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The hypothesis that increases in plasma sodium induce natriuresis independently of changes in body fluid volume was tested in six slightly dehydrated seated subjects on controlled sodium intake (150 mmol/day). NaCl (3.85 mmol/kg) was infused intravenously over 90 min as isotonic (Iso) or as hypertonic saline (Hyper, 855 mmol/l). After Hyper, plasma sodium increased by 3% (142.0 [+ or -] 0.6 to 146.2 [+ or -] 0.5 mmol/l). During Iso a small decrease occurred (142.3 [+ or -] 0.6 to 140.3 [+ or -] 0.7 mmol/l). Iso increased estimates of plasma volume significantly more than Hyper. However, renal sodium excretion increased significantly more with Hyper (291 [+ or -] 25 vs. 199 [+ or -] 24 [micro]mol/min). This excess was not mediated by arterial pressure, which actually decreased slightly. Creatinine clearance did not change measurably. Plasma renin activity, ANG II, and aldosterone decreased very similarly in Iso and Hyper. Plasma atrial natriuretic peptide remained unchanged, whereas plasma vasopressin increased with Hyper (1.4 [+ or -] 0.4 to 3.1 [+ or -] 0.5 pg/ml) and decreased (1.3 [+ or -] 0.4 to 0.6 [+ or -] 0.1 pg/ml) after Iso. In conclusion, the natriuretic response to Hyper was 50% larger than to Iso, indicating that renal sodium excretion may be determined partly by plasma sodium concentration. The mechanism is uncertain but appears independent of changes in blood pressure, glomerular filtration rate, the renin system, and atrial natriuretic peptide. hypertonic sodium loading; osmoreceptors; renin-angiotensin-aldosterone system

The responses to A[T.sub.1]-receptor blockade (candesartan 1 mg/kg) and to concomitant volume expansion (saline 35 ml/kg for 90 min) with and without nitric oxide synthase (NOS) inhibition ([N.sup.G]-nitro-Larginine methyl ester 30 [micro]g*[kg.sup.-1]*[min.sup.-1]) were investigated in separate experiments in normal dogs. A[T.sub.1] blockade decreased arterial pressure (106 [+ or -] 4 to 96 + 5 mmHg) and increased glomerular filtration rate (GFR) by 17% and sodium excretion threefold. NOS inhibition increased arterial pressure (103 [+ or -] 3 to 116 [+ or -] 3 mmHg) and decreased GFR by 21% and reduced sodium excretion by some 80%. Volume expansion increased arterial pressure significantly in all series involving this procedure, most pronounced during combined AT1 blockade and NOS inhibition (21 [+ or -] 4 mmHg). Volume expansion during A[T.sub.1] blockade elicited marked natriuresis (26 [+ or -] 11 to 274 [+ or -] 55 [micro]mol/min) that was severely reduced by concomitant NOS inhibition (10 [+ or -] 3 to 45 [+ or -] 11 [micro]mol/min), but still much larger than that seen with volume expansion during NOS inhibition alone (2 [+ or -] 1 to 23 [+ or -] 7 [micro]mol/min). Volume expansion during A[T.sub.1] blockade increased GFR (+30%), less so during combined A[T.sub.1] blockade and NOS inhibition (+ 13%), but it did not increase GFR significantly (P = 0.07) during NOS inhibition alone. Plasma ANG II increased greater than sevenfold with A[T.sub.1] blockade and doubled with NOS inhibition (paired t-test, P < 0.05), whereas it decreased by 50-80% during volume expansion irrespective of pretreatment, i.e., during NOS inhibition, volume expansion did not generate subnormal plasma ANG II concentrations. In conclusion, 1) acute A[T.sub.1] blockade leads to hyperfiltration, natriuresis, and hyperresponsiveness to volume expansion, 2) these responses are >85% inhibitable by unspecific NOS inhibition, and 3) NOS inhibition alone is followed by increases in plasma ANG II, hypofiltration, and severe antinatriuresis that may be counterbalanced but not overwhelmed by volume expansion. Thus NOS inhibition virtually abolishes the volume expansion natriuresis, at least in part, due to the lack of appropriate inhibition of the renin-angiotensin-aldosterone system. sodium excretion; blood pressure; glomerular filtration rate; [N.sup.G]-nitro-L-arginine methyl ester; candesartan

This review describes the renal dopamine system in relation to its role in the interactive regulation of sodium metabolism in kidneys. Data point out that the natriuretic hormonal activity of dopamine is documented by its ability to inhibit renal tubule sodium transporters.

Natriuretic peptides (NPs), mainly produced in heart [atrial (ANP) and B-type (BNP)], brain (CNP), and kidney (urodilatin), decrease blood pressure and increase salt excretion. These functions are mediated by natriuretic peptide receptors A and B (NPRA and NPRB) having cytoplasmic guanylyl cyclase domains that are stimulated when the receptors bind ligand. A more abundantly expressed receptor (NPRC or C-type) has a short cytoplasmic domain without guanylyl cyclase activity. NPRC is thought to act as a clearance receptor, although it may have additional functions. To test how NPRC affects the cardiovascular and renal systems, we inactivated its gene (Npr3) in mice by homologous recombination. The half life of [125I]ANP in the circulation of homozygotes lacking NPRC is two-thirds longer than in the wild type, although plasma levels of ANP and BNP in heterozygotes and homozygotes are close to the wild type. Heterozygotes and homozygotes have a progressively reduced ability to concentrate urine, exhibit mild diuresis, and tend to be blood volume depleted. Blood pressure in the homozygotes is 8 mmHg (1 mmHg = 133 Pa) below normal. These results are consistent with the sole cardiovascular/renal function of NPRC being to clear natriuretic peptides, thereby modulating local effects of the natriuretic peptide system. Unexpectedly, Npr3 -/homozygotes have skeletal deformities associated with a considerable increase in bone turnover. The phenotype is consistent with the bone function of NPRC being to clear locally synthesized CNP and modulate its effects. We conclude that NPRC modulates the availability of the natriuretic peptides at their target organs, thereby allowing the activity of the natriuretic peptide system to be tailored to specific local needs.

A study was conducted to investigate the short-term hemodynamic and renal effects of the administration of synthetic leptin in normotensive, hypertensive and obese Sprague Dawley rats. The parameters of hemodynamics and the renal effects were the mean arterial pressure, creatinine clearance and urinary potassium excretion. The findings suggest that the acute infusion of synthetic leptin improved the excretion of sodium at the tubular level. The data also imply the significance of leptin in understanding obesity and hypertension.

The effects of varying degrees of acute systemic nitric oxide (NO) synthesis inhibition on renal and systemic hemodynamic, natriuretic and neurohumoral responses were investigated. Three different intravenous infusions of N(super G)-nitro-L-arginine methyl ester were studied for arterial pressure, renal blood flow, systemic vascular resistance, fractional sodium and lithium excretion, glomerular filtration rate and renal vascular resistance in healthy men. It was found that renal circulation is not more sensitive to the effects of NO synthesis inhibition than systemic circulation.

Experiments were performed to determine the presence, abundance and activities of the sodium-potassium-adenosine triphosphatase (Na+-K+-ATPase) in the kidney cortex and medulla of virgin, mid- and late-pregnant rats. It was hypothesized that massive plasma volume expansion (PVE) in late pregnancy involves net renal Na and fluid retention and that Na restriction inhibits PVE. Results indicated that the renal cortical Na+-K+-ATPase activity and abundance were restricted in normal mid- and late-pregnancy while the activity and abundance were constant in the renal medulla.

Research suggests that hormone estrogen stimulates uterine CNP transcription via nuclear estrogen receptor. Drug estradiol induces a 3-fold increase in uterine immunoreactive C-type natriuretic peptide (CNP)production in mice. Experiments using radioimmunoassay techniques are described. Hormone progesterone has the opposite regulatory effect on estrogen-stimulated CNP expression.

Age-related changes in the pressure diuresis and natriuresis response were analyzed using anesthetized young, adult and senscent rats. Results of the study indicated that age-related decline in the pressure-dependent sodium and water excretion is caused by a decrease in glomerular filtration and an increase in tubular sodium reabsorption. On the other hand, there was no difference between young and adult rats at each level of renal perfusion pressure.

Researchers have investigated the impact of diltiazem on renal function in spontaneously hypertensive rats (SHR), considering how it compared with the impact in normotensive Wistar-Kyoto (WKY) rats. Attention was given to whether the renal dopaminergic defect of SHR which had previously been established would produce changes in the response. It was found that the natriuretic impact of diltiazem in WKY rats or SHR is not the result of effects on renal dopamine production. Nevertheless, the natriuretic effect of diltiazem in WKY rats is partly the result of inhibition of Na+-K+-ATPase activity in the renal cortex.

A temporary fall in mean arterial pressure of 28 plus or minus 3 mmHg occurs in anesthetized Sprague-Dawley rats as a result of intermittent bilateral carotid artery traction (BilCAT). There is also a progressive rise in sodium excretion accompanied by an increase in glomerular filtration rate. It was concluded that reflect natriuresis takes place after repetitive, intermittent BilCAT via a pathway which needs intact renal innervation. Impaired reflex natriuresis is probably due to an extrarenal defect in spontaneously hypertensive rats which is likely to be connected with altered efferent renal nerve activity.

Researchers have examined expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) at both messenger RNA (mRNA) and protein levels in order to assess the contributions of humoral and hemodynamic factors to cardiac phenotypic changes connected with chronic pressure overload. Proportions of myosin isoforms in transplanted cervical hearts that were mechanically unloaded were also investigated. It was found that the cardiac hypertrophic response was boosted by humoral factor(s) secondary to the pressure overload produced by aortic coarctation.

Researchers have tested the belief that the persistent antihypertensive effect of long-term angiotensin-converting enzyme inhibitor treatment in spontaneously hypertensive rats (SHR) a long time after treatment has ceased is associated with a shift in the pressure-natriuresis relation. Attention was also given to the mechanism of resetting of pressure natriuresis after long-term angiotensin I-converting enzyme (ACE) inhibition in SHR. It was established that ACE inhibitors have specific actions on vascular structure, producing significant long-term effects on renal function.

The influence of small physiological elevations of plasma arginine vasopressin (AVP) on pressure-natriuresis-diuresis and pressure-renal blood flow (RBF) was analyzed in decerebrated rat preparations. Analysis of medullary hemodynamics in decerebrated, hypophysectomized, renal-denervated rats indicated the role of AVP in the modulation of the sensitivity of pressure natriuresis. The effects of AVP elevations were also related to the vasoconstrictor influence of the hormone on vessels that supply renal medullary blood flow.

The activity of substance P (SP) on proximal tubule transport was analyzed in isolated rabbit perfused proximal tubules. Systemic infusion of SP on isolated rabbit proximal tubules inhibited fluid absorption at lower concentrations. The effects of SP on the rates of fluid reabsorption after partial ureteric blockade were also initiated by a very complex cascade of events that increased urine flow rates. Furthermore, the activity of SP on proximal absorption was not affected by NO inhibition.

The role of brain natriuretic peptides on the pathogenesis of acute heart failure (AHF) was analyzed in anesthetized dogs after rapid left ventricular pacing (RLVP). Analysis of hemodynamic and renal responses during RLVP-induced AHF in anesthetized dogs indicated the role of elevated atrial filling pressures in increasing the levels of circulating atrial natriuretic peptide. However, BNP was not affected by cardiac filling pressures.

The diuretic and natriuretic responses of conscious monkeys to volume expansion were analyzed to determine the renal functions of nitric oxide (NO). Inhibition of NO by Ng-nitro-L-arginine methyl ester (L-NAME) during intravenous volume expansion in conscious monkeys attenuated renal natriuretic and diuretic responses. The effects of L-NAME exhibited the importance of NO on the modulation of renal function in response to changes in blood volume.

The urinary excretion and plasma concentrations of cotransport inhibitory factors (CIF) were analyzed in prehypertensive Dahl salt-sensitive rats (DS) to determine the role of the DS Na-K-Cl cotransport system. Analysis of CIF excretion and plasma concentrations in DS and Dahl salt-resistant rats (DR) indicated the presence of elevated sodium and water excretion in DS compared to DR. Furthermore, DS exhibited increased plasmatic and urinary CIF levels which acted as a compensatory mechanism against enhanced chloride reabsorption at the thick ascending limb of Henle's loop.

The role of the prostaglandin system and renal nerve activity in adrenomedullin (ADM)-mediated natriuresis was analyzed in the denervated kidney of anesthetized mongrel dogs. Administration of ADM in the denervated kidney of anesthetized mongrel dogs increased urinary sodium secretion and renal blood flow. The natriuretic actions of ADM were mediated by the renal nerves and the prostaglandin system. Furthermore, inhibition of prostaglandin activity attenuated ADM-induced natriuresis.

The potential effects of glucagon-like peptide (GLP)-1-(7-39) amide on feeding and drinking behavior were analyzed in rats under a food restriction diet schedule. A marked inhibition in eating and drinking behavior was detected in rats after the administration of GLP-1. Furthermore, the rats also exhibited natriuresis and diuresis indicating the regulatory activity of GLP-1 in ingestion and water homeostasis on localized brain receptors.

The effects of intrarenal atrial natriuretic peptide (ANP) synthesis on renal regulation of sodium homeostasis were analyzed by measuring the expression of ANP messenger ribonucleic acid (mRNA) in rat renal tissue. Rat kidney cortex and outer medulla exhibited the presence of pro-ANP-like proteins indicating that the proximal tubular cells and distal cortical cells are the sites of ANP synthesis. The paracrine activity of ANP was also detected when ANP levels increased after the administration of deoxycorticosterone acetate.

Urodilatin is a member of the natriuretic peptide family synthesized by the kidney to regulate renal function. In a study of eight healthy, male subjects, ingestion of 52, 172.6 and 347.8 mmol sodium/day for seven days resulted in increased urodilatin and sodium excretion at the end of the diet. Infusion of urodilatin at the end of each diet caused a marked increase in natriuresis and diuresis. These results suggest that urodilatin contributes to the regulation of sodium fluid balance and that renal function in response to urodilatin is modulated by sodium balance.

The removal of apical Na+/H+ exchangers and basolateral Na+ pumps controls proximal tubule natriuresis caused by sharp rise in arterial pressure. A fall in total Na+ pump activity also controls the process. A redistribution of apical Na+/H+ exchanger NHE3, alkaline phosphatase, and dipeptidyl peptidase IV to higher density membranes occurs under conditions of acute hypertension. The membranes are rich in the intracellular membrane markers.

Pathophysiological levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were co-infused into normal male subjects to determine if there are synergistic effects between ANP and BNP. Both peptides have similar physiological effects and are released into the plasma following myocardial infarction of congestive heart failure. The results show that co-infusion causes additive physiological effects, probably by causing the dissociation of pre-bound peptides from their clearance or biological receptors.

The sensitivity of hepatoportal NaCl receptors to NaCl loading in rats with carbon tetrachloride-induced liver cirrhosis was examined to determine the effect of liver dysfunction on the regulation of natriuresis by the hepatic nerve. The results show that NaCl receptor sensitivity to NaCl was significantly reduced even when damage due to liver cirrhosis is slight, and confirm previous findings that the hepatoportal NaCl receptors play a key role in the regulation of natriuresis after ingestion of food with high NaCl content.

The effect of proANF-(31-67), the amino-terminal portion of atrial natriuretic factor (ANF), on renal sodium excretion was examined in the intact kidneys of conscious monkeys. The results show that proANF-(31-67) promotes renal sodium excretion. Furthermore, proANF-(31-67) has an additive effect on the natriuretic effect of ANF-(99-126), the carboxy-terminal portion of ANF.

Natriuretic and blood pressure changes due to hypertonic saline injections in brain are controlled by a central angiotensinergic mechanism. There is a concentration-dependent increase of renal sodium excretion after bolus injections of hypertonic saline. There is a notable increase in mean arterial blood pressure (MAP) after injection of two highest saline concentrations. High saline concentration in cerebrospinal fluid causes angiotensin II-controlled natriuresis.

Adrenomedullin (ADM) has been located in glomeruli, cortical distal tubules and medullary collecting duct cells of the kidney by immunohistochemical analysis. Being a natriuretic peptide, ADM has a major role in the regulation of sodium excretion. Due to this, intrarenal infusion of ADM results in diuretic and natriuretic response. This is marked by a complementary increase in glomerular filtration rate and fractional sodium excretion and a decrease in distal tubular sodium reabsorption.

Urethane-anesthetized Sprague-Dawley rats are experimentally investigated to determine the dependency of renal responses on pregnancy and the atrial natriuretic factor (ANF). The investigation reveals that weaking of the renal effects of ANF during pregnancy is caused by the progesterone, which increases the intrarenal metabolism of ANF.

Dahl salt-sensitive (DS) rats exhibit a weak pressure-natriuresis response due to hindered transmission of renal perfusion pressure into the renal interstititum. This can be corrected by infusion of L-arginine into the body of these animals. Renal interstitial hydrostatic pressure, an important component of the natriuretic response, is decreased by renal decapsulation in L-arginine-treated DS rats.

Analysis of the level of diuretic and natriuretic responses and the function of enhanced mean arterial pressure (MAP) reveals that diuretic and natriuretic responses of spontaneously hypersensitive rats (SHR) to the NG-monomethyl L arginine (L-NMMA) dose are more than those of Wistar-Kyoto (WKY) rats and are not influenced by modifications in MAP. Introduction of L-NMMA does not influence plasma levels of endothelin-1 and atrial natriuretic factor.

Chronic angiotensin II (Ang II) infusion increases mean arterial pressure in uninephrectomized animals. The pressure-natriuresis curve is shifted to the right in animals with chronic Ang II hypertension. ANG II infusion of 10 or 30 ng/min increases the arterial pressure by 26 and 29 mmHg, respectively.

The resetting of input-output balances during reduction of renal perfusion pressure (rRPP) may result from factors such as a decline in plasma aldosterone concentration, shifts in intrarenal hemodynamics, an enhancement in atrial natriuretic factor and physical factors. This is evident because servo control of rRPP ensures that enhanced system mean systemic blood pressure does not exercise direct pressure effects on the kidneys.

A study examined the theory that natriuresis is caused by NG-monomethyl-L-arginine (L-NMMA) injection is connected with enhancement in renal interstitial hydrostatic pressure (RIHP) following an increase in renal perfusion pressure (RPP). Increase in RPP, RIHP and sodium and water excretion results from restriction of nitric oxide by L-NMMA infusion. L-NMMA infusion leads to considerable enhancement in RPP when enhanced RIHP is lowered by heightened renal decapsulation, but natriuretic and diuretic responses are lowered. The exhibition of the natriuresis and diuresis of L-NMMA infusion requires an increase of RIHP.

A cyclic guanosine monophosphate (cGMP) analogue was utilized in the investigation of the modulation of the renal parameter alterations brought about by inhibition of nitric oxide synthase with N(sup G)-nitro-L-arginine methyl ester (L-NAME). The cGMP analogue was able to suppress L-NAME-induced changes in mean arterial pressure and renal parameters. This suggests that L-NAME inhibition is mediated via reduction of cGMP levels as administration ofits analogue reversed the observed effects.

Receptors for the C-type natriuretic peptide (CNP) was demonstrated in cell membrane preparations from the rectal gland of the shark, Squalus acanthias. Competitive binding with rat atrial natriuretic peptide (rANP) reveal the presence of two classes of receptors depending on rANP affinity. CNP binding activated guanylate cyclase activity. The use of other ligands and modified CNPdid not elicit the same response suggesting that the receptors are highly specific for CNP.

Urodilatin (URO), an atrial natriuretic peptide (ANP) analogue, was demonstrated to have high affinity to ANP receptorsnot linked to guanylate cyclase (ANPR-C) and less affinity to receptors which utilizes cyclic guanosimne monophosphate (cGMP) as second messengers (ANPR-A). Further, URO was demonstrated to be as effective as ANP in promoting water and sodium excretion but very ineffective in inducing cGMP generation. These results suggest that the natriuresis and diuresis induced by URO is mediated through ANPR-C.

Selective denervation of the heart or the kidney in conscious dogs was used to investigate the reflex mechanism promoting natriuresis upon left atrial distention. Renal sympathetic nerve activity (RSNA) was also monitored using implanted electrodes. Sham operated subjects exhibited reduced RSNA and elevated urine flow as well as increased osmolal and sodium excretion with the distention of the left atrium. These effects were not observed with denervationof either the heart or the kidney. Further, cardiac denervation did not affect RSNA. These results indicate that the left atrial distention causes a reductionin RSNA which in turn regulate natriuresis.

Three groups of dogs were utilized in the investigationof the role of the C-type natriuretic peptide (CNP) with reference to that of the atrial natriuretic peptide (ANP). Although the two factors are structurallyrelated, CNP causes a greater magnitude in blood pressure reduction compared with ANP. Also, CNP does not induce natriuresis in contrast with the renal response to ANP. Further studies suggest that picomolar levels of CNP circulatein dogs and that they may be involved in vascular tone regulation because of their strongly vasoactive nature.

Salt infusion to a kidney viathe renal artery increased the excretion of sodium without concommitant changesin arterial pressure, kidney prefusion and glomerular filtration rate. The contralateral kidney likewise exhibited this response after some time. Cross circulation and blood infusion experiments utilizing the salt recipient and an uninfused rats show that the the same response can be induced in uninfused subjects. These results suggest that increased blood osmolality induces the perfused kidney to excrete more sodium and to release a natriuretic factor.

The possible role of nitric oxide (NO) in sodium excretion which occurs in response to alterations in renal arterial pressure was investigated. Other studies have shown that intrarenal administration of nitro-L-arginine (NLA), which inhibits NO synthesis, causes a decrease in urinary sodium excretion concomitant with an increase in renal vascular resistance. Analysis of sodium excretion before and after intrarenal NLA infusion in anesthetized dogs with acute changes in RAP was conducted. The results indicate a role for NO in pressure-natriuresis response.

The direct effect of prostaglandin E2 (PGE2) on ouabain binding and Na-K-adenosine triphosphatase (Na-K-ATPase) activity in MDCK cells, a kidney epithelial cell line with collecting duct properties, was examined. A rapid reduction in the activity of Na-K-ATPase and in ouabain binding to intact cells was observed when cells were incubated with low concentrations of PGE2. The results suggested that PGE2 acts to reduce the number of active Na-K-ATPase units via a prostglanding receptor.

The physiological role of C-type natriuretic peptide (CNP) was examined. CNP is a 22-amino acid peptide that is structurally related to atrial natriuretic peptide (ANP) and brain natriuretic peptid and has been isolated from various mammalian tissues. Comparisons of its effects on blood vessels with those of ANP suggest that CNP is a vascular relaxing factor and thus has a role in cardiovascular tone distinct from that of ANP.

Activation of [[Alpha].sub.2]-receptors in the rostral ventrolateral medulla evokes natriuresis by a renal nerve mechanism. Am J Physiol Regulatory Integrative Comp Physiol 281: R98-R107, 2001.--The contribution of [[Alpha].sub.2]-receptor mechanisms in the rostral ventrolateral medulla (RVLM) in mediating the enhanced renal excretory responses evoked by the intravenous infusion of the [[Alpha].sub.2]-receptor agonist xylazine was examined in ketamine-anesthetized rats. In ketamine-anesthetized rats, the bilateral microinjection of the [[Alpha].sub.2]-receptor antagonist yohimbine into the RVLM significantly reduced the enhanced levels of urine flow rate (V) and urinary sodium excretion (UNaV) produced by xylazine. In contrast, microinjection of yohimbine into the RVLM of chronically bilaterally renal-denervated rats significantly reduced the xylazine-evoked diuretic, but not natriuretic, response. In separate ketamine-anesthetized rats, intravenous xylazine infusion produced a near complete inhibition of renal sympathetic nerve activity (RSNA). The subsequent microinjection of yohimbine into the RVLM reversed this neural response and concurrently decreased V and UNaV. Together, these results indicate that during intravenous infusion, xylazine activates [[Alpha].sub.2]-receptor mechanisms in the RVLM to selectively promote urinary sodium excretion by a renal nerve-dependent pathway. In contrast, activation of [[Alpha].sub.2]-receptor in the RVLM affects the renal handling of water by a pathway independent of the renal nerves. This latter pathway may involve an interaction with other brain regions involved in antidiuretic hormone release (e.g., paraventricular nucleus of the hypothalamus). renal sympathetic nerves; renal excretory function; urine flow rate; urinary sodium excretion; central nervous system; microinjection