Noradrenaline attenuates the natriuretic effect of atrial natriuretic factor in man.

1. The effects of noradrenaline (0.025 micrograms kg-1 min-1) and atrial natriuretic factor (0.04 micrograms kg-1 min-1) alone, and in combination, were studied in eight healthy salt replete men. 2. Atrial natriuretic factor increased urinary sodium excretion and flow rate without changing glomerular filtration rate or systemic haemodynamics. 3. Noradrenaline decreased urinary sodium excretion without changing glomerular filtration rate, urinary flow rate or systemic haemodynamics. 4. When atrial natriuretic factor was administered against a background infusion of noradrenaline the natriuretic response to the peptide was significantly attenuated. 5. Further analysis showed that this attenuation was due to the additive antinatriuretic effect of noradrenaline rather than to a specific interaction between atrial natriuretic factor and noradrenaline. 6. The possible significance of this interplay between noradrenaline and atrial natriuretic factor is discussed in the context of experimental evidence for an important role of the sympathetic nervous system in modulating the renal effects of atrial natriuretic factor in animals.     

RENAL EFFECTS OF ATRIAL NATRIURETIC FACTOR (99–126) IN POTASSIUM LOADED SHEEP

1. The renal response to renal arterial infusion of synthetic atrial natriuretic factor (ANF 99-126) was examined in conscious sheep following dietary K loading, and compared with the response in normal sheep. 2. Renal arterial infusion of ANF in K loaded sheep increased the excretion of Na and Ca, but did not affect the excretion of K. 3. The natriuretic effect of ANF was attenuated in K loaded animals, possibly as a consequence of the reduction in Na status which is associated with K loading.     

Captopril reduces renal excretion of prostaglandin E2 in the sodium-depleted rabbit

The effects of captopril on renal function and prostaglandin E2 excretion were investigated in rabbits undergoing chronic sodium depletion. Captopril administered for six days, via rate-controlled osmotic pumps, caused diuresis and marked natriuresis which were accompanied by a significant reduction of urinary prostaglandin E2 excretion and of glomerular filtration rate. It is concluded that captopril reduces the renal excretion of prostaglandin E2 and that its diuretic and natriuretic effects are prostaglandin E2-independent.     

INTERACTION OF EXOGENOUS OUABAIN AND CHRONIC MINERALOCORTICOID TREATMENT IN THE KIDNEY OF THE CONSCIOUS SHEEP

1. Ouabain is known to have natriuretic effects only at high doses, and therefore if endogenously produced ouabain has a role in the regulation of sodium excretion, the renal response to ouabain must be increased substantially in certain physiological situations. The aim of this study is to determine whether treatment with the mineralocorticoid, aldosterone, potentiates that natriuretic response to ouabain. 2. Six conscious sheep received renal arterial infusion of either vehicle or aldosterone (3 μg/h). Forty hours after commencement of infusion ouabain was infused into the renal artery at 400 μg/h for 60min. A second infusion of ouabain was administered on the 6th day of aldosterone treatment. 3. In the absence of aldosterone, the effects on sodium excretion produced by ouabain infusion at 400 μg/h into the renal artery were variable and not statistically significant. Ouabain infusion after 40 h of aldosterone treatment increased sodium excretion from 40 ± 14 to 676 ± 69 μmol/min in the second hour following cessation of ouabain infusion (P< 0.001). Ouabain infusion after 6 days of aldosterone treatment increased sodium excretion similarly. Ouabain-stimulated sodium excretion was significantly greater during aldosterone treatment compared to vehicle treatment (P<0.05). In contrast, no enhancement of effect was observed after acute treatment with aldosterone. 4. These results demonstrate potentiation of the natriuretic response to ouabain infusion by chronic mineralocorticoid treatment and suggest a potential role of endogenous digitalislike factor in the physiological control of sodium homeo stasisaldo sterone, endogenous digitalis-like factor, ouabain, sodium excretion.     

Lithium does not alter the renal response to a pressor dose of tyramine in man.

Renal clearance of lithium has been used as a marker of proximal tubular function in man. Recently, lithium pre-treatment has been shown to interfere with the natriuretic actions of some natriuretic agents in man. We have therefore investigated the effects of oral lithium carbonate (500 mg) on the natriuretic response to a pressor dose of tyramine (15 micrograms kg-1 min-1) in six normal volunteers. Lithium had no effect on baseline sodium excretion, nor did it affect the tyramine-induced increase in blood pressure and subsequent natriuresis. These results show that oral lithium carbonate (500 mg) does not appear to interfere with the pressure natriuretic response to tyramine in man.     

Atrial natriuretic peptide and urinary prostaglandins in man.

1. In order to assess the effects of atrial natriuretic factor on the renal biosynthesis of prostaglandins (PG), the urinary excretion of PGE2, PGF2 alpha, 6-keto-PGF1 alpha and thromboxane (Tx)B2 were followed in eight salt-loaded healthy volunteers infused for 2 h with a non hypotensive dose of human atrial natriuretic peptide (hANP, 0.7 nmol min-1). 2. Within 1 h, hANP, infusion produced a marked increase in the urinary PG output, especially of PGE2 and 6-keto-PGF1 alpha (188 +/- 21% and 202 +/- 24% of the pre-infusion values respectively), followed by a significant decrease during the recovery period. 3. No correlations could be uncovered between the urinary excretion of sodium and that of any of the PGs. In contrast, during the infusion of hANP, the urinary output of PGE2 and of 6-keto-PGF1 alpha was found positively related to the urinary flow rate (r = 0.42; P less than 0.05; n = 32 and r = 0.43; P less than 0.05; n = 32 respectively) as well as during the recovery period (r = 0.66, P less than 0.001; n = 32 and r = 0.55; P less than 0.01; n = 32 respectively). 4. It was concluded that, in man, infusion of a non hypotensive dose of hANP is followed by a rise in urinary PG excretion presumably reflecting enhanced renal PG biosynthesis. This increased urinary PG excretion does not seem to be involved in the natriuretic action of hANP but might participate to its diuretic effect.     

Inhibitors of 20-hydroxyeicosatetraenoic acid (20-HETE) formation attenuate the natriuretic effect of dopamine

Endogenous renal dopamine is a major physiological regulator of renal ion transport; however its intracellular signaling pathways are not thoroughly understood. The present study examined the role of 20-hydroxyeicosatetraenoic acid (20-HETE), the major cytochrome P450 (CYP4A) metabolite of arachidonic acid formed in the renal cortex, on the natriuretic response to dopamine in Sprague Dawley rats. Infusion of dopamine (1.5μg/kg/min, i.v.) increased urine flow (1.9 fold over basal), sodium excretion (UNaV, 2.7 fold), fractional sodium excretion (FENa, 3.3 fold) and proximal and distal delivery of sodium by 1.5- and 2-fold respectively. Administration of two inhibitors of the synthesis of 20-HETE, 1-aminobenzotriazole (ABT) and N-hydroxy-N'-(-4-butyl-2-methylphenyl)formamidine (HET0016) reduced the response to dopamine by 65%. Induction of the renal expression of CYP4A enzymes with clofibrate did not alter the response to dopamine. The natriuretic response to dopamine was lower in Dahl salt-sensitive rats in comparison to an SS.BN5 consomic strain in which transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats upregulates the renal expression of CYP4A protein and the production of 20-HETE. Treatment with HET0016 blocked the renal effects of dopamine in SS.BN5 rats. We also examined the influence of 20-HETE in the natriuretic response to acute volume expansion that is in part mediated via the release of endogenous dopamine. The increase in urine flow, UNaV, FENa and distal FENa following volume expansion was markedly reduced in rats treated with ABT. These results suggest that 20-HETE plays at least a permissive role in the natriuretic response to dopamine.     

Renal effects of the new calcium channel blocking drug isradipine

Summary The acute effect of a single oral dose of isradipine 5 mg on blood pressure, renal haemodynamics, electrolyte excretion and plasma renin activity was studied in 10 healthy males.Isradipine did not produce a significant change in systolic or diastolic blood pressure, and glomerular filtration rate, renal plasma flow, renal vascular resistance, and urinary albumin excretion remained constant. There was a marked natriuretic and diuretic effect about 1–3 h after isradipine. Plasma renin activity showed a slight, insignificant increase 1 h after dosing. Uric acid clearance and 2-microglobulin excretion showed no significant changes, despite an increase in sodium clearance, suggesting an additional mechanism of action other than the proximal tubular natriuretic effect of isradipine in normotensive volunteers.     

Effect of endopeptidase-24.11 inhibition and of atrial natriuretic peptide clearance receptor ligand on the response to rat brain natriuretic peptide in the conscious rat.

1. The present studies examined the effect of (a) a specific endopeptidase-24.11 (E-24.11) inhibitor (candoxatrilat) and (b) a ligand for the atrial natriuretic peptide (ANP) clearance receptor (SC 46542) on the renal and blood pressure response to brain natriuretic peptide (BNP) in conscious rats. 2. Infusion of BNP 200 ng kg-1 min-1 for 60 min produced a small rise in urinary sodium and guanosine 3':5'-cyclic monophosphate (cyclic GMP) excretion with a non-significant fall in mean arterial blood pressure. 3. Candoxatrilat (3 mg kg-1) alone had no significant effect on sodium excretion or blood pressure but markedly potentiated the natriuretic response to BNP. 4. Similarly SC 46542 (68 micrograms kg-1; 6.8 micrograms kg-1 min-1) which produced no significant effect on its own, potentiated the natriuresis-induced by BNP, although the effect was of shorter duration compared to that of candoxatrilat. 5. The data indicate two approaches to the potentiation of the renal activity of BNP and suggest that BNP may mediate some of the activity of E-24.11 inhibitors reported in cardiac failure.     

EFFECTS OF ANF PROHORMONE PEPTIDES IN CONSCIOUS PRIMATES

1. Recent studies suggest that amino-terminal peptides from the atrial natriuretic factor (ANF) prohormone are natriuretic. 2. The effects of pro ANF 31–67 and ANF 99–126 on renal function were studied in conscious non-human primates (Macaca fuscicularis). 3. Results show that pro ANF 31–67 and ANF 99–126 are diuretic and natriuretic and that when the two peptides are given in combination sodium excretion increases in an additive fashion. 4. These results indicate that multiple peptides from the ANF prohormone are natriuretic. Furthermore, these findings suggest that the combined action of these peptides causes the natriuresis that occurs after the release of endogenous atrial peptides.     

Effects of Hydroflumethiazide in Congestive Heart Failure: Renal Electrolyte Excretion Related to Urinary Thiazide Excretion and Aldosterone

Abstract: The effect of hydroflumethiazide (HFT) on renal excretion of sodium, chloride, and potassium was studied in congestive heart failure and related to urinary excretion of thiazide and aldosterone. HFT 75 or 150 mg was administered orally once daily for 4 days to 8 male patients with roentgenological evidence of enlarged heart and slight or no peripheral oedema receiving digitalis and controlled diet. Urinary excretion of HFT did not change after repeated doses, whereas urinary excretion of a metabolite increased significantly. Initially, HFT induced a significant increase in the urinary excretion of sodium and potassium. After repeated doses, the natriuretic effect declined gradually in 6 of the patients. There was consistently a small natriuretic effect and a large kaliuretic effect at high serum aldosterone concentrations and high urine aldosterone excretion rates, whereas at low aldosterone levels, there was a wide range in magnitude of these effects. Relationships of the log urinary excretion rate of HFT to the increase in urinary excretion rate of sodium, chloride, and potassium showed positive and significant correlations. It was concluded that reduced natriuretic effect of HFT in congestive heart failure is not due to reduced delivery of thiazide to renal tubular cells but to compensatory adjustments of the kidney in part induced by aldosterone.     

Thiorphan, an inhibitor of endopeptidase 24.11, potentiates the natriuretic activity of atrial natriuretic peptide

To evaluate the role of endopeptidase 24.11 in metabolism of atrial natriuretic peptide (ANP) in vivo, we examined the effect of thiorphan, an inhibitor of this enzyme, on plasma ANP concentrations and the cardiovascular and renal actions of ANP(99-126). Thiorphan alone produced a modest increase in urinary sodium excretion in anesthetized rats; however, urine flow, arterial pressure, and basal plasma ANP concentrations were unchanged. When administered during an infusion of ANP(99-126) (330 ng/kg/min i.v.), thiorphan increased the plasma concentration of ANP and enhanced the diuretic and natriuretic activity of this hormone. The effects on urine flow and urinary sodium excretion were most pronounced immediately after the inhibitor was administered and later diminished in magnitude. Thiorphan did not alter the depressor activity of exogenous ANP(99-126). These data suggest that endopeptidase 24.11 participates in metabolism of ANP(99-126) and that thiorphan potentiates the renal actions of this hormone by inhibiting its degradation.     

Furosemide interaction with the prostaglandin and kallikrein-kinin systems of the kidneys

Indomethacin (3 mg/kg, orally for 5 days) prevented the increase of blood flow in the internal zone of the renal cortical layer but failed to interfere with the increase of diuresis and sodium secretion produced by furosemide (2 mg/kg, subcutaneously) in anesthetized rats. Contrykal (6000 ED, subcutaneously) failed to alter the character of the hemodynamic changes in the renal cortex but enhanced the diuretic and natriuretic effects of furosemide. In unanesthetized rats indomethacin prevented creatinine urine excretion but didn't attenuate the diuretic and natriuretic effects of furosemide.     

Adenosine A1 antagonists. 2. Structure-activity relationships on diuretic activities and protective effects against acute renal failure.

Diuretic activities of xanthine or nonxanthine adenosine antagonists and their ameliorative effects against glycerol-induced acute renal failure in rats were investigated in order to clarify the physiological and pathological function of adenosine receptors in the kidney. Diuretic and natriuretic activities of a variety of adenosine antagonists clarified systematically for the first time that the blockade of A1 receptors is more important than that of A2 receptors in sodium and water excretion and support the hypothesis that endogenous intrarenal levels of adenosine directly enhance tubular sodium readsorption. Studies of structure-activity relationships of 8-substituted xanthines in the acute renal failure demonstrated that the activation of adenosine A1 receptor was an important factor in developing such a renal failure. A series of 8-(3-noradamantyl)xanthines exhibited the extremely potent diuretic and natriuretic activities (24; 2.5 micrograms/kg, po, the ratio of urinary excretion value in treated rats to urinary excretion value in control rats = 1.69, the ratio of Na+/K+ in treated rats to Na+/K+ in control rats = 1.76) and potent ameliorative effects against glycerol-induced acute renal failure (24; 10 micrograms/kg, ip, 55% inhibition). From our detailed studies of structure-activity relationships, we can speculate that some tissue differences of the adenosine A1 receptor might exist between kidney and brain and sites of action for adenosine antagonists could be different between two renal pharmacological assays. 1,3-Dipropyl-8-(3-noradamantyl)xanthine, KW-3902 (24), was chosen for further studies and is under development as a drug for treating the acute renal failure.     

Influence of new neurohypophyseal hormone analogs on sodium and water reabsorption in rat kidney

New analogs of some neurohypophyseal hormones (oxypressin, hydrin, glumitocin, vasotocin) have been synthesized. Experiments with injection of these peptides to rats showed that substitution of C-terminal glycinamide on beta-ethanolamine (glycinol) or ethylamine in 1-deamino-arginine vasotocin resulted in loss of natriuretic but not antidiuretic activity. Analogs of oxypressin and hydrin exhibited neither natriuretic activity nor ability to affect water reabsorption. Glumitocin analog induced renal sodium ion excretion and did not influence potassium ion excretion.     

Effects of direct renal arterial infusion of bufalin and ouabain in conscious sheep.

1. The presence of an endogenous digitalis-like factor (EDLF) in the plasma of both normal and volume expanded animals is well documented. In this study we have used ouabain and bufalin as pharmacological analogues to mimic the renal effects of EDLF and to investigate whether any interaction occurs between atrial natriuretic factor (ANF) and EDLF. 2. Conscious Na replete sheep with chronically indwelling catheters in the renal artery received renal arterial infusion of ouabain (1000 micrograms h-1) or bufalin (500 micrograms h-1) for 60 min. Renal arterial infusion of bufalin increased sodium excretion (UNaV) from 120 +/- 13 to 596 +/- 161 mumol min-1 after 45 min. Bufalin infusion did not alter glomerular filtration rate (GFR), effective renal plasma flow (ERPF), or lithium clearance. Ouabain infusion increased UNaV from 124 +/- 57 to 764 +/- 123 mumol min-1 in the first hour after infusion. 3. ANF infusion increased UNaV from 159 +/- 34 to 583 +/- 134 mumol min-1. When renal arterial bufalin infusion was followed by renal arterial ANF infusion (50 micrograms h-1) UNaV was increased from 155 +/- 31 to 795 +/- 96 mumol min-1. This increase in UNaV is approximately equal to the sum of the separate effects of bufalin and ANF. 4. The natriuretic effects of ouabain at pharmacological doses in sheep are confirmed by this study. The data presented here do not support the hypothesis that EDLF sensitizes the kidney to the natriuretic effects of ANF.     

Frusemide pretreatment blunts the inhibition of renal tubular sodium reabsorption by ANF in man

Summary The effects of atrial natriuretic factor (ANF) 15 pmol/kg/min on renal function were studied in 7 normal male volunteers during maximal water diuresis. Subjects were studied in neutral salt balance either before, or after, seven days treatment with 40 mg oral frusemide. The post-frusemide state was associated with activation of the renin-angiotensin system (RAAS) and generally higher noradrenaline levels; this state was also associated with sodium retention, mainly due to enhanced distal nephron reabsorption.Without diuretic pretreatment ANF produced a natriuresis and diuresis associated with inhibition of both proximal and distal nephron sodium reabsorption. In contrast, after frusemide pretreatment, ANF caused an increase in water excretion (urinary flow rate) but no change in sodium excretion. In the post-diuretic condition ANF did not affect renal tubular handling of sodium.The enhanced tubular reabsorption of sodium post-frusemide, and the failure of ANF to suppress this, could be due to activation of the RAAS and SNS.     

Atrial Natriuretic Peptide and Cyclic Guanosine-3′5′-monophosphate in Hypertensive Pregnancy and During Nifedipine Treatment

Atrial natriuretic peptide exhibits natriuretic. diuretic and vasodilatory properties. We compared plasma concentrations of atrial natriuretic peptide, cyclic guanosine-3′,5′-monophosphate (cGMP), electrolytes and urinary excretion of cGMP and electrolytes in hypertensive pregnant women to those in normotensive pregnant and normotensive non-pregnant women. Plasma atrial natriuretic peptide concentrations in hypertensive pregnant and normotensive nonpregnant women were equal, whereas in normotensive pregnant women it was lower (P<0.05), than in non-pregnant. Urinary cGMP excretion was higher in both normotensive and hypertensive pregnant than in non-pregnant women (P<0.01). whereas plasma cGMP levels were similar. A five-day nifedipine treatment (10 mg t.i.d.) had no effects on any of the variables. In hypertensive pregnancy, a reduction of systolic blood pressure by nifedipine correlated with the initial plasma atrial natriuretic peptide (P<0.05) and a decrease in diastolic blood pressure with the initial plasma cGMP concentration (P<0.05). The results of this small material suggest that plasma atrial natriuretic peptide concentration predicts the response to nifedipine in hypertensive pregnancy. However, the atrial natriuretic peptide-cGMP system does not seem to mediate the antihypertensive effect of nifedipine, while plasma atrial natriuretic peptide remained unaltered. Increased urinary cGMP excretion in both pregnant groups but lowered plasma atrial natriuretic peptide in normotensive pregnancy suggest other factors than circulating atrial natriuretic peptide to promote renal cGMP excretion during pregnancy.     

Renal effects of glucagon-like peptide in rats.

The present study examined the effects of recombinant glucagon-like peptide-1-(7-36)amide (rGLP-1) on renal hemodynamics and excretory function in innervated and denervated kidneys of anesthetized rats. Intravenous infusion of rGLP-1 at a dose of 1 microg x kg(-1) x min(-1) increased urine flow and Na(+) excretion 13-fold in the innervated kidney. The natriuretic and diuretic response to rGLP-1 was attenuated in the denervated kidney in which urine flow and Na(+) excretion only increased 3-fold. Fractional excretion of Li(+), an index of proximal tubular reabsorption, increased 219% in the innervated kidney but only 54% in the denervated kidney during infusion of rGLP-1. The diuretic and natriuretic response to rGLP-1 was associated with an increase in glomerular filtration rate (39%) in the innervated kidney, but it had no effect on glomerular filtration rate in the denervated kidney. These results indicate that the natriuretic and diuretic effects of rGLP-1 are due to inhibition of Na(+) reabsorption in the proximal tubule. It also increases glomerular filtration rate in kidneys with an intact renal innervation.     

ATTENUATED RENAL RESPONSE TO ATRIAL NATRIURETIC PEPTIDE INFUSION IN RATS WITH HEART FAILURE

1. The natriuretic and diuretic effects of three atrial natriuretic peptide (ANP) infusion rates were examined in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. 2. The natriuretic and diuretic effects of ANP were observed in controls and rats with infarction, but the effects were significantly attenuated in the latter. 3. Rats with chronic left heart failure were less sensitive to the renal effects of ANP compared with controls. 4. Impaired sodium and water excretion in chronic heart failure may be due partly to an attenuated renal response to ANP.