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PubMed1999

Angiotensin-converting enzyme inhibition and AT1 receptor blockade modify the pressure-natriuresis relationship by additive mechanisms in rats with human renin and angiotensinogen genes.

The intrarenal factors responsible for hypertension in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes are unclear. The pressure-natriuresis and -diuresis relationships in response to chronic angiotensin-converting enzyme (ACE) inhibition and AT1 receptor blockade were evaluated. Renal renin-angiotensin and nitric oxide (NO) system gene expression was also investigated. Six-week-old dTGR were treated for 3 wk with submaximal doses of cilazapril (10 mg/kg, orally) or losartan (10 mg/kg, orally) or with the drug combination. In untreated dTGR, pressure-natriuresis relationships were maximally shifted rightward by approximately 70 to 80 mmHg, and both renal blood flow (RBF) and GFR were markedly decreased. Submaximal cilazapril and losartan dosages both decreased systolic BP by 30 mmHg and shifted the pressure-natriuresis curves leftward by 25 to 30 mmHg. Cilazapril increased RBF and GFR to values observed in normotensive control animals but did not significantly affect fractional sodium excretion (FENa) or fractional water excretion (FEH2O) curves. In contrast, losartan had no significant effect on RBF or GFR but shifted the FENa and FEH2O curves leftward. The cilazapril and losartan combination completely normalized BP and shifted the pressure-natriuresis curves leftward more than did either drug alone. When cilazapril and losartan were administered at higher doses (30 mg/kg, orally), the two drugs equally shifted the pressure-natriuresis curves leftward, by 50 mmHg. Both drugs increased RBF and GFR; however, only losartan shifted FENa and FEH2O curves leftward. Human and rat renin and angiotensinogen genes were downregulated in dTGR and were increased by losartan and cilazapril treatments, whereas no changes in the expression of rat ACE and AT1A receptor genes were observed. Endothelial NO synthase expression was increased by cilazapril but not by losartan. Neither inducible NO synthase nor neural NO synthase gene expression was affected by drug treatments. Therefore, submaximal ACE inhibition enhanced sodium excretion mainly by increasing RBF and GFR, whereas submaximal AT1 receptor blockade decreased tubular sodium and water reabsorption. The combination of the two drugs produced an additive effect. The ACE inhibitor effects may involve increased endothelial NO synthase expression, perhaps related to the inhibition of bradykinin degradation.

Angiotensin Receptor Antagonists↗

PubMed1998

Pressure-natriuresis and -diuresis in transgenic rats harboring both human renin and human angiotensinogen genes.

The hypertensive double transgenic rat harboring both the human renin and human angiotensinogen genes (dTGR) offers a unique opportunity to study the human renin-angiotensin system in an experimental animal model. Since nothing is known about the control of sodium and water excretion in these rats, this study was performed to compare pressure-natriuresis relationships in hypertensive dTGR and normotensive control rats harboring only the human renin gene (hREN), in order to determine how the pressure-natriuresis relationship is reset in hypertensive dTGR. To differentiate between extrinsic and intrinsic renal mechanisms, experiments were performed with and without renal denervation, and with and without infusions of vasopressin, norepinephrine, 17-OH-corticosterone, and aldosterone. Human and rat angiotensinogen and renin mRNA expression were also determined. In hREN without controlled renal function, urine flow and sodium excretion increased from 13 to 169 microl/min per g kidney wet weight (kwt) and from 1 to 30 micromol/min per g kwt, respectively, as renal perfusion pressure was increased from 67 to 135 mmHg. Renal blood flow (RBF) and GFR ranged between 3 to 7 and 0.9 to 1.5 ml/min per g kwt. In dTGR, pressure-natriuresis-diuresis relationships were shifted approximately 40 mmHg rightward. RBF was lower in dTGR than in hREN; GFR was not different. In dTGR with neurohormonal factors controlled, RBF was decreased and pressure-natriuresis-diuresis curves were not different compared to dTGR curves without these interventions. By light microscopy, the kidneys of these 6-wk-old dTGR and hREN rats were normal and indistinguishable. Both human and rat renin and angiotensinogen mRNA were expressed in the kidneys of dTGR. The two renin mRNA were decreased in dTGR, indicating a physiologic downregulation of renin gene expression by high BP. It is concluded that the renal pressure-natriuresis mechanism is reset toward higher pressure levels in dTGR and participates in the maintenance of hypertension. The reduced excretory function in dTGR depends on hREN and human angiotensinogen gene expression and is intrinsic to the kidney as opposed to extrarenal regulators.

Aldosterone↗

PubMed1998

Interactions between nitric oxide and renal nerves on pressure-diuresis and natriuresis.

The present study examined the effect of renal denervation on the impairment of the pressure-diuresis response produced by nitric oxide synthesis blockade. The experiments were performed in Inactin-anesthetized Munich-Wistar rats. The animals with innervated kidneys had lower baseline values of renal blood flow, GFR, sodium excretion (UNaV), and urine flow (V) than rats with denervated kidneys. Also, renal denervation shifted pressure-diuresis and natriuresis toward lower pressures. A low dose of N(omega)-nitro-L-arginine methyl esther (NAME, 3.7 nmol/kg per min) reduced UNaV and the fractional excretion of sodium (FENa) and blunted pressure-natriuresis only in rats with innervated kidneys, whereas it had no effects in rats with denervated kidneys. A medium dose of NAME (37 nmol/kg per min) lowered FENa only in rats with innervated kidneys. The administration of NAME (37 nmol/kg per min) blunted pressure-diuresis and natriuresis in kidneys with or without the renal nerves, but the effect was more pronounced in rats with innervated kidneys. A high dose of NAME (3.7 micromol + 185 nmol/kg per min) increased UNaV and FENa only in rats with innervated kidneys, whereas it reduced GFR, V, UnaV, and FENa in rats with denervated kidneys. However, pressure-natriuresis and diuresis were blunted by this high dose of NAME independently of the presence or absence of renal nerves. These results demonstrate that renal nerves potentiate the renal effects of low doses of NAME on renal function and pressure-diuresis and natriuresis. However, high doses of NAME abolish pressure-diuresis independently of renal nerves, and the natriuretic effect of NAME in innervated kidneys may be attributed to reflex inhibition of sympathetic tone due to the rise in arterial pressure.

Analysis of Variance↗

PubMed1991

Selective role of dopamine in the natriuresis produced by iso-osmotic saline infusion.

Endogenous dopamine (DA) selectively contributes to the natriuresis (UNaV) produced by infusion and dietary consumption of sodium chloride. The present study in anesthetized rats determined whether DA has a role in the natriuresis produced by small (2.0 +/- 0.11% increase in body weight) and large (17.9 +/- 0.58% increase in body weight) increments in extracellular fluid volume with iso-osmotic saline. Small volume expansion increased urine flow (V) by 59 +/- 15%, UNaV by 155 +/- 31%, and dopamine excretion by 25 +/- 9%. DA1-receptor blockade with SCH 23390 (SCH, 1.0 microgram/kg/min), attenuated the natriuresis; an increase in UNaV of only 69 +/- 15%. Large volume expansion increased V by 1,026 +/- 215% and UNaV by 2,735 +/- 899%, without affecting dopamine excretion. Increments in V and UNaV were unaffected by increasing doses of SCH (1.0 microgram/kg/min; 10 micrograms/kg/min; and 50 micrograms/kg bolus, followed by 10 micrograms/kg/min). Adequacy of DA1-receptor blockade was demonstrated by the fact that SCH (1.0 microgram/kg/min) attenuated the natriuresis produced by the DA1-receptor agonist, fenoldopam (0.1 micrograms/kg/min ia). We conclude that endogenous DA contributes to the natriuresis produced by small, but not large, increases in extracellular fluid volume with iso-osmotic saline.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2006

Role of brain angiotensin AT1 receptor in the carbachol-induced natriuresis and expression of nNOS in the locus coeruleus and proximal convoluted tubule.

Central administration of losartan effectively blocked the increase of blood pressure and drinking response induced by angiotensin II (Ang II) or carbachol. However, the relationship between angiotensin AT(1) receptors and the natriuresis induced by brain cholinergic stimuli is still not clear. The purpose of the study is to reveal the role of brain angiotensin AT(1) receptor in the carbachol-induced natriuresis and expression of neuronal nitric oxide synthase (nNOS) in the locus coeruleus (LC) and proximal convoluted tubule (PCT). Our results indicated that 40 min after intracerebroventricular (ICV) injection of carbachol (0.5 microg), urinary sodium excretion was significantly increased to 0.548+/-0.049 micromol x min(-1) x 100 g(-1). Immunohistochemistry showed that carbachol induced an increase of neuronal nitric oxide synthase immunoreactivity (nNOS-IR) in the LC and renal proximal tubular cells. After pretreatment with losartan (20 microg), carbachol-induced urinary sodium excretion was reduced to 0.249+/-0.067 micromol x min(-1) x 100 g(-1). The same was true for carbachol-induced increase of nNOS-IR in the LC and PCT. The present data suggest that ICV cholinergic stimulation could induce a natriuresis and upregulate the activity of nNOS in the LC and PCT. The blockade of AT(1) receptors might downregulate the effects induced by carbachol in the LC and PCT. Consequently, we provide a new evidence that brain angiotensinergic pathway and NO-dependent neural pathway contribute to the natriuresis following brain cholinergic stimulation and thus play an important role in the regulation of fluid homeostasis. Furthermore, the final effect of nitric oxide on proximal tubular sodium reabsorption participated in the natriuresis induced by brain cholinergic stimulation.

Angiotensin II Type 1 Receptor Blockers↗

PubMed1990

The effect of fenoldopam on renal haemodynamics and natriuresis in chronic renal failure.

The effect of oral administration of fenoldopam, a dopamine-1 receptor agonist, on blood pressure, renal haemodynamics and natriuresis was studied in 12 patients with chronic renal insufficiency. In addition, the effect of administering a low intravenous dose of fenoldopam on top of the oral dose was compared with the effect of the same intravenous dose given immediately before oral fenoldopam. Oral administration of fenoldopam (50 mg t.i.d. for 3 +/- 1 days followed by 100 mg t.i.d. for 8 +/- 1 days) induced a significant fall in blood pressure (median MAP from 107 to 101 mm Hg). Compared to baseline values, body weight, effective renal plasma flow (ERPF), glomerular filtration rate (GFR) and fractional sodium excretion remained unchanged. Infusion of fenoldopam (0.05-0.1 micrograms/kg/min) on day 1 led to a significant fall in blood pressure (median mean arterial pressure from 107.0 to 98.5 mm Hg), and a significant rise in effective renal plasma flow (median ERPF from 132 to 146 ml/min/1.73 m2). Median fractional sodium excretion increased significantly from 2.1 to 3.3%. GFR, filtration fraction and plasma aldosterone concentration did not change. No relationship was found between the fenoldopam-induced changes in ERPF and natriuresis, nor between baseline GFR or ERPF and fenoldopam-induced urinary sodium loss. Infusion of fenoldopam while patients were on oral fenoldopam had no effect on blood pressure, ERPF or GFR. However, again natriuresis was induced, which did not differ significantly from the fenoldopam-induced natriuresis on day 1. We conclude that oral fenoldopam has a moderate blood pressure lowering effect in patients with chronic renal insufficiency, but exerts no effect on ERPF or GFR. Secondly, a fenoldopam-induced natriuresis does not appear to be related to changes in ERPF or aldosterone secretion.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1985

Role of prostaglandins in captopril-induced natriuresis.

To determine whether prostaglandins (PG) contribute to captopril-induced natriuresis, 20 hypertensive subjects were assigned to one of the following three groups: group a, captopril (C) administration; group b, C + indomethacin (I); group c, I alone. Captopril was given in a dose of 100, 200, 400 mg/day and indomethacin in a dose of 100mg/day for one week. In group a (n = 10), natriuresis was clearly increased in the seven day periods with captopril in a dose of 200 and 400mg/day but not at 100mg/day. After captopril 200 or 400mg/day, but not 100mg/day, urinary PGE2 and PGI2 excretion significantly increased while filtration fraction fell due to a rise in renal plasma flow. Plasma aldosterone (PA) significantly decreased after C(p less than 0.05). In group b (n = 7), natriuresis disappeared during captopril 200 or 400mg/day and indomethacin administration even when PA decreased as in group a. In group c (n = 3), natriuresis was unchanged. In conclusion, natriuresis by C is critically dependent upon increased secretion of PG.

Adult↗

PubMed1998

Complementary antihypertensive action of rilmenidine on the pressure-natriuresis relationship and sodium preference in spontaneously hypertensive rats.

Previously, changes in position and slope of the pressure-natriuresis relationship have been used to characterize antihypertensive drugs in basic research. Rilmenidine may chronically reduce arterial pressure via central nervous system and renal imidazoline receptors. The present experiments were used to examine the shift in the pressure-natriuresis relationship during rilmenidine administration. We examined the effects of twice daily doses (1 and 3 mg/kg) for 6 days on the pressure-natriuresis relationship determined for control and treated spontaneously hypertensive rats (SHR) drinking tap water or 1% NaCl. The pressure-natriuresis relationship was shifted to the left for the 3 mg/kg dose and the slope was no different from the control. These experiments also indicated that rilmenidine might have an effect on sodium preference which was confirmed in a third series of experiments by permitting control and treated (3 mg/kg) SHR access to both tap water and 1% NaCl. This lack of change in slope indicates that, during rilmenidine treatment, the arterial pressure is relatively insensitive to sodium intake. The shift to the left indicates a restoration of the pressure-natriuresis relationship after chronic treatment with rilmenidine and a resetting of the long-term blood pressure control. Rilmenidine also reduces salt appetite in the SHR.

Animals↗

PubMed1987

Role of prostaglandin and angiotensin II in ANP-induced natriuresis.

The aim of the present study was to examine if the natriuresis induced by a dose of ANP that does not alter glomerular filtration rate (GFR) or mean arterial pressure (MAP) is accompanied by changes in renin release urinary excretion of prostaglandins and intrarenal blood flow distribution. It was found that the intrarenal infusion of ANP (8-33) at a dose of 0.05 micrograms/kg min in seven anaesthetized dogs did not produce any change in GFR or MAP, but its natriuretic effect was similar to that induced by a larger dose (0.3 micrograms/kg min, n = 5) that produces significant changes in both MAP and GFR. The natriuresis induced by the lower dose of ANP was associated with a redistribution of RBF to the deep cortical nephrons and with an increase (p less than 0.05) in urinary excretion of prostaglandins E2 and 6 keto-F1 alpha. Renin secretion rate decreased by a 54% (p less than 0.05). The role of angiotensin II (AII) suppression on the natriuresis induced by ANP was examine in another experimental group (n = 6). It was found that the infusion of ANP during fixed intrarenal levels of AII produced a natriuretic effect that was significantly lower (38%) than that produced by the infusion of ANP alone. The results of this study show that the natriuresis induced by ANP is not necessarily produced by an increase in GFR and is associated with a redistribution of RBF to the deep cortex an increase in urinary excretion of prostaglandins and a decrease of renin release. These results also suggest that the natriuretic effect of ANP is partly mediated by the intrarenal suppression of AII.

Angiotensin II↗

PubMed1994

Central and renal I1 imidazoline preferring receptors: two unique sites mediating natriuresis in the rat.

Based on previous studies we postulated that, whereas the natriuresis observed following intracerebroventricular (i.c.v.) moxonidine was mediated by a decrease in renal sympathetic nerve activity, the natriuresis observed following intrarenal (i.r.) infusion of moxonidine was mediated by a direct stimulation of renal I1-imidazoline preferring receptors. Sprague-Dawley rats were unilaterally nephrectomized and i.c.v. cannulated 7 to 10 days and 3 days prior to the day of the experiment, respectively. On the day of the experiment, rats were anesthetized (pentobarbital) and the renal function was isolated. Administration of i.c.v. as well as i.r. moxonidine produced an increase in sodium excretion and urine flow fate. Pretreatment with intravenous prazosin (0.15 mg/kg) completely attenuated the response to i.c.v. moxonidine (1 nmol/5 microliters) but only slightly altered the response to i.r. moxonidine (3 nmol/kg/min). Conversely, intravenous pretreatment with the imidazoline preferring receptor antagonist idazoxan (0.3 mg/kg) completely blocked the response to i.r. moxonidine (3 nmol/kg/min) without altering the response to i.c.v. moxonidine (0.3 nmol/kg). These results would be consistent with the natriuresis observed following i.c.v. moxonidine as being mediated by imidazoline preferring receptors located centrally, whereas that following i.r. moxonidine was mediated directly by renal imidazoline-preferring receptors, with a small component of this response conceivably due to activation of central imidazoline preferring receptors. In summary, the antihypertensive effect of imidazoline preferring receptor agonists may be associated with a natriuresis that is due to stimulation of these receptors, found both peripherally (renal) and centrally.

Adrenergic alpha-Antagonists↗

PubMed1991

Natriuresis, kaliuresis and antidiuresis induced by central carbachol injection are mediated by muscarinic M1 receptors.

The present study investigated the effect of selective muscarinic antagonists on natriuresis, kaliuresis and antidiuresis induced by intracerebroventricular (i.c.v.) injection of carbachol in the rat. The muscarinic antagonists were given by i.c.v. injection 1 min before carbachol (1 microgram/rat). 4-Diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), a rather selective M1 and M3 receptor antagonist, was the most potent inhibitor of carbachol-induced natriuresis, kaliuresis and antidiuresis, its ID50 being respectively 0.12, 0.04 and 0.56 nmol/rat. Pirenzepine, a selective M1 antagonist, potently inhibited the above mentioned carbachol effects, its ID50 being 1.85, 3.25 and 1.49 nmol/rat, respectively. On the other hand, the M2-selective antagonist methoctramine and the M3-selective antagonist p-fluoro-hexahydro-sila-difenidol were very weak inhibitors. Methoctramine at doses up to 60 nmol/rat produced non statistically significant inhibition of carbachol-induced natriuresis, kaliuresis and antidiuresis. Para-fluoro-hexahydro-sila-diphenidol showed an ID50 of 64.4 nmol/rat on carbachol-induced natriuresis, while at the maximum dose employed, 100 nmol/rat, the inhibition of carbachol-induced kaliuresis and antidiuresis was lower than 50%. The rank order of potency of the antagonists tested proved to be related to their pA2 values for muscarinic M1 receptors, suggesting that this receptor subtype mediates the central effects of cholinergic mechanisms on water and electrolyte excretion.

Animals↗

PubMed1991

Central alpha-2 adrenergic mechanisms in the renal nerve mediated natriuresis and diuresis produced by acute volume expansion.

To determine whether central alpha-2 adrenergic mechanisms are involved in the renal nerve mediated natriuresis and diuresis produced by acute volume expansion, urine flow and sodium excretion from innervated and denervated kidneys were measured before and after acute volume expansion (1 ml/min for 20 min) in the presence or absence of intracerebroventricular yohimbine (8 micrograms/kg/min), an alpha-2-antagonist, in Inactin-anesthetized Sprague-Dawley rats. The innervated to denervated (I/D) ratio for urine flow and sodium excretion indicated that acute volume expansion caused a greater natriuresis and diuresis from the intact kidney compared to the denervated kidney. However, these I/D ratios during acute volume expansion were significantly reduced in the presence of yohimbine i.c.v. Furthermore, central administration of clonidine, an alpha-2 agonist, produces a renal nerve mediated natriuresis. These data suggest that central alpha-2 adrenergic mechanisms may be involved in producing the renal sympatho-inhibition, which subsequently produces natriuresis and diuresis, in response to acute volume expansion.

Animals↗

PubMed1998

The acute pressure natriuresis response blunted and the blood pressure response reset in the normal pregnant rat.

OBJECTIVES: Our purpose was to test the hypothesis that the acute pressure natriuresis curve was reset in pregnancy to facilitate the volume expansion. STUDY DESIGN: Studies were done with 14- to 16-day pregnant (n = 8) and age-matched virgin female (n = 6) Sprague-Dawley rats that were under general anesthesia. The left kidney was denervated, and mechanical clamps were placed on the aorta above and below the renal arteries for manipulation of renal perfusion pressure. Rats received intravenous 0.9% sodium chloride (1.5% body weight/h) and a cocktail of vasoactive factors to suppress variation in endogenous hormones. Renal perfusion pressure was varied acutely from 125 to 95 mm Hg, and glomerular filtration rate, renal plasma flow, sodium excretion, and urine flow were measured in both kidneys at each renal perfusion pressure. Data were analyzed by unpaired t test and by homogeneity by slopes. RESULTS: The acute pressure natriuresis curve was blunted in pregnant rats versus virgins, and the renal nerves were not responsible. The blunted natriuretic response in pregnancy was due to loss of tubular epithelial responsiveness to increased blood pressure. CONCLUSION: The pressure natriuretic response is markedly blunted in pregnancy, permitting the cumulative plasma volume expansion to occur. Contrary to nongravid states, blunting of the acute pressure natriuresis curve in pregnancy is not associated with increased blood pressure because of the profound peripheral vasodilation. This suggests an alteration in the mechanism(s) normally linking blood pressure control to the acute pressure natriuresis relationship.

Animals↗

PubMed2001

Abnormal pressure-natriuresis in hypertension: role of cytochrome P450 metabolites of arachidonic acid.

The pressure-natriuresis relationship is shifted to higher pressures in genetic and experimental models of hypertension; however, the factors responsible for altering kidney function remain to be determined. In spontaneously hypertensive (SHR) and Lyon hypertensive rats, the resetting of pressure-natriuresis results from increased preglomerular renal vascular tone, whereas sodium reabsorption is elevated in the thick ascending loop of Henle (TALH) of Dahl S rats. Recently, a new route for the renal metabolism of arachidonic acid (AA) has been described, and there is evidence that this pathway contributes to the resetting of renal function in hypertension. In the kidney, cytochrome P450 (CYP) enzymes metabolize AA primarily to 20-HETE and EETs. 20-HETE is a potent constrictor of renal arterioles that has an important role in autoregulation of renal blood flow and tubuloglomerular feedback. 20-HETE and EETS also inhibit sodium reabsorption in the proximal tubule and TALH. In the SHR, the renal production of 20-HETE is elevated and inhibitors of the formation of 20-HETE decrease arterial pressure. Blockade of 20-HETE formation also reduces blood pressure or improves renal function in deoxycorticosterone acetate (DOCA)-salt, angiotensin II--infused, and Lyon hypertensive rats. In contrast, 20-HETE formation is reduced in the TALH of Dahl S rats and this contributes to elevated sodium reabsorption. Induction of 20-HETE synthesis improves pressure-natriuresis and lowers blood pressure in Dahl S rats, whereas inhibitors of the synthesis of 20-HETE promote the development of hypertension in Lewis rats. These findings indicate that the renal production of CYP metabolites of AA is altered in genetic and experimental models of hypertension and that this system contributes to the resetting of pressure-natriuresis and the development of hypertension in some models.

Animals↗

PubMed2002

Impaired stress-induced pressure natriuresis increases cardiovascularload in African American youths.

BACKGROUND: We hypothesized that impaired stress-induced pressure natriuresis increases blood pressure (BP) load. METHODS: The 118 African American youths were brought into similar levels of sodium balance. The protocol consisted of a 2-h baseline period, a 1-h stress period (competitive video games), and a 2-h recovery period. RESULTS: Normal pressure natriuresis (n = 80) resulted from a resistance-mediated (r = 0.23; P <.03) increase in BP (P <.001). In contrast, impaired pressure natriuresis (n = 38), leading to an extended period of elevated BP (P <.05), resulted from a volume-mediated (r = 0.55; P <.002) increase in BP (P <.001). CONCLUSIONS: Impaired stress-induced pressure natriuresis may contribute to the development of essential hypertension, particularly in African Americans.

Adolescent↗

PubMed1988

Contrasting plasma atrial natriuretic factor concentrations during comparable natriuresis with infusions of atrial natriuretic factor and saline in normal man.

1. To explore the role of atrial natriuretic factor (ANF) in the response to an acute saline load, we compared plasma hormone and urinary electrolyte interrelationships during administration of ANF and saline. Plasma concentrations of ANF, renin, angiotensin II and aldosterone, together with urine volume and electrolytes, were measured during infusions of placebo, ANF [alpha-human ANF (99-126)] and 0.9% (w/v) NaCl solution in normal subjects under standardized conditions of diet and posture. 2. Saline loading and ANF infusions initially induced similar natriuresis and suppression of renin-angiotensin-aldosterone system activity in association with markedly disparate values of plasma ANF. Plasma ANF levels rose to two- and eight-fold placebo values with saline and ANF, respectively (P less than 0.001). Conversely, in the period after infusion plasma ANF values were similar while natriuresis differed significantly. Peak natriuresis lagged behind peak plasma ANF values with both stimuli. 3. ANF, but not saline, enhanced urinary excretion of calcium and magnesium. Saline, but not ANF, caused increased kaliuresis. 4. The data suggest that ANF makes only a minor contribution to natriuresis induced by saline challenge, although full confirmation of this point requires quantification of end-organ responses to endogenous ANF in the face of changing arterial pressure and circulating volume.

Adult↗

PubMed2003

Role of prostaglandin cyclooxygenase and cytochrome P450 pathways in the mechanism of natriuresis which follows hypertonic saline infusion in the rat.

AIM: The prostaglandin cyclooxygenase (COX) and P450 cytochrome (CYP450) pathways of arachidonic acid metabolism are functionally interrelated and both engaged in control of sodium excretion; the study focused on their contribution to the natriuresis which follows hypertonic saline infusion in the rat. METHODS: In anaesthetized rats, clearance studies were conducted, supplemented with laser-Doppler measurements of the cortical and medullary blood flow (CBF, MBF), and measurement of medullary tissue admittance (Y), an index of interstitial ion concentration. RESULTS: Indomethacin (Indo), 5 mg kg(-1) i.v. paradoxically enhanced the natriuresis secondary to intra-aortic suprarenal 5% saline load, further increasing sodium excretion by 385 +/- 73% (P < 0.01). After acute clotrimazole, 10 mg kg(-1) i.v. an inhibitor of CYP450 epoxygenase, the increase in natriuresis was smaller and did not differ from that observed after the drug's ethanol solvent. In rats pre-treated with clotrimazole for 3 days, hypertonic saline loading increased sodium excretion (U(Na)V) to 0.94 +/- 0.22 micromol min(-1) , compared with a significantly greater (P < 0.05) increase to 2.76 +/- 0.48 micromol min(-1) measured in untreated controls. Indo increased U(Na)V twofold, similarly in the clotrimazole and in the control group; in the absence or presence of clotrimazole treatment, COX blockade significantly decreased MBF and increased Y. CONCLUSION: The data indicate that blockade of the CYP450 epoxygenase significantly impairs excretion of sodium in rats acutely loaded with hypertonic NaCl solution. The paradoxical post-Indo natriuresis is preserved in clotrimazole treated rats, which speaks against the role of CYP450 pathway in the response.

Animals↗

PubMed1999

The role of nitric oxide in saline-induced natriuresis and diuresis in rats.

This study was designed to determine to what extent nitric oxide (NO) mediates the natriuretic and diuretic responses to acute isotonic saline (0.9 gram % NaCl) volume expansion (SVE, 0.5 ml min-1 kg-1). Studies were performed on 49 pentobarbital anesthetized (65 mg/kg) female Sprague-Dawley rats with or without a NO synthase inhibitor, Nomega-nitro-L-arginine (LNA). Group 1 received saline at 27 microliter/min for 1 hr (baseline) and then SVE for 1 hr; Groups 2-4 received LNA at 10, 150, and 200 microgram kg-1 min-1, respectively, for 1 hr followed by LNA + SVE. To determine to what extent inhibition of NOS would reverse an ongoing SVE-induced natriuresis and diuresis, Group 5 was saline-volume-expanded for hours 1 and 2 whereas Group 6 was administered SVE during the first hour and then SVE + 150 microgram kg -1 min-1 LNA during the second hour. SVE caused a significant (P < 0.05) increase in the glomerular filtration rate (GFR) of Group 1 and the LNA-treated rats (Groups 2-4). This SVE-induced increase in the GFR occurred despite the fact that baseline GFR was significantly lower in the two groups of rats that were infused with the highest doses of LNA (Groups 3-4). SVE was also associated with similar increases in urine flow rate, sodium and potassium excretion, and total osmolar excretion in Groups 1-4. On the other hand, mean arterial pressure (MAP) was significantly higher in Group 2 during SVE + LNA and during the baseline as well as during the SVE periods in Groups 3-4; MAP was also significantly elevated in Group 6 during SVE + LNA. Thus, despite the fact that MAP was higher in LNA-treated rats, sodium and urine flow rates were the same as in Group 1 (i.e., there was no evidence of a pressure natriuresis or diuresis in these animals). Along these lines, there was a small but significant positive linear correlation coefficient (r = 0.41, P = 0.05) between sodium excretion values and corresponding MAP values in SVE control rats but not in Groups 3-4 during SVE (r = 0.28, P = 0.26). The current data demonstrate that 1) NO does not mediate SVE-induced hyperfiltration in the rat, 2) NO also does not mediate SVE-induced natriuresis or diuresis, and 3), consistent with other reports, NO appears to mediate pressure natriuresis and diuresis.

Animals↗