuretic peptide (ANP) is related to the natriuresis in SIADH, serum samples were obtained from 8 neurosurgical patients with intracranial disease seen consecutively who fulfilled the traditional clinical and laboratory criteria for SIADH. In one patient with a hemorrhagic cerebral infarction an elevation of serum ADH (5.7 pg/ml; normal = 1 to 5 pg/ml) in association with a normal level of serum ANP (49.8 pg/ml; normal = 10 to 60 pg/ml) was seen. Six patients (2 with intracerebral hemorrhage and 1 with hemorrhagic cerebral infarction, 1 with aneurysmal subarachnoid hemorrhage, 1 with glioblastoma multiforme, and 1 with Creutz-feldt-Jakob disease) had elevated serum ANP levels (197.0, 112.0, 92.0, 432.0, 97.5, and 138.0 pg/ml, respectively) associated with either normal or low ADH levels (1.3, 2.5, 1.2, 0.7, 2.3, and 0.5 pg/ml, respectively). Another patient with an intracerebral hemorrhage had a normal serum ANP level (37.0 pg/ml) and undetectable ADH level (less than 0.5 pg/ml). In the 7 patients in whom either ADH or ANP alone was elevated, a reciprocal relationship was observed between serum ADH and ANP levels, which could be expressed in logarithmic form (correlation coefficient, r = 0.727). In the 6 patients in whom serum ANP level alone was elevated, a near linear relationship was observed between serum ANP levels and urine sodium excretion (r = 0.851).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of calcitonin gene-related peptide in conscious dogs.

To elucidate the cardiovascular effects of alpha-human calcitonin gene-related peptide (CGRP), we infused CGRP intravenously at increasing rates of 3, 10, and 30 pmol.kg-1.min-1 during successive 15-min intervals into intact dogs, cardiac-denervated (CD) dogs, and cardiac-denervated dogs pretreated with beta-blockers. In intact dogs, the initial infusion rate of CGRP at 3 pmol.kg-1.min-1 did not produce significant hemodynamic changes, but the two higher infusion rates produced dose-dependent decreases in total peripheral resistance, mean arterial pressure, and left and right atrial pressures and produced dose-dependent increases in heart rate (HR) and cardiac output (CO). In addition, stroke volume decreased and pulmonary vascular resistance increased at the highest infusion rate. In CD dogs, CGRP produced qualitatively similar responses, although the increase in HR was markedly attenuated. The increase in CO was also attenuated, but the difference did not reach statistical significance. In CD dogs pretreated with beta-blockers, CGRP did not increase HR and the increase in CO was further attenuated. In a separate experiment, the lowest dose of CGRP (3 pmol.kg-1.min-1) was infused intravenously for 60 min in intact dogs; significant cardiovascular responses, qualitatively similar to those produced by higher rates of infusion, occurred. We conclude that CGRP is an extremely potent vasodilator and that the increase in HR is mediated primarily by autonomic reflexes.

Menstrual status and plasma vasopressin, renin activity, and aldosterone exercise responses.

The effects of menstrual cycle phase (early follicular vs. midluteal) and menstrual status (eumenorrhea vs. amenorrhea) on plasma arginine vasopressin (AVP), renin activity (PRA), and aldosterone (ALDO) were studied before and after 40 min of submaximal running (80% maximal O2 uptake). Eumenorrheic runners were studied in the early follicular and midluteal phases determined by urinary luteinizing hormone and progesterone and plasma estradiol and progesterone assays; amenorrheic runners were studied once. Menstrual phase was associated with no significant differences in preexercise plasma AVP or PRA, but ALDO levels were significantly higher during the midluteal phase than the early follicular phase. Plasma AVP and PRA were significantly elevated at 4 min after the 40-min run in the eumenorrheic runners during both menstrual phases and returned to preexercise levels by 40 min after exercise. Plasma ALDO responses at 4 and 40 min after exercise were higher in the midluteal phase than the early follicular phase. Menstrual status was associated with no significant differences in preexercise AVP or PRA; however, ALDO levels were significantly higher in the amenorrheic runners. After exercise, responses in the amenorrheic runners were comparable with the eumenorrheic runners during the early follicular phase. Thus, submaximal exercise elicits significant increases in plasma AVP and PRA independent of menstrual phase and status. However, plasma ALDO is significantly elevated during the midluteal phase, exercise results in a greater response during this menstrual phase, and amenorrheic runners have elevated resting levels of ALDO.

CSF norepinephrine in schizophrenia is elevated prior to relapse after haloperidol withdrawal.

Thirty-two male DSM-III diagnosed schizophrenic patients received a lumbar puncture (LP) during chronic haloperidol treatment that was followed by replacement with placebo for up to 6 weeks. Fourteen patients relapsed on placebo within 6 weeks. Patients received a second LP at the time of relapse or at the end of 6 weeks if they had not relapsed. Bunney-Hamburg Global Psychosis Ratings of the day and the hours of sleep of the night before the LP were obtained, as were the Brief Psychiatric Ratings Scale (BPRS) ratings during the week of the LPs. CSF norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5 HIAA) concentrations were measured with high-pressure liquid chromatography (HPLC). Patients who relapsed had significantly higher CSF NE levels on and off haloperidol than patients who did not relapse. CSF MHPG was higher in the relapsers in the drug-free condition only, but CSF HVA and 5-HIAA were not significantly different in either condition. In the drug-free relapsed patients, CSF NE correlated significantly with the psychosis ratings of the day and hours of sleep the night prior to the LP. Our data indicate that elevated CSF NE levels during neuroleptic treatment may predict behavioral decompensation after discontinuing the medication.

Cardiovascular, renal, and endocrine responses to intravenous endothelin in conscious dogs.

Endothelin is a recently discovered vasoconstrictor peptide that is synthesized in certain vascular endothelial cells. We have identified the cardiovascular, renal, and hormonal responses that can be elicited in conscious dogs by intravenous administration of endothelin at rates of 10 and 30 ng.kg-1.min-1 for 60 min (0.24 and 0.72 nmol.kg-1/1-h infusion). Each dose of endothelin increased total peripheral resistance, arterial pressure, and left atrial pressure and decreased heart rate and cardiac output. Hematocrit increased by 4.8% (NS) and 22.9% (P less than 0.01) in response to the lower and higher infusion rates, respectively. Urinary sodium excretion, urine osmolality, and osmolar clearance decreased and free water clearance increased. The lower dose of endothelin decreased plasma norepinephrine and increased plasma atriopeptin. The higher dose increased plasma levels of vasopressin, renin, aldosterone, norepinephrine, epinephrine, and atriopeptin. The higher infusion rate of the peptide caused one or more brief vomiting episodes in four of five dogs. Although it is not yet known whether endothelin is a circulating hormone, it is clear that this peptide is capable of causing profound cardiovascular, renal, and endocrine alterations in conscious dogs. The possible relevance of these observations to physiological processes and to pathological conditions such as hypertension remains to be established.

Natriuresis during atrial distension and a concurrent decline in plasma atriopeptin.

In the conscious dog, left atrial distension elicits a composite response that modulates both cardiovascular and renal function. The response to atrial distension may be mediated by the combined effects of neural reflexes and the release of atriopeptin. To assess the relative contributions of atrial reflex mechanisms and circulating atriopeptin to the renal response elicited by atrial distension, alpha-human atrial natriuretic peptide (alpha-hANP) was infused into conscious dogs at 50 ng.kg-1.min-1 for 60 min. Then the infusion was stopped abruptly, and left atrial pressure was increased 8 mmHg by inflating a balloon positioned above the mitral valve. Plasma atriopeptin decreased during the 40-min period of atrial distension, but urine flow and sodium excretion increased during this time. In another series of experiments, volume expansion was substituted for atrial distension. Saline (24 ml/kg) was infused intravenously for 5 min immediately after the 60-min period of alpha-hANP infusion. Urine flow and sodium excretion increased after administration of saline even though plasma atriopeptin decreased substantially during the same time period. These results provide evidence that circulating levels of atriopeptin do not play a dominant role in influencing sodium excretion either during atrial distension or in response to saline infusion.

A high-salt meal produces natriuresis in humans without elevating plasma atriopeptin.

The effects of a high-sodium meal on plasma atrial natriuretic peptide (atriopeptin) and renal sodium excretion were studied in eight normal human subjects. As expected, sodium excretion and urine osmolality increased following the meal. Plasma atriopeptin levels did not increase, however, after the high-sodium meal. In a control experiment, consumption of a low-sodium meal by six of the same subjects did not increase either urinary sodium excretion or plasma atriopeptin concentration. We conclude that the natriuresis elicited by a high-salt meal is not mediated by the atrial peptides.