Tubulointerstitial injury and loss of nitric oxide synthases parallel the development of hypertension in the Dahl-SS rat.

OBJECTIVE: Alterations in renal nitric oxide (NO) are involved in the hypertension of the Dahl salt-sensitive (Dahl-SS) rat We sought to identify the kinetics and sites of expression of the major NO synthase (NOS) isoforms. DESIGN: The renal expression of the major NOS were examined in Dahl-SS and salt-resistant rats (Dahl-SR) while on a low salt (0.1% NaCl) diet at 3 and 9 weeks of age. METHODS: Renal biopsies from Dahl-SS and Dahl-SR rats were compared for evidence of renal injury and for alterations in expression of the NOS enzymes by quantitative immunohistochemistry. RESULTS: At 3 weeks of age Dahl-SS and Dahl-SR rats have normal renal histology and similar immunohistochemical expression of NOS1, -2, and -3. At 9 weeks Dahl-SS rats had significantly higher blood pressure than Dahl-SR rats (P< 0.005 ), and lower macula densa NOS1 (P< 0.05) and cortical and medullary NOS3 (P< 0.05). NOS2 was reduced in cortical tubules in biopsies showing severe tubulointerstitial damage, but was not significantly different between Dahl-SS and Dahl-SR groups as a whole. Dahl-SS rats also manifested glomerular and tubulointerstitial injury. Tubular expression of osteopontin (OPN), which is an inhibitor of NOS2, correlated with the systolic BP in individual Dahl-SS rats (r2 = 0.80, P < 0.0001 ). CONCLUSION: Tubulointerstitial injury and the loss of NOS occur after birth and parallel the development of hypertension. We suggest that the structural and functional changes that occur with renal injury in the Dahl-SS rat may contribute to the development of hypertension.

Effects of long-term vasopressin receptor stimulation on medullary blood flow and arterial pressure.

Studies were carried out using instrumented unanesthetized rats to determine the long-term effects of arginine vasopressin (AVP) and a specific vasopressin V1 receptor agonist (V1AG; [Phe2, Ile3, Orn8]- vasopressin) on the renal medullary blood flow and arterial blood pressure. It was hypothesized that the hypertension observed with chronic medullary infusion of a V1 receptor agonist may be associated with a sustained reduction of blood flow, whereas infusion of AVP may fail to produce a sustained reduction of blood flow and thereby be unable to produce hypertension. Uninephrectomized Sprague-Dawley rats were prepared with implanted renal cortical and medullary optical fibers for daily measurements of cortical and medullary blood flow using laser-Doppler flowmetry techniques. An implanted renal medullary interstitial infusion catheter delivered either AVP or a specific V1AG at a dose of 2 ng . kg-1 . min-1 over a period of 5 days. The V1AG produced no change of cortical blood flow but a chronic 35% reduction of medullary blood flow (P < 0.05) and mild hypertension (11 +/- 4 mmHg, P < 0.05). AVP produced only an initial, nonsignificant 1- to 2-day reduction of medullary blood flow (-13%) and failed to raise arterial pressure significantly. We conclude that a sustained V1AG response is necessary to achieve a chronic reduction of medullary blood flow and hypertension. The present data are consistent with the idea that chronic stimulation of V2 receptors by AVP offsets the vasoconstrictor and hypertension actions of AVP-induced stimulation of medullary V1 receptors.

Effects of daily sodium intake and ANG II on cortical and medullary renal blood flow in conscious rats.

Implanted optical fibers and laser-Doppler flow measurement techniques were used for the sequential measurement of regional renal blood flow in conscious rats to determine the effects of an increase of daily NaCl intake on the renal cortical blood flow and blood flow to the outer and inner medulla. Cortical blood flow was increased significantly (32%) by the second day when NaCl intake was increased from 1 to 7 meq/day and was increased further (50%) on the second day after a further elevation of NaCl intake to 13 meq/day. Blood flow to the outer and inner medulla was not changed as NaCl intake was elevated. The increase in renal cortical flow was closely associated with significant reductions in circulating concentrations of ANG II from 31 to 16 pg/ml. Rats given a continuous infusion of nonpressor does of ANG II (5.0 ng.kg(-1).min-1) to maintain constant plasma concentrations of ANG II as sodium intake was increased exhibited no increase of cortical flow. We conclude that reductions of plasma ANG II associated with incremental increases of daily sodium intake result in a rise of renal cortical flow. The elevated blood flow to the renal cortex may enhance sodium excretion and contribute to long-term sodium homeostasis.

Localization of the vasopressin V1a and V2 receptors within the renal cortical and medullary circulation.

Arginine vasopressin (AVP) is a potent vasoconstrictor that preferentially reduces renal medullary blood flow through the stimulation of the vasopressin V1a receptor (V1aR). Studies have also shown that the vasopressin V2 receptor (V2R) may modulate AVP-mediated vasoconstriction. At present, the distribution of the V1aR and V2R within the renal cortical and medullary microcirculation has not been determined. This study was designed to localize the transcriptional and translational sites of the V1aR and V2R in microdissected intrarenal vascular segments from both the cortex and medulla, specifically the interlobar, arcuate, and interlobular arteries; afferent and efferent arterioles; glomeruli; and single outer medullary vasa recta capillaries using reverse transcription-polymerase chain reaction and Western blot analyses. The results indicated that V1aR mRNA and proteins were present in the isolated cortical or medullary vasculature, but the V2R mRNA and proteins were not found. This study suggests that the vasoconstrictor action of AVP within the renal medulla is mediated through the V1aR and that the modulatory V2R-mediated vasodilation is probably through the release of paracrine hormones found within the renal interstitial or tubular cells.

In vivo diuretic actions of renal vasopressin V1 receptor stimulation in rats.

The specific vasopressin V1 receptor agonist (V1AG; [Phe2,Ile3,Orn8]vasopressin) was infused (2.0 ng.kg-1.min-1) into the renal medullary interstitial space to determine the effects of selective medullary V1 receptor stimulation on sodium and water excretion in normal rats. Responses were compared with those of arginine vasopressin (AVP) and vasopressin V2 receptor stimulation resulting from infusion of a V1 receptor antagonist with AVP. Medullary infusion of V1AG or AVP in euvolemic rats produced no changes in hemodynamics or glomerular filtration rate. V1AG increased urine flow > 60% in euvolemic rats, whereas no change was observed with AVP. This response could not be explained by a rise of arterial pressure or by volume retention. With V2 stimulation in euvolemic rats, urine flow was decreased. In water diuretic rats, V1AG produced no change, whereas AVP infusion decreased urine flow. The results provide in vivo evidence that tubular V1 vasopressin receptor activity results in increased urine flow and thereby modulates the antidiuretic actions of vasopressin in the euvolemic state.

Hypertension induced by high salt intake in absence of volume retention in reduced renal mass rats.

Reduction of renal mass (RRM) combined with a high-salt diet results in volume retention, a rise of cardiac output, and hypertension. The present studies were designed to determine whether prevention of volume retention would alter the rise of mean arterial pressure (MAP) in RRM rats given high salt. Rats were studied in a modified metabolic cage to permit continuous determination of total body weight (TBW). In group 1, NaCl was increased from 1 to 14.5 meq/day and delivered isotonically. In group 2, NaCl was increased while TBW was servo-controlled to a constant level. Group 3 was also servo-controlled, but rats received an intravenous infusion of an arginine vasopressin V1 antagonist throughout the study. MAP in group 1 rose 24 mmHg by day 4 of high salt with a parallel increase of TBW of 26 g. In group 2, MAP rose 48 mmHg by day 4 of high salt, while TBW was controlled to within 0.6% of control body weight. With inhibition of vasopressin V1 receptors (group 3), MAP rose 39 mmHg. Nearly equivalent amounts of NaCl were retained in all groups, which was associated with no change of plasma Na in group 1 but an increase of nearly 7 meq/ml in groups 2 and 3. Hematocrit fell nearly 9% in groups 2 and 3 compared with a 4% reduction in group 1. The results suggest that under conditions where net retention cannot occur, high salt intake increases MAP by an osmotically driven fluid transfer from cells, which results in an even greater expansion of blood volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged stimulation of intrarenal V1 vasopressin receptors results in sustained hypertension.

In an earlier study, we reported that chronic intravenous administration of the V1 agonist [Phe2,Ile3,Orn8]vasopressin (V1AG) results in sustained hypertension. The present study was designed to determine whether V1-induced hypertension may be related specifically to intrarenal actions of this peptide. Chronic infusion of the V1 agonist into the medullary interstitial space of a single remaining kidney of normal, conscious Sprague-Dawley rats at the rate of 2 ng.kg-1.min-1 for 14 days resulted in a sustained rise of 18 mmHg of mean arterial pressure (MAP). After withdrawal of V1AG, MAP returned to the baseline level. During the first day of V1AG infusion, there was a net loss of body sodium and no evidence of fluid retention throughout the period of hypertension. Plasma osmolality, sodium and potassium concentration, and water intake and body weight were not significantly affected by medullary interstitial infusion of V1AG. Renal medullary interstitial infusion of an equimolar amount of arginine vasopressin (AVP) did not affect MAP. Chronic medullary interstitial infusion of the selective V1 antagonist d(CH2)5[Tyr(Me)2,Ala-NH(2)9]AVP in equimolar amounts (2.5 ng.kg-1.min-1) prevented the MAP increase elicited by intravenous V1AG. However, intravenous administration of the V1 antagonist at the same rate together with V1AG (n = 7) failed to prevent hypertension. The results indicate that hypertension can be elicited by chronic stimulation of renal medullary V1 vasopressin receptors. They also suggest that some V2 agonistic properties of AVP may restrict the hypertensive action of this hormone. The mechanism for the rise of arterial pressure remains to be determined.

Physiopathogenesis of acute aortic coarctation hypertension in conscious rats.

We investigated the role of vasopressin, angiotensin II, and catecholamines in the onset of acute (45-minute) aortic coarctation hypertension in conscious rats. Partial aortic constriction was performed by means of a pneumatic cuff placed around the abdominal aorta above the renal arteries for 15 or 45 minutes. A sham-operated group was used as control. Mean carotid pressure before aortic constriction did not differ between rat groups. Aortic constriction produced a similar increase of mean carotid pressure during 15 minutes (36 +/- 3 to 37 +/- 3 mm Hg above basal levels) and 45 minutes (37 +/- 2 to 39 +/- 3 mm Hg). Plasma vasopressin concentration after 15 minutes of coarctation (4.4 +/- 0.5 pg/mL) did not differ from that observed in control rats (3.0 +/- 0.8 pg/mL), whereas after 45 minutes, it was significantly higher (14.3 +/- 3.3 pg/mL). Plasma renin activity increased significantly after coarctation (21.7 +/- 4.1 and 29.9 +/- 2.9 ng angiotensin I/mL per hour, at 15 and 45 minutes, respectively) when compared with control rats (3.9 +/- 0.5 ng angiotensin I/mL per hour). After coarctation, plasma norepinephrine concentration was consistently reduced, whereas plasma epinephrine concentration did not differ from control rats. In conclusion, these data provide evidence for an effective vasopressor role for vasopressin in the genesis of acute (45-minute) aortic coarctation hypertension in conscious rats. In addition, although the results confirm that the renin-angiotensin system participates earlier in the onset of coarctation hypertension, they rule out a significant vasopressor role for catecholamines in the early development of hypertension.

Chronic pressure-natriuresis relationship in dogs with inherited essential hypertension.

A genetic model of essential hypertension in the dog was studied to describe the phenotypic expression of the arterial pressure, as well as to determine the relationship between mean arterial blood pressure (MAP), hormone, and renal excretory responses to four different levels of sodium intake (5, 40, 120, 240 mEq/day) delivered intravenously and isotonically. This model was developed at the University of Pennsylvania (U/Penn) and termed Pennsylvania hypertensive dogs (PHD). The MAP was recorded beat-by-beat, 24 h/day, in 16 dogs. Water and sodium balances were determined daily for 4 days at each level of intake and blood samples were collected on the last day of each salt step for analysis of plasma renin activity (PRA), atrial natriuretic peptide (ANP), aldosterone (ALDO), and vasopressin (AVP). After the study, the dogs were designated as hypertensive (PHD-HT) when the 24-h average MAP was greater than 110 mm Hg and systolic pressure was greater than 160 mm Hg. Dogs that failed to meet both criteria were designated as normotensive genetic controls (PHD-NT). Although sodium was retained during the first day of each increase of salt intake in both groups, a return to balance was observed within the 4 days. There was no apparent change in the slope of the chronic renal function curve in either group of PHD studied, although the PHD-HT exhibit a curve shifted to a higher level of MAP. Plasma hormone levels in both groups of PHD studied responded in a manner similar to normal mongrel dogs with reductions of PRA, ALDO, elevations of ANP, and no change in AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Saline diuresis and natriuresis in unanesthetized dogs: a missing atrial factor?

Recent studies in our laboratory indicated that a blunted (40-50%) renal excretory response to isotonic intravenous saline loads occurred in conscious, renal-denervated dogs after 70% of the atrial mass was removed. The blunted responses could not be explained by differences in the responses of arterial pressure, renal nerve activity, or by measured changes of plasma immunoreactive atrial natriuretic peptide (iANP), arginine vasopressin (AVP), plasma renin activity (PRA), or aldosterone (Aldo). The present study was designed to determine whether the central nervous system (CNS) was the source of an unidentified substance, which could account for the blunting of the urine excretory response seen in the atrial-resected dogs. Renal denervation was performed in all dogs to eliminate alterations in efferent renal sympathetic nerve activity derived from reflexes activated during volume expansion. Cardiac denervation (CDX) was used to eliminate sensory cardiac afferent nerve activity to the CNS. A group of five renal-denervated dogs was given an isotonic volume load (400 ml/30 min) before and after complete CDX. Plasma AVP was fixed at normal plasma levels of 3 pg/ml by continuous intravenous infusion. Na and H2O excretion were not different in renal-denervated dogs compared with combined renal and cardiac denervation during the 5 h after the saline load. Plasma AVP and Aldo were unchanged with the volume loads, although PRA rose gradually over the 5 h after the saline loads. Plasma iANP increased transiently in the combined renal and cardiac-denervated state rising from a control of 65-120 pg/ml at the end of the load period.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluid-regulating hormones during exercise when central blood volume is increased by water immersion.

To examine the influence of an increase in central blood volume with head-out water immersion (WI) on fluid-regulating hormones during exercise, 10 healthy men underwent upright leg cycle exercise on land and with WI. Venous plasma renin activity and plasma venous concentrations of atrial natriuretic peptide, plasma aldosterone, and arginine vasopressin were determined at exercise intensities corresponding to approximately 40, 60, 80, and 100% peak oxygen consumption (VO2) and at minutes 1 and 5 of seated rest recovery within each environment. Peak VO2 did not differ on land and with WI. Atrial natriuretic peptide concentration was higher (P less than 0.05) and plasma renin activity was lower (P less than 0.05) in water than on land at 40% peak VO2 through minute 5 of recovery. Plasma aldosterone and arginine vasopressin concentrations were lower (P less than 0.05) in water at peak exercise and at minutes 1 and 5 of recovery. Osmolality and plasma sodium and potassium concentrations during exercise were similar in water and on land. The results indicate that WI alters the circulating levels of several hormones involved in fluid and electrolyte regulation during exercise. These hormonal alterations can best be explained by stimulation of low-pressure baroreceptors and atrial stretch due to increased central blood volume with head-out WI.

Dominance of colloid osmotic pressure in renal excretion after isotonic volume expansion.

Studies were carried out in unanesthetized dogs to determine the relative importance of neural, endocrine, and colloid osmotic pressure (COP) in the diuretic and natriuretic responses associated with volume expansion. Renal excretory responses to 30-min intravenous infusions of isotonic saline (400 ml) or whole blood (100 ml) were compared while various controllers of sodium and water excretion were either eliminated or held constant. Dogs were studied in the normal state; with plasma arginine vasopressin (AVP) fixed by intravenous infusion; with bilateral renal denervation and plasma AVP fixed; renal denervated with plasma AVP, angiotensin II, aldosterone, atrial natriuretic factor fixed; and renal denervated with these same hormones fixed and with renal arterial pressure servo-controlled at a constant level. Normal uncontrolled dogs increased sodium and water excretion nearly fourfold by the end of the saline load and excreted 85% of the load within 5 h. Urine excretion was minimally affected when the various neural and endocrine controllers were fixed or eliminated. There were no changes of mean arterial pressure with the saline volume loads, but COP fell 2.5 mmHg. Equivalent expansion of the blood volume (100 ml) with whole blood in which COP was unchanged resulted in nearly no increase of urine excretion in renal-denervated dogs with plasma hormones fixed and renal perfusion pressure held constant. We conclude that the rapid diuresis and natriuresis following isotonic volume expansion is predominantly a result of plasma protein dilution and a reduction of COP.

Cortisol inhibition of vasopressin and ACTH responses to arterial hypotension in conscious dogs.

We evaluated the role of cortisol as a feedback inhibitor of the vasopressin response to arterial hypotension. Conscious dogs (n = 5) were each studied on 10 different days. There were five different pretreatments: 1) isotonic saline (control), 2) 5.5 or 3) 11 nmol cortisol.kg-1.min-1 iv for 30 min, 4) 6.8 pmol ACTH-(1-24).kg-1.min-1 iv for 30 min, or 5) 1.5 mg dexamethasone im given the night before experimentation. These pretreatments were followed by a stimulus period (30 min) during which mean arterial pressure was decreased a moderate (-19 +/- 1 mmHg) or severe (-29 +/- 1 mmHg) degree with a controlled infusion of intravenous sodium nitroprusside. The vasopressin response to moderate hypotension was not consistently inhibited by any of the pretreatments. In contrast, the large vasopressin response to severe hypotension in the control experiments (from 3.1 +/- 0.3 to 270 +/- 113 pg/ml) was significantly attenuated by cortisol infusion in a dose-dependent manner. Adrenocorticotropin infusion was more effective than dexamethasone as an inhibitor of the vasopressin response to severe hypotension. The data suggest that physiological increases in cortisol inhibit the large increase in vasopressin in response to severe arterial hypotension.

Stimulation of atrial natriuretic peptide and vasopressin during percutaneous transluminal aortic valvuloplasty.

The objective of this study was to determine the effects of transient aortic valve occlusion (balloon valvuloplasty) on vasoactive hormones in patients with heart failure. Plasma atrial natriuretic peptide, vasopressin, aldosterone, adrenocorticotropic hormone (ACTH), and plasma renin activity were measured before, immediately after, and 30 minutes and 18 to 24 hours following balloon inflation in 18 patients. Mean right atrial and pulmonary wedge pressures were 6 and 18 mm Hg before inflations, respectively, and were unchanged after balloon inflations (5 and 13 mm Hg, respectively). Systemic systolic/diastolic pressures were 139 +/- 8/65 +/- 4 mm Hg before occlusion, decreased to 47 +/- 5/34 +/- 3 mm Hg during occlusion, and returned to baseline after occlusions. Baseline atrial natriuretic peptide levels were 267 +/- 43 pg/ml and increased to 513 +/- 71 pg/ml after balloon inflations. Vasopressin levels before occlusion were 9.1 +/- 2.2 pg/ml and increased to 21.4 +/- 4.8 pg/ml after balloon inflations. Plasma renin activity was 5.4 +/- 1.4 ng/ml/hr before inflations and was not significantly changed after balloon inflations. No clinically significant changes in plasma sodium, potassium, creatinine, and osmolality were observed after the procedure. Aldosterone increased from 23 +/- 4 to 40 +/- 7 ng/dl 10 minutes after the last inflation. Plasma ACTH measured in seven patients with increased aldosterone was 28 +/- 8 pg/ml before and increased to 295 +/- 157 pg/ml 10 minutes after balloon inflations. The increases in natriuretic peptide and vasopressin were likely due to elevated intracardiac and decreased arterial pressures, respectively; they persisted in spite of no clinically significant changes in filling pressures 12 to 24 hours after the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of plasma sodium on aldosterone secretion during angiotensin II stimulation in normal humans.

Studies were carried out in normal male subjects (n = 6, age 20-35 years) to determine the interaction of angiotensin II and plasma sodium on aldosterone secretion. These relations were quantified by elevation of plasma sodium with an infusion of 5% sodium chloride (4 ml/kg/30 min i.v.) with measurements of plasma aldosterone, atrial natriuretic factor (ANF), and arginine vasopressin (AVP) over 3 hours. Two hours before sodium chloride infusion, an intravenous infusion of angiotensin II was begun at 0.5 or 5.0 ng/kg/min and continued throughout the study. Plasma potassium was maintained constant by the addition of potassium to the infusate. NaCl/KCl infusion raised plasma sodium 4 meq/l with no decreases of plasma potassium. Plasma aldosterone averaged 7 +/- 1.8 ng/dl before NaCl infusion in subjects infused with 0.5 ng angiotensin II and was not significantly reduced with sodium chloride infusion. Angiotensin II infused at 5 ng/kg/min resulted in average plasma aldosterone levels of 31 +/- 3.6 ng/dl, which sodium chloride infusion decreased to 16.6 +/- 1.3 ng/dl (p less than 0.05) in 60 minutes. Plasma aldosterone remained depressed for the remaining period of study. Plasma ANF increased from 40 to 60 pg/ml with sodium chloride infusion. We conclude that small physiological elevations of plasma sodium concentrations can signal substantial decreases of plasma aldosterone in normal human subjects in situations where plasma angiotensin II is moderately elevated. The precise mechanisms of these responses remain to be determined.

Feedback control of vasopressin and corticotrophin secretion in conscious dogs: effect of hypertonic saline.

Glucocorticoids are known to inhibit the ACTH response to a variety of stimuli. It has been suggested that vasopressin secretion is also inhibited by glucocorticoid negative feedback. The purpose of this study was to (1) determine the ACTH response to hypertonic saline and its sensitivity to glucocorticoid negative feedback and (2) to determine whether physiological elevations of plasma cortisol inhibit subsequent vasopressin responses to hypertonic saline. Five mongrel dogs (15-18 kg) were prepared with chronic arterial and venous catheters and studied while conscious. Ten experiments were performed on each dog in a randomized design separated by at least 5 days. Each experiment consisted of a pretreatment period (from -60 to -30 min except for dexamethasone administration) during which a glucocorticoid feedback signal was applied and a stimulus period (from 0 to 30 min) during which hypertonic saline was infused. The pretreatment and stimulus periods were separated by 30 min. Pretreatments were as follows: isotonic saline (control), half-maximal and maximal cortisol infusion (5.5 or 11 nmol/kg per min), ACTH(1-24) infusion (6.8 pmol/kg per min) which produces increases in endogenous cortisol, and dexamethasone (1.5 mg i.m.) given at 17.00 h the day before experimentation. Stimuli were as follows: hypertonic saline was infused at 0.2 or 0.4 mmol/kg per min which increased plasma sodium by about 6 or 12 mmol/l respectively. NaCl infusion at 0.2 mmol/kg per min had no effect on plasma ACTH or cortisol except when subsequent to ACTH(1-24) pretreatment when plasma ACTH actually increased to 41.4 +/- 2.9 pmol/l in response to hypertonic saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic, renal, and hormonal responses to incremental ANF infusions in humans.

The effects of incremental exogenous alpha-human atrial natriuretic factor (ANF) infusion (10 and 25 ng.kg-1. min-1) on the cardiovascular, renal, and hormonal systems were examined in 22 healthy males. Successive 45-min infusions of ANF increased plasma levels five- and ninefold from a basal 42 +/- 5 pg/ml (P less than 0.01 and P less than 0.001). Hemodynamic responses provoked by ANF consisted solely of progressive reductions in central venous pressure (CVP) (P less than 0.05). Heart rate and mean arterial pressure were unaltered. Plasma renin activity, aldosterone, and vasopressin were not modified by either dose of ANF. However, plasma norepinephrine increased 32% during the 10-ng.kg-1.min-1 infusion (P less than 0.05) and remained elevated during the higher dose of ANF. Renal function was unaltered by the 10-ng.kg-1.min-1 infusion of ANF when compared with base line and placebo responses. The 25-ng.kg-1. min-1 infusion of ANF increased sodium excretion 100% from base line (P less than 0.05), whereas potassium excretion decreased 47% (P less than 0.05). Urine output increased significantly from 7.7 +/- 0.6 to 12.5 +/- 0.7 ml/min (P less than 0.05). These responses were not observed in the placebo group or in an additional group of four volunteers who received a continuous low-dose infusion of ANF (10 ng.kg-1.min-1) for two consecutive 45-min periods. Neither dose of ANF altered creatinine clearance or free water clearance. The data indicate that fivefold elevations (physiological levels) of plasma ANF do not influence renal or hormonal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute saline loading in normal and bilaterally atrial-resected conscious dogs.

Acute isotonic saline volume loads (400 ml) were intravenously administered to conscious, renal-denervated dogs before and after bilateral removal of the atrial free walls and atrial appendages to determine the role of atrial-mediated hormonal factors in the renal excretory response. In one group of dogs (n = 11), the volume was given in 10 min; in another group (n = 5), the volume was given in 30 min while arginine vasopressin (AVP) was infused to maintain plasma AVP at a fixed, normal level (3 pg/ml). Sodium and water excretion, mean arterial pressure, and plasma hormone levels were determined before and for 5 h after volume loads. Atrial resection resulted in a 40-50% reduction of sodium and water excretion in both groups during the first 2 h after volume expansion. The blunted renal excretory responses could not be explained by differences in arterial pressure, renal sympathetic nerve activity, or by hormonal differences of plasma immunoreactive atrial natriuretic factor (iANP), plasma AVP, plasma renin activity, or plasma aldosterone. Plasma iANP was not significantly increased by the volume load in either the normal or atrial-resected state. Atrial-resected dogs exhibited normal plasma levels of iANP. The data indicate the presence of an unidentified diuretic and natriuretic substance, which is released with volume expansion from either the cardiac atria or via the central nervous system, and that the release of this factor is removed by atrial resection.

Dynamic cardiovascular responses to infusions of atrial natriuretic factor in humans.

We sought to demonstrate a hypotensive effect from infusions of atrial natriuretic factor (ANF) into humans and to describe the mechanism(s) of this effect. Cardiovascular and hormonal responses to human ANF-(99-126) (125 ng/kg bolus followed by a 30-minute infusion at 25 ng/kg/min) were determined in eight conscious volunteers and compared with responses of eight time-control subjects who received isotonic saline. Baseline levels of ANF (52.8 +/- 5.5 pg/ml) increased 8.8-fold after 30 minutes of ANF infusion but were unchanged in the time controls. Plasma levels of renin, aldosterone, vasopressin, sodium, potassium, and osmolality did not change during infusions. A transient 5% reduction in mean arterial pressure related to a 12% reduction in peripheral resistance was observed 10 minutes after the priming bolus of ANF. This response was not sustained during the remainder of the ANF infusion period, nor did it occur in two additional subjects who received ANF infusions without the priming bolus. Steady state responses consisted of significant reductions in central venous pressure (15%), stroke volume (13%), and cardiac output (10%), but no reduction in blood pressure. Plasma norepinephrine levels and peripheral resistance increased (34% and 9%, respectively) during ANF administration. These data indicate that steady state responses to ANF in humans consist of decreases in cardiac filling pressures, which reduce cardiac output, unload cardiopulmonary baroreceptors, and activate the sympathetic nervous system. Blood pressure is well maintained despite striking increases in plasma ANF.

Diarrheal infections.

Infectious agents usually cause diarrhea by invading and damaging the intestinal mucosa or by producing enterotoxins that alter the secretory and absorptive capacities of the intestinal mucosa. Some infectious agents may do both. Physical malabsorption produced by proliferative outgrowth of bacteria or protozoa may also occur. Rotavirus is the most common cause of pediatric infectious diarrhea in the United States. Escherichia coli and Campylobacter species are the most common bacterial agents.