The interaction between atrial natriuretic peptides and angiotensin II in controlling sodium and water excretion in the rat.

1. The present study was designed to determine how the natriuretic and diuretic actions of atrial natriuretic peptides were modulated by circulating angiotensin II. 2. In sodium pentobarbitone-anaesthetized rats, administration of bolus doses of atriopeptin III (1000 ng kg-1) had no effect on blood pressure, renal blood flow, or glomerular filtration rate but caused reversible increases (all P less than 0.001) in urine flow, of 53.9 +/- 14.4 microliters kg-1 min-1, absolute sodium excretion, of 13.4 +/- 2.9 mumol kg-1 min-1 and fractional sodium excretion of 3.26 +/- 0.74%. Similar effects were seen following a second dose of the atriopeptin III. 3. Following blockade of the renin-angiotensin system with captopril (900 micrograms kg-1 h-1), control levels of blood pressure and haemodynamics were unchanged but there were significant (all P less than 0.001) increases in urine flow, from 39.96 +/- 5.05 to 88.70 +/- 8.41 microliters kg-1 min-1, absolute sodium excretion, from 8.35 +/- 1.08 to 21.62 +/- 1.62 mumol kg-1 min-1 and fractional sodium excretion, from 3.82 +/- 0.23 to 5.34 +/- 0.32%. Under these conditions, atriopeptin III-induced increases in urine flow (110.2 +/- 8.7 versus 43.9 +/- 6.2 microliters kg-1 min-1) absolute (24.0 +/- 1.8 versus 9.3 +/- 1.2 mumol kg-1 min-1) and fractional (5.16 +/- 0.24 versus 2.08 +/- 0.33%) sodium excretions were significantly (P less than 0.001) greater.(ABSTRACT TRUNCATED AT 250 WORDS)     

The action of atriopeptin III on renal function in two models of chronic renal failure in the rat.

1. The natriuretic and diuretic effects of atriopeptin III (125, 250 and 500 ng kg-1, i.v.) were studied in groups of rats anaesthetized with pentobarbitone which were either sham controls, unilaterally nephrectomized controls, adenine-fed or subtotal nephrectomy chronic renal failure models. 2. Atriopeptin III given at these doses to the sham control animals had no effect on blood pressure, renal blood flow or glomerular filtration rate but reversibly increased urine flow, between 46% to 54%, absolute sodium excretion, between 52% to 61%, and fractional sodium excretion, between 48% to 54% (all P values less than 0.05) from the lowest to the highest dose. The adenine-fed chronic renal failure group of rats had a reduced renal blood flow of between 30 and 75%, and glomerular filtration rate of approximately 20%, compared to the sham controls. Administration of atriopeptin at 125, 250 and 500 ng kg-1 to the animals with renal failure increased water and sodium excretion to the same degree as observed in the sham group of rats. 3. In the group of unilaterally nephrectomized rats, atriopeptin III, at 125, 250 and 500 ng kg-1 increased urine flow by 36%, 47% and 72%, respectively, absolute sodium excretion by 37%, 57% and 106%, respectively, and fractional sodium excretion by 46%, 45% and 102%, respectively. A similar pattern of responses was observed in the subtotal nephrectomy, chronic renal failure group in which filtration rate was approximately 4 times less than the controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal actions of atriopeptin III in genetic and renovascular models of hypertension in the rat

The renal actions of atriopeptin III were compared in sham control, spontaneous and Goldblatt (2-K 1-C) hypertensive rats. Atriopeptin III, administered at 125. 250 and 500 ng/kg or 1.0, 1.5 and 2.0 micrograms/kg, into sham control rats had no effect on blood pressure or renal haemodynamics but caused dose related increases in urine flow, absolute and fractional sodium excretions, from 44 to 248%. Similar excretory responses to this dose range of atriopeptin III were obtained in spontaneously hypertensive rats. Atriopeptin III given at 125, 250 and 500 ng/kg into 2-K 1-C Goldblatt hypertensive rats increased reversibly left kidney urine flow, absolute and fractional sodium excretion by between 55 and 74% which were similar responses to those of sham control left kidneys. By contrast, atriopeptin III had much smaller effects on water and sodium excretions of the right clipped kidneys. These results suggest that atrial natriuretic peptides may be useful in mobilising fluid in genetic hypertension but their usefulness may be restricted in renovascular forms of hypertension.     

The cardiovascular and renal functional responses to the 5-HT1A receptor agonist flesinoxan in two rat models of hypertension.

1. This study investigated the importance of renal sympathetic nerves in regulating sodium and water excretion from the kidneys of stroke prone spontaneously hypertensive and 2K1C Goldblatt hypertensive rats anaesthetized with chloralose/urethane (17.5/300 mg initially and supplemented at regular intervals), and prepared for measurement of renal function. 2. In stroke prone spontaneously hypertensive rats, flesinoxan, 30-1000 micrograms kg-1, i.v., caused graded reductions in blood pressure and heart rate of 74 +/- 5 mmHg and 63 +/- 9 beats min-1, respectively at the highest dose (P < 0.001). Renal blood flow did not change at any dose of drug while glomerular filtration rate fell by some 20% (P < 0.001) at the highest dose of drug, absolute and fractional sodium excretions, approximately doubled at 100 micrograms kg-1, and thereafter fell to below the baseline level at 1000 micrograms kg-1. 3. This pattern of excretory response was abolished following acute renal denervation when flesinoxan caused dose-related reductions in urine flow and sodium excretion, similar to that obtained by a mechanical reduction of renal perfusion pressure. 4. Flesinoxan administration (30-1000 micrograms kg-1, i.v.) into 2K1C Goldblatt hypertensive rats caused a maximum decrease in blood pressure and heart rate (both P < 0.001) of 34 +/- 3 mmHg and 20 +/- 6 beats min-1 and while renal blood flow and glomerular filtration rate were autoregulated, from 160 to 125 mmHg, there were dose-related decreases in urine volume and sodium excretion from the clipped and non-clipped kidneys of approximately 50-60% at the highest dose. 5. These findings suggest that in the stroke prone spontaneously hypertensive rat the renal nerves importantly control sodium and water reabsorption at the level of the tubules, whereas in 2K1C Goldblatt hypertensive rats, they play a minor role.     

A study in the rat of the renal actions of nitrendipine and diltiazem on the adrenergic regulation of calcium and sodium reabsorption.

In pentobarbitone-anaesthetized rats, intravenous administration of diltiazem at 5 micrograms kg-1 min-1 did not change blood pressure or renal blood flow but increased glomerular filtration rate by approximately 16%, urine flow by 85%, calcium excretion by 151% and absolute and fractional sodium excretions by 100% and 69%, respectively. A similar pattern of responses was obtained in renally denervated animals, except that calcium excretion did not change statistically. Diltiazem given at 20 micrograms kg-1 min-1 into renally innervated and denervated groups of animals depressed blood pressure between 15-17 mmHg but had no effect on renal haemodynamic or tubular function. Nitrendipine administered at 0.5 microgram kg-1 min-1 to renally innervated and denervated animals significantly depressed blood pressure in intact animals by 6 mmHg and in both groups did not change renal haemodynamics but caused similar increases in urine flow of between 79-98%, calcium excretion of between 87 and 125%, absolute sodium excretion of between 108 and 140% and fractional sodium excretion of between 83 and 170%. Infusion of nitrendipine at 1.0 micrograms kg-1 min-1 into intact or renally denervated animals decreased blood pressure by 18-20 mmHg and increased urine flow by 84-111%, calcium excretion by 85%, absolute sodium excretion by 81-137% and fractional sodium excretion by 52-102%. Stimulation of the renal nerves at low frequencies (0.8 to 1.5 Hz) caused minimal changes in renal haemodynamics but decreased urine flow by 27%, calcium excretion by 35%, absolute and fractional sodium excretions 32% and 36%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atriopeptin III improves renal functions in a ureter-obstructed rat kidney model

The renal hemodynamic and excretory effects of atriopeptin III were studied in normal rat kidneys and in kidneys made dysfunctional by the application and release of a 24 h unilateral ureteral obstruction (UO24h), which decreased baseline glomerular filtration rate (GFR) by 80%. Atriopeptin III (0.5 nmol/kg i.v.) decreased blood pressure (10-15%) for more than 30 min, and increased urine flow rate and sodium excretion in normal and diseased kidneys for ca. 15 min. An initial enhancement of renal blood flow (ca. 20%) was apparent for less than 5 min. Atriopeptin III (bolus injection) temporarily enhanced the GFR 2-3-fold in the diseased (UO24h) kidneys, whereas no changes of GFR were noted in control kidneys. When atriopeptin III was continuously infused at a rate of 0.1 nmol/kg per min, GFR in UO24h kidneys increased from 0.28 +/- 0.08 ml/g per min to a stable level of 0.82 +/- 0.10 ml/g per min. Again, GFR in the control kidneys remained unaffected (1.25 +/- 0.08 ml/g per min). The enhancement of GFR in the UO24h kidney was associated with large increases of urine flow rate and sodium excretion.     

Role of brain angiotensin II in the somatosensory induced antinatriuresis in the anaesthetized rat

1. The present study set out to explore the importance of angiotensin (Ang)II in the brain in allowing the somatosensory system to cause a reflex renal nerve-mediated reduction in renal sodium and water excretion. 2. In chloralose-urethane-anaesthetized rats receiving saline i.c.v. (2 microL + 1 microL/h), the administration of capsaicin (0.5 mg, s.c.) increased blood pressure by 14% (P < 0.001) and, while renal perfusion pressure was regulated at an unchanged level, neither renal blood flow (RBF) nor glomerular filtration rate was changed. However, urine flow and absolute and fractional sodium excretion was reduced between 29 and 38% (P<0.05-0.01). All variables had returned to control levels 30 min later. 3. The administration of captopril (40 microg + 20 microg/h i.c.v.) decreased blood pressure and sodium excretion by 6 and 17%, respectively (both P < 0.05). Under these conditions, capsaicin s.c. increased blood pressure by 9% (P<0.05); however, with renal perfusion pressure regulated at a constant level, neither renal haemodynamics nor water nor sodium excretion were changed. 4. A final group of animals received AngII (100 ng + 50 ng/h) concomitantly with captopril i.c.v., which increased blood pressure, RBF and urine flow, absolute and fractional sodium excretions by 8 (P < 0.05), 22 (P < 0.001 ) and 52-149% (P < 0.05-0.01), respectively. Capsaicin given s.c. under these conditions increased blood pressure by 6% (P < 0.05) and, while renal perfusion pressure was maintained at an unchanged value and renal haemodynamics remained constant, urine flow and absolute and fractional sodium excretion were reduced by 35-38% (all P < 0.05). 5. These data show that for the somatosensory system to induce a reflex increase in renal sympathetic nerve activity sufficient to cause an antinatriuresis and antidiuresis, the presence of AngII is necessary in the brain. How AngII exerts this facilitatory action within the central nervous system remains to be investigated.     

EFFECTS OF RENAL DENERVATION AND ATRIAL NATRIURETIC FACTOR ON TUBULAR REABSORPTION IN ANAESTHETIZED RATS

1. The effects of acute unilateral renal denervation were examined in 17 anaesthetized rats. Renal haemodynamic changes were monitored using standard clearance techniques. Lithium clearance was used to assess fractional proximal sodium and water reabsorption. 2. Denervation resulted in ipsilateral renal vasodilatation with marked natriuresis and diuresis, a small increase (15%, P less than 0.05) in glomerular filtration rate (GFR) and a consequent reduction in filtration fraction. Fractional lithium reabsorption decreased (67.3 +/- 2.9% to 54.5 +/- 4.0%, P less than 0.01) and absolute proximal reabsorption did not change, indicating impairment of proximal glomerulotubular balance (GTB). No similar changes in haemodynamic or transport parameters were observed in the contralateral, innervated kidney, although vascular resistance increased. 3. In 9 experiments following denervation of the left kidney, systemic low dose infusion (10 ng/min) of atrial natriuretic factor (ANF) resulted in a fall in mean arterial blood pressure from 116 +/- 3 mmHg to 107 +/- 3 mmHg (P less than 0.05). In the denervated kidney ANF increased urine flow rate and sodium excretion to rates above those established following denervation alone. However, in the right kidney, despite the increased filtered load (35%, P less than 0.01), the natriuretic and diuretic responses to ANF were abolished. 4. In the denervated kidney, ANF further reduced the fractional reabsorption of lithium from 53.6 +/- 2.3% to 45.6 +/- 3.8% (P less than 0.05). GFR increased by 32% (a total of 49% higher than during pretreatment) but absolute proximal reabsorption (APR) did not change. However, in the right, innervated kidney ANF infusion produced a 35% increase in GFR accompanied by a 53% rise in APR. 5. It is concluded that the natriuresis induced by unilateral denervation is due predominantly to impaired proximal GTB. The natriuretic action of ANF was associated with further impairment of proximal GTB, not dependent upon decreasing activity of renal sympathetic nerves, but was abolished when filtration fraction and renal sympathetic tone were elevated.     

RENAL DENERVATION POTENTIATES THE NATRIURETIC AND DIURETIC EFFECTS OF ATRIAL NATRIURETIC PEPTIDE IN ANAESTHETIZED RABBITS

1. The role of the renal nerves in modulating the action of atrial natriuretic peptide (ANP) in the kidney was studied by comparing the responses to ANP in innervated and surgically denervated kidneys in anaesthetized rabbits. 2. A low dose of ANP (0.05 μg/kg per min, i.v.) was used to minimize the confounding effects of systemic hypotension. 3. The natriuretic and diuretic responses to ANP were significantly greater in denervated kidneys than in kidneys with intact innervation. Sodium excretion from denervated kidneys rose by 7.49 ± 3.11 μmol/min in response to ANP (-55%, P<0.05) compared to 0.84 ± 0.59 μmol/min (-28%, NS) in innervated kidneys. Urine flow increased markedly in denervated kidneys by 73.2 ± 29.9 μmol/min (-60%, P<0.05) but not in innervated kidneys. 4. Fractional sodium excretion increased significantly in denervated kidneys in response to ANP (median 2.3% to median 3.0%, P<0.05). 5. Renal blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure were unchanged in response to ANP in either denervated or innervated kidneys. Pre-glomerular vascular resistance fell in denervated kidneys during ANP infusion. 6. The natriuresis and diuresis observed in the denervated kidneys, due to an increased fractional excretion of sodium without increases in GFR or glomerular capillary pressure, is consistent with effects of ANP on tubular reabsorption of sodium. 7. Thus, ANP produced a natriuresis and diuresis at a low dose in denervated but not in innervated kidneys. This indicates that reflex activation of renal nerves may antagonize the renal effects of ANP.     

A study of the action of amlodipine on adrenergically regulated sodium handling by the kidney in normotensive and hypertensive rats.

1. An investigation was undertaken to examine the effect of calcium channel blockade, induced by amlodipine, on the ability of the renal sympathetic nerves to cause an antidiuresis and anti-natriuresis in normotensive Sprague Dawley and spontaneously hypertensive rats anaesthetized with pentobarbitone. 2. Low frequency renal nerve stimulation in normotensive rats, which did not change renal blood flow, caused a 15% reduction in glomerular filtration rate and was associated with falls in urine flow of 37%, absolute sodium excretion of 47%, and fractional sodium excretion of 38%. The magnitude of these renal excretory changes was unaffected by prior administration of amlodipine at either 200 micrograms kg-1 plus 50 micrograms kg-1 h-1 or 400 micrograms kg-1 plus 100 micrograms kg-1 h-1. Amlodipine given in the higher dose, decreased basal levels of blood pressure and increased basal urine flow and sodium excretion. 3. In spontaneously hypertensive rats, renal nerve stimulation minimally affected renal haemodynamics but decreased urine flow, absolute and fractional sodium excretion by 29%, 31% and 24%, respectively. 4. Similar renal nerve stimulation in spontaneously hypertensive rats given amlodipine at 200 micrograms kg-1 plus 50 micrograms kg-1 h-1 or 400 micrograms kg-1 plus 100 micrograms kg-1 h-1 caused minimal changes in renal haemodynamics and in the excretion of water and sodium. The higher dose of drug resulted in decreased blood pressure and increased basal rates of urine flow and sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

BLUNTED NATRIURETIC RESPONSE TO ENDOGENOUS ATRIAL NATRIURETIC PEPTIDE DURING RAPID CARDIAC PACING IN ANAESTHETIZED DOGS

1. We investigated whether diuresis and natriuresis induced by endogenous atrial natriuretic peptide (ANP) were blunted during rapid cardiac pacing. 2. Changes in plasma ANP, renal function and haemody-namics during rapid cardiac pacing were studied in anaesthetized closed-chest dogs. Dogs were paced via the right ventricle at a rate of 200 b.p.m. (moderate pacing) or 250 b.p.m. (severe pacing) for 180 min. 3. The maximal increases in plasma ANP and urinary excretion of cGMP during severe pacing were four- and three-fold higher, respectively, than those during moderate pacing. Despite the higher concentration of plasma ANP, the maximal increases in urine volume, urinary excretion of sodium and fractional excretion of sodium during severe pacing were similar to those during moderate pacing. Mean arterial pressure and renal vascular resistance were decreased only by severe pacing. The increase in total peripheral resistance during severe pacing was significantly smaller than that during moderate pacing. However, the glomerular filtration rate was kept at basal levels by both moderate and severe pacing. 4. These results suggest that there are certain mechanisms that counteract renal tubular sodium reabsorption induced by endogenous ANP under conditions of severe pacing. The suppression occurs at tubular sites but not at glomerular sites. One of the possibilities for the suppression is the decrease in renal perfusion pressure accompanied by decreases in peritubular capillary hydrostatic pressure.     

Interactive effects of indomethacin, angiotensin II and frusemide on renal haemodynamics and natriuresis in man.

The responses of renal haemodynamic and natriuretic indices to the oral prostaglandin synthetase inhibitor indomethacin (200 mg), to infused angiotensin II (1 ng min-1 kg-1) and to the combination of the two were studies in placebo-controlled fashion in eight normal male subjects both prior to and following administration of intravenous frusemide (20 mg). As compared with placebo, angiotensin II infusion alone caused significant reductions in absolute rate of sodium excretion, fractional sodium excretion, urine flow rate and effective renal plasma flow (all P < 0.001 vs placebo) but had no effect on glomerular filtration rate. The only change observed in these parameters with indomethacin alone was a small but significant reduction in urine flow rate (P < 0.005 vs placebo). As compared with the effects of angiotensin II alone, indomethacin pre-treatment followed by angiotensin II infusion led to much greater falls in absolute rate of sodium excretion, fractional sodium excretion, urine flow rate and effective renal plasma flow (all P < 0.0001 vs placebo) associated with a significant reduction in glomerular filtration rate (P < 0.0001) not observed with angiotensin II alone. Frusemide administration at the midpoint of each study limb resulted in each case in a prompt 15 to 20 fold increase in natriuresis. The renal haemodynamic and natriuretic effects of angiotensin II, indomethacin and their combination were not qualitatively different from those observed in the pre-frusemide phase. Our findings provide a clear demonstration in man of the important homeostatic role of renal prostaglandins in preserving renal function, particularly glomerular filtration, under conditions of elevated circulating angiotensin II.     

Differential renal responses to atrial natriuretic peptide in two-kidney, one clip goldblatt hypertensive rats

Bilateral renal clearance experiments were performed to examine the effects of synthetic rat atrial natriuretic peptide (ANP, atriopeptin II) on the arterial blood pressure (BP) and individual kidney function in anesthetized 2-kidney, 1 clip Goldblatt hypertensive rats (n = 14) and normotensive rats (n = 15). Bolus administration of graded doses of ANP from 2.5 to 10 micrograms/kg produced dose-related reductions in BP in hypertensive and normotensive rats. Despite profound reductions in BP, there were significant increases in glomerular filtration rate, urine flow, absolute and fractional excretion rates of sodium and potassium, osmolar clearance, and free water clearance in the nonclipped kidney, whereas no significant changes in these renal indices occurred in the clipped kidney. The enhanced renal responses were dose-dependent. The normal kidney responded to ANP with similar magnitude. When ANP was infused intravenously (0.3 microgram/kg.min i.v.) during 2 h, BP maximally reduced by 36 +/- 2 mm Hg (24 +/- 1%) in the hypertensive group and by 27 +/- 2 mm Hg (22 +/- 2%) in the control group. Again, there were distinct renal responses between the two kidneys of hypertensive rats. These results indicate that ANP effectively reduces BP and preferentially increases the excretory function of the nonclipped kidney without compromising the function of the clipped kidney in this hypertensive model.     

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.     

A comparison of the ability of two angiotensin II receptor blocking drugs, 1-Sar, 8-Ala angiotensin II and 1-Sar, 8-Ile angiotensin II, to modify the regulation of glomerular filtration rate in the cat

1 Modest stimulation of the renal nerves in the anaesthetized unilaterally nephrectomized cat resulted in a 15% fall in renal blood flow, no change in glomerular filtration rate and significant falls in both the absolute and fractional rates of sodium excretion.

2 The haemodynamic responses to nerve stimulation were not modified by angiotensin II blockade with 1-Sar, 8-Ala angiotensin II although the fall in absolute, but not fractional sodium excretion was significantly larger. In contrast, stimulation of renal nerves following administration of 1-Sar, 8-Ileangiotensin II caused a significant fall in glomerular filtration rate. The reductions in both absolute and fractional sodium were of the same magnitude as in the absence of drug.

3 Both renal blood flow and glomerular filtration rate were autoregulated during the reduction of renal perfusion pressure and this was associated with reductions in both absolute and fractional sodium excretions.

4 In the presence of 1-Sar, 8-Ala angiotensin II, the haemodynamic and sodium excretory responses to reductions in renal perfusion pressure were not significantly different from those recorded in the absence of drug. However, following administration of 1-Sar, 8-Ile angiotensin II, renal blood flow but not glomerular filtration rate, was autoregulated during reduction in renal perfusion pressure. The falls in absolute and fractional sodium excretions caused by this manoeuvre were of similar magnitude to those obtained in the absence of drug.

5 The results obtained using the 1-Sar, 8-Ile angiotensin II are consistent with angiotensin II having an important intra-renal site of action to regulate glomerular filtration rate, possibly via an action at the efferent arteriole. Administration of 1-Sar, 8-Ala angiotensin II was without effect on the regulation of renal haemodynamics which it is suggested reflects a limitation in the use of this particular compound as an intrarenal angiotensin II antagonist.

     

Influence of captopril on renal hemodynamics and segmental tubular reabsorption of sodium in humans

Acute angiotensin-converting enzyme inhibitors (ACEIs) have been found to induce natriuresis in humans as well as in experimental animals. However, the tubular sites involved have not been precisely evaluated in humans. Using both free-water and lithium clearance, the latter as a marker of proximal tubular reabsorption, we measured segmental tubular movement of sodium before and after acute captopril administration in eight healthy normotensive volunteers on normal sodium diet. Captopril decreased slightly but significantly glomerular filtration rate (GFR), filtration fraction, and mean arterial pressure (MAP), whereas renal plasma flow (RPF) was unchanged. Captopril acutely increased excretion rate and fractional excretion of sodium. When assessed by lithium clearance, both absolute and fractional proximal reabsorption of sodium and fractional distal reabsorption of sodium were found to be decreased by captopril. When assessed by free-water clearance, both fractional proximal and distal reabsorption of sodium were found to be decreased by captopril but only the decrease in fractional proximal reabsorption was significant. These results indicate that captopril-induced natriuretic effect is due to decreased sodium reabsorption in both proximal and distal sites of the nephron. Shifts in segmental tubular sodium reabsorption obtained from either free-water or lithium clearance are directionally similar but quantitatively different. Results obtained from lithium clearance indicate that the rate of fluid delivery to the diluting segment is at least twice as great as that estimated from free-water calculations. Lithium clearance techniques therefore appear to be more sensitive in detecting subtle changes in segmental tubular reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)     

An orally active adenosine A1 receptor antagonist,FK838, increases renal excretion and maintains glomerular filtration rate in furosemide-resistant rats

1. Loop and thiazide diuretics are common therapeutic agents for the treatment of sodium retention and oedema. However, resistance to diuretics and decreases in renal function can develop during diuretic therapy. Adenosine causes renal vasoconstriction, sodium reabsorption, and participates in the tubuloglomerular feedback mechanism for the regulation of glomerular filtration rate. 2. We tested the hypothesis that the selective adenosine A(1) receptor antagonist FK838 is orally active and causes diuresis and natriuresis, but maintains glomerular filtration rate in normal rats or in rats with furosemide resistance. 3. In normal male Sprague - Dawley rats, FK838 dose-dependently increased urine flow and sodium and chloride excretion while sparing potassium. In combination with furosemide, FK838 enhanced the diuretic and natriuretic actions of furosemide to the same extent as hydrochlorothiazide and did not increase the potassium loss in normal rats. In furosemide-resistant rats, FK838 increased urine flow and electrolyte excretion to a greater extent than hydrochlorothiazide. In addition, hydrochlorothiazide significantly decreased glomerular filtration rate, whereas FK838 maintained glomerular filtration rate in furosemide-resistant rats. 4. This study shows that the adenosine A(1) receptor antagonist FK838 is orally active and causes potent diuresis and natriuresis and maintains glomerular filtration rate in normal or furosemide-resistant rats. Adenosine A(1) receptor antagonists may be novel therapeutics for the treatment of oedema in normal or otherwise diuretic-resistant patients.     

Effects of rilmenidine on stress-induced peak blood pressure and renal function.

Rilmenidine is an imidazoline I1-receptor agonist that centrally acts by reducing the sympathetic tone. There is strong experimental evidence that natriuresis could be evoked by proximal tubular I1-receptors that have also been isolated in human kidneys. However, in humans, the natriuretic effects of proximal tubular I1-receptors have never been demonstrated. Because stress tests elicited a sympathetically mediated increase in blood pressure and in sodium reabsorption, this study examined whether a short-term infusion of rilmenidine (1 mg) may interfere with stress-induced cardiovascular response and renal sodium handling in normotensive men, in a double-blind, crossover, placebo-controlled study. The stress test used is an efficient and reproducible computerized version of the Stroop's stress test. During the experimental sessions, both basal and stress renal functional parameters were determined: glomerular filtration rate, renal plasma flow, filtration fraction, sodium excretion, and segmental sodium tubular reabsorption (lithium clearance). During the placebo phase, stress induced a significant increase in systolic blood pressure (SBP; 22.2+/-10.1 mm Hg) and diastolic blood pressure (DBP; 11.0+/-5.0 mm Hg). During stress, glomerular filtration rate and renal plasma flow tended to decrease, resulting in a nonsignificant increase in filtration fraction. Despite the increase in BP, stress induced a significant decrease in sodium excretion that was due mainly to a nonsignificant increase in sodium reabsorption in the proximal parts of the tubules. Rilmenidine significantly reduced rest and stress BP, but the cardiovascular reactivity to stress was not altered. The treatment slightly decreased basal glomerular filtration rate and increased renal plasma flow, so that the filtration fraction significantly decreased. The treatment-related decrease in BP was associated with a significant increase in basal sodium reabsorption. Stress-induced modifications in renal function and sodium handling were not altered by the treatment. In conclusion, rilmenidine reduced rest BP and preserved stress-induced reactivity in BP and heart rate. Renal effects of rilmenidine are characterized by a decrease in glomerular filtration rate and in filtration fraction and an increase in sodium reabsorption. The study failed to demonstrate any effect of rilmenidine on stress-induced increase in sodium reabsorption.     

An investigation into the alpha-adrenoceptor mediating renal nerve-induced calcium reabsorption by the rat kidney.

An investigation was undertaken in pentobarbitone-anaesthetized rats to determine the sub-type of alpha-adrenoceptor responsible for the renal nerve-induced increases in the reabsorption of calcium and sodium by the tubules of the kidney. Stimulation of the renal nerves at low frequencies (0.8-1.5 Hz) did not change either renal blood flow or glomerular filtration rate but significantly reduced urine flow by 32%, calcium excretion by 36% and absolute and fractional sodium excretions by 36% and 22%, respectively. In the presence of the selective alpha 1-adrenoceptor antagonist prazosin, renal nerve stimulation (2-3 Hz) caused a significant reduction in renal blood flow of 7% but did not change either glomerular filtration rate, urine flow, calcium excretion or absolute and fractional sodium excretions. During administration of the selective alpha 1-adrenoceptor antagonist, idazoxan, renal nerve stimulation (1.0-1.5 Hz) significantly reduced renal blood flow by 4% and glomerular filtration rate by 7%; at the same time there were significant falls in urine flow of 43%, calcium excretion of 43% and absolute and fractional sodium excretions of 41% and 37%, respectively. These results show that low frequency renal nerve stimulation causes an anticalciuresis, independent of renal haemodynamics, which represents an increase in tubular reabsorption of calcium. This effect was blocked by prazosin but not idazoxan which is consistent with the mediation of alpha 1-adrenoceptors. The neurally-induced antinatriuresis also appeared to be dependent on the activation of alpha 1-adrenoceptors.     

Effects of the selective neutral endopeptidase inhibitor, retrothiorphan, on renal function and blood pressure in conscious normotensive Wistar and hypertensive DOCA-salt rats.

Atrial natriuretic peptide (ANP) is degraded by neutral endopeptidase (NEP) mainly in the proximal tubule of the kidneys. We studied the effects of retrothiorphan, a potent and highly specific NEP inhibitor on renal function and blood pressure (BP). A 25-mg/kg bolus injection (group bolus), or bolus injection plus infusion 25 mg/kg + 25 mg/kg/h (group infusion), was given to conscious normotensive Wistar and hypertensive DOCA-salt rats. Bolus and infusion produced increases in diuresis (110 +/- 15 vs. 103 +/- 15 vs. 42 +/- 9 microliters/min) and natriuresis (10.6 +/- 3.0 vs. 7.0 +/- 1.0 vs. 5.4 +/- 1.0 mumol/min) in normotensive rats, with a maximum change at 30 min. Change in kaliuresis was not significant. These renal effects were associated with nonsignificant increases in urinary cyclic GMP and ANP. Arterial pressure and heart rate (HR) were not affected. Bolus or infusion of retrothiorphan also induced increases in diuresis (92 +/- 16 vs. 124 +/- 13 vs. 38 +/- 6 microliters/min) and natriuresis (10.3 +/- 2.0 vs. 12.5 +/- 1.0 vs. 5.0 +/- 1.0 mumol/min) in DOCA-salt hypertensive rats, with a maximum change at 30 min. The changes in diuresis and natriuresis induced by retrothiorphan were correlated with a significant increase in urinary cyclic GMP excretion (r = 0.89, p < 0.001 and r = 0.91, p < 0.001). Urinary ANP did not change in controls but significantly increased in the treated rats; urinary immunoreactive bradykinin (BK) also tended to increase. Plasma ANP and hematocrit did not change after retrothiorphan, but plasma cyclic GMP increased significantly after infusion. Only infusion caused a decrease in arterial pressure in DOCA-salt rats (-20 mm Hg at 120 min). Renal clearance studies in DOCA-salt rats showed that retrothiorphan has a transient effect on renal hemodynamics, with increases in glomerular filtration and renal blood flow (RBF) and a decrease in renal vascular resistance (RVR). Its renal action was also tubular, with an increase in fractional sodium excretion. We also compared the effects of retrothiorphan in normotensive Brown-Norway kininogen-deficient rats (BN-Kat) and DOCA-salt hypertensive kininogen-deficient rats. The NEP inhibitor induced increases in diuresis and natriuresis in both groups, with increased urinary cyclic GMP. Urinary immunoreactive BK did not change significantly in normotensive or DOCA-salt hypertensive kininogen-deficient rats.(ABSTRACT TRUNCATED AT 400 WORDS)