Endogenous adenosine restrains renin release during sodium restriction

The purpose of this study was to determine the role of endogenous adenosine in controlling renin release during both a normal and low sodium diet. To probe the involvement of endogenous adenosine in the control of renin release, we examined the effects of an adenosine receptor antagonist, 1,3-dipropyl-8-(p-sulfophenyl)xanthine (DPSPX), on renin release in rats fed either a normal or low sodium diet. All studies were conducted in the in situ autoperfused kidney. DPSPX significantly increased arterial and renal venous levels of renin in both groups of animals; however, statistical analysis of the data (2-factor analysis of variance) indicated that DPSPX increased aortic and renal venous levels of renin more in rats fed a low sodium diet compared to rats fed a normal sodium diet. Also, whereas DPSPX did not significantly increase the venoarterial difference of renin activity across the kidney or the calculated net secretion rate of renin in rats on a normal sodium diet, both of these indices of renin release were significantly increased by DPSPX in rats on a low sodium diet. The effects of DPSPX on renin release could not be explained by changes in renal hemodynamics or excretory function. Additional experiments with rats on a low sodium diet that were treated with propranolol demonstrated that the effects of DPSPX on renin release were independent of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Natriuresis and renin release by the denervated dog kidney during furosemide administration.

Renal excretion of sodium and water, renal venous plasma renin activity and renin secretion rate were measured during the administration of furosemide (5 mg/kg) to 10 anesthetized dogs, previously subjected to unilateral splanchnicotomy ("renal denervation"). Denervation diuresis and natriuresis, observed during control periods, did not occur when the diuretic was given and there were no significant changes in glomerular filtration rate or renal plasma flow in either the intact or denervated kidneys. Despite the abolition of denervation natriuresis with furosemide, plasma renin activity and renin secretion rate were depressed by splanchnicotomy. Thus, changes in the sodium load to the macula densa do not seem to play a decisive role in decreasing renin release following renal denervation.     

Natriuresis and Renin Release by the Denervated Dog Kidney During Furosemide Administration

Renal excretion of sodium and water, renal venous plasma renin activity and renin secretion rate were measured during the administration of furosemide (5 mg/kg) to 10 anaesthetized dogs, previously subjected to unilateral splanchnicotomy (“renal denervation”). Denervation diuresis and natriuresis, observed during control periods, did not occur when the diuretic was given and there were no significant changes in glomerular filtration rate or renal plasma flow in either the intact or denervated kidneys. Despite the abolition of denervation natriuresis with furosemide, plasma renin activity and renin secretion rate were depressed by splanchnicotomy. Thus, changes in the sodium load to the macula densa do not seem to play a decisive role in decreasing renin release following renal denervation.     

Possible role of adenosine in the macula densa mechanism of renin release in rabbits.

This study was designed to examine: (a) the effects of adenosine and its analogues on renin release in the absence of tubules, glomeruli, and macula densa, and (b) whether adenosine may be involved in a macula densa-mediated renin release mechanism. Rabbit afferent arterioles (Af) alone and afferent arterioles with macula densa attached (Af + MD) were microdissected and incubated for two consecutive 30-min periods. Hourly renin release rate from a single arteriole (or an arteriole with macula densa) was calculated and expressed as ng AI X h-1 X Af-1 (or Af + MD-1)/h (where AI is angiotensin I). Basal renin release rate from Af was 0.69 +/- 0.09 ng AI X h-1 X Af-1/h (means +/- SEM, n = 16) and remained stable for 60 min. Basal renin release rate from Af + MD was 0.20 +/- 0.04 ng AI X h-1 X Af + MD-1/h (n = 6), which was significantly lower (P less than 0.0025) than that from Af. When adenosine (0.1 microM) was added to Af, renin release decreased from 0.72 +/- 0.16 to 0.24 +/- 0.04 ng AI X h-1 X Af-1/h (P less than 0.025; n = 9). However, when adenosine was added to Af + MD, no significant change in renin release was observed. N6-cyclohexyl adenosine (an A1 adenosine receptor agonist) at 0.1 microM decreased renin release from Af from 0.69 +/- 0.14 to 0.39 +/- 0.12 ng AI X h-1 X Af-1/h (n = 5, P less than 0.05). However, 5'-N-ethylcarboxamide adenosine (an A2 adenosine receptor agonist) either at 0.1 microM or at 10 microM had no effect. Theophylline, at a concentration (10 microM) that does not block phosphodiesterase but does block adenosine receptors, increased renin release from Af + MD from 0.21 +/- 0.03 to 0.46 +/- 0.08 ng AI X h-1 X Af + MD-1/h (P less than 0.05; n = 8). The results are consistent with the hypotheses that adenosine decreases renin release via the activation of A1 adenosine receptors, and that adenosine may be an inhibitory signal from the macula densa to juxtaglomerular cells.     

The extracellular cAMP-adenosine pathway significantly contributes to the in vivo production of adenosine

The extracellular cAMP-adenosine pathway is the cellular egress of cAMP followed by extracellular conversion of cAMP to adenosine by the sequential actions of ecto-phosphodiesterase and ecto-5'-nucleotidase. Although detailed studies in isolated organs, tissues, and cells provide evidence for an extracellular cAMP-adenosine pathway, whether this mechanism contributes significantly to adenosine production in vivo is unclear. 1,3-Dipropyl-8-p-sulfophenylxanthine is restricted to the extracellular compartment due to a negative charge at physiological pH and, at high concentrations (> or =0.1 mM), blocks ecto-phosphodiesterase. Here, we show that administration of 1,3-dipropyl-8-p-sulfophenylxanthine at a dose that provided concentrations in plasma and urine of approximately 0.3 and 6 mM, respectively, inhibited urinary adenosine excretion. In Sprague-Dawley rats i.v., 1,3-dipropyl-8-p-sulfophenylxanthine (10 mg + 0.15 mg/min) significantly decreased by 48 and 39% the urinary excretion of adenosine (from 3.57 +/- 0.38 to 1.87 +/- 0.14 nmol/30 min; p = 0.0003) and the ratio of urinary adenosine to cAMP (from 0.93 +/- 0.08 to 0.57 +/- 0.06; p = 0.0044), respectively, without altering blood pressure, renal blood flow, or glomerular filtration rate. Although 1,3-dipropyl-8-p-sulfophenylxanthine transiently increased urine volume and sodium excretion, these effects subsided, yet adenosine excretion remained reduced. Thus, changes in systemic and renal hemodynamics and excretory function could not account for the effects of 1,3-dipropyl-8-p-sulfophenylxanthine on adenosine excretion. Additional experiments showed that 1,3-dipropyl-8-p-sulfophenylxanthine, as in Sprague-Dawley rats, significantly attenuated adenosine excretion and the ratio of urinary adenosine to cAMP in both Wistar-Kyoto rats and spontaneously hypertensive rats. We conclude that the extracellular cAMP-adenosine pathway significantly contributes to the in vivo production of adenosine.     

Diuretic and non-diuretic actions of furosemide: effects of probenecid.

Furosemide causes not only natriuresis, but a rapid (5-10 min) increase in plasma renin activity. The latter has been attributed both to the release of eicosanoids from renal blood vessels and to changes in sodium delivery to the macula densa. Drugs like indomethacin abolish the renin increment and could potentially affect both mechanisms: they inhibit cyclooxygenase but could also compete with furosemide for transport into the tubular lumen, reducing furosemide concentration at its site of action. We studied the effects of probenecid, a weak acid without cyclooxygenase activity, on the responses to furosemide in 20 healthy young men. Each received placebo and low (1000 mg/d) or high (2000 mg/d) doses of probenecid for one week in double-blind, randomized trials, crossover fashion. One hour after the last dose, all participants were given furosemide 0.5 mg/kg intravenously. Probenecid reduced serum uric acid in a dose-dependent manner but did not change platelet thromboxane B2 production. Similarly, there was no change in urine excretion rates of thromboxane B2 or 6ketoprostaglandin F1 alpha, or in baseline or stimulated plasma renin activity. The total natriuresis in 4 h was also unchanged. By contrast, the sodium excretion rate in the first 30 min was reduced after both probenecid regimens while that of later periods was increased. These findings are consistent with the proposed effect of probenecid as reducing furosemide secretion in the proximal tubule, which reduces its concentration at the lumenal surface of the thick ascending limb of Henle's loop, but also prevents its excretion from the body.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of adenosine1-receptor blockade on renin release from rabbit isolated perfused juxtaglomerular apparatus.

Adenosine has been proposed to act within the juxtaglomerular apparatus (JGA) as a mediator of the inhibition of renin secretion produced by a high NaCl concentration at the macula densa. To test this hypothesis, we studied the effects of the adenosine1 (A1)-receptor blocker 8-cyclopentyl-1,3-dipropylxanthine (CPX) on renin release from single isolated rabbit JGAs with macula densa perfused. The A1-receptor agonist, N6-cyclohexyladenosine (CHA), applied in the bathing solution at 10(-7) M, was found to inhibit renin secretion, an effect that was completely blocked by adding CPX (10(-5) M) to the bath. Applied to the lumen, 10(-5) M CPX produced a modest stimulation of renin secretion rates suppressed by a high NaCl concentration at the macula densa (P less than 0.05). The effect of changing luminal NaCl concentration on renin secretion rate was examined in the presence of CPX (10(-7) and 10(-5) M) in the bathing solution and in vehicle control experiments. The control response to increasing luminal NaCl concentration was a marked suppression of renin secretion, that was maintained as long as luminal NaCl concentration was high and was promptly reversible when concentration was lowered. CPX did not alter renin release when luminal NaCl was low, but diminished the reduction caused by high NaCl (P less than 0.01). It is concluded that A1-receptors are located within the JGA, and that A1-receptor activation inhibits renin release. A high NaCl concentration at the macula densa appears to influence A1-receptor activation, but a low NaCl concentration does not. The findings support participation of adenosine in macula densa control of renin secretion.     

Effects of indomethacin on furosemide induced renal prostaglandin synthesis and action in man

We had previously shown that the early increment in plasma renin activity occurring within ten minutes of intravenous furosemide is accompanied by an increase in urine 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) the hydrolysis product of prostacyclin. Renal prostacyclin and thromboxane A2 synthesis are apparently limited to the cortex. To assess whether indomethacin would inhibit renal cortical eicosanoid synthesis and whether such reduction correlated with reduced early renin release, we assessed responses to intravenous furosemide (0.5 mg/kg) before and after indomethacin (150 mg/day for seven days) in ten normal male volunteers. Indomethacin did not change blood pressure but increased weight slightly (79.7 +/- 2.5 kg to 80.4 +/- 2.4 kg, p less than 0.05). Serum thromboxane B2 (TXB2), a measure of platelet thromboxane A2 production, was profoundly depressed (142 +/- 29 ng/ml to 4.8 +/- 1.6 ng/ml, p less than 0.001). Neither diuresis nor natriuresis were changed by indomethacin but potassium excretion was reduced (33 +/- 4 mmol/4 hr to 27 +/- 3 mmol/4 hr, p less than 0.05). Basal as well as furosemide stimulated plasma renin activity (at 10, 30 and 240 minutes) was reduced, as well as the transient increase in excretion rates of 6-keto-PGF1 alpha and TXB2. We conclude that the reduction in furosemide stimulated renin release by indomethacin is due to renal cyclo-oxygenase inhibition which is reflected in decreased excretion rates of hydrolysis products of renal eicosanoids.     

Role of Renal Prostaglandins in Sympathetically Mediated Renin Release in the Rat

Renal prostaglandins (PG) appear to mediate renin release due to stimulation of the intrarenal baroreceptor, but not that due to activation of the macula densa. However, as the role of PG in sympathetically mediated renin release remains unclear, a possible interrelationship between these factors was examined in conscious rats. Hydralazine increased the serum renin levels from 3.1+/-0.8 to 16.7+/-3.0 ng/ml per h at a dose of 1 mg/kg. Indomethacin (5 mg/kg) suppressed urinary PGE(2) and PGF(2alpha) excretion by 89 and 74%, respectively, arachidonate hypotension by 82%, and inhibited the elevated renin levels from hydralazine by 100% without altering the hypotensive effect of the drug. Another PG synthetase inhibitor, meclofenamate, was also effective in attenuating hydralazine-induced renin release, urinary PGE(2) and PGF(2alpha) excretion, and arachidonate hypotension. Isoproterenol, a nonselective beta-adrenergic agonist, increased heart rate, lowered blood pressure, and also stimulated the release of renin when administered intraperitoneally. However, intrarenal infusion of the drug only resulted in increased renin release. Indomethacin inhibited isoproterenol-induced renin release by 66 and 67%, respectively, without altering the hemodynamic effects associated with the intraperitoneal administration of the drug. The selective beta(1) agonist, H133/22, increased the release of renin and heart rate in a dose-related manner without altering blood pressure. H133/22-induced renin release was inhibited by 80% by indomethacin pretreatment. Finally, intrarenal infusions of dibutyryl cyclic AMP (3 mg/kg per min) increased the serum activity from 4.1+/-0.2 to 20.4+/-3.9 ng/ml per h without altering mean arterial pressure. Indomethacin inhibited this renin response to dibutyryl cyclic AMP by 96%. Thus, renal PG appear to be important mediators of sympathetically stimulated renin release acting as a site distal to the beta-adrenergic receptor.     

Responses to furosemide in normotensive and hypertensive subjects

As well as inducing natriuresis, intravenous furosemide increases renal prostanoid synthesis and induces renal vasodilation and a rapid rise in plasma renin activity (PRA). Patients with hypertension have abnormalities in renin release and renal vascular resistance that might be due to abnormalities in renal prostaglandin synthesis. We investigated responses to furosemide and placebo in normotensive (n = 13) and hypertensive (n = 14) subjects. There were no clear differences in PRA, sodium and water excretion, or excretion of prostanoid hydrolysis products (6-ketoprostaglandin F1 alpha and thromboxane B2) after placebo. In the hours after furosemide, 0.5 mg/kg-1, hypertensive subjects excreted more sodium, 189 +/- 13 mEq (mean +/- SE) and 154 +/- 8, and water, 1990 +/- 116 ml and 1614 +/- 109, than normotensive subjects. Excretion rates of creatinine and 6-ketoprostaglandin F1 alpha were much the same. Thromboxane B2 excretion rose in hypertensive subjects and was greater than in normotensive subjects (117.6 +/- 17.2 and 58.3 +/- 8.2 ng). With timed urine samples the excretion rate of 6-ketoprostaglandin F1 alpha and thromboxane B2 increased transiently for 30 min or less, whereas sodium and water excretion rates remained elevated for 4 hr. PRA rose in both groups 10 min after injection but reached a higher level in normotensive subjects. These differences in excretion of prostanoid hydrolysis products likely reflect renal synthesis of prostanoids and may be responsible for functional abnormalities of the kidney of hypertensive patients.     

Effects of physiological increments in renal arterial plasma osmolality on renin secretion rate

The present study was performed in anesthetized dogs to examine the effects of physiological increments in renal arterial plasma osmolality on basal renin secretion rate and on the response of renin secretion rate to RNS. Three concentrations of hypertonic NaCl were infused into the renal artery (i.r.a.) at 0.38 ml/min for 3 min; i.r.a. Hypertonic NaCl at 0.45M, 0.9M, and 1.8M increased the renal arterial plasma osmolality by 6 +/- 2, 8 +/- 2, and 28 +/- 9 mOsm/kg H2O, respectively. NaCl, 0.45M, did not affect renal function, whereas both 0.9M and 1.8M NaCl increased renal blood flow and urinary sodium excretion; neither 0.45M, 0.9M, nor 1.8M NaCl affected renin secretion rate. RNS was applied at two different frequencies: LFRNS and HFRNS. LFRNS did not affect renal blood flow, whereas HFRNS reduced renal blood flow by 50%. Both LFRNS and HFRNS increased renin secretion rate significantly. An i.r.a. infusion of 0.9M NaCl increased urinary sodium excretion and reduced the renin secretion rate response to LFRNS (-52% +/- 15, p less than 0.02) and HFRNS (-25% +/- 8, p less than 0.01). These findings demonstrate that increases in renal arterial plasma osmolality within the physiological range increase renal blood flow but do not affect renal secretion rate. The renal secretion rate response to RNS is attenuated by increased renal arterial plasma osmolality, an effect consistent with increased sodium chloride delivery to the distal tubular macula densa receptor.     

Caffeine potentiates vasodilator-induced renin release

Previous studies strongly suggest that adenosine receptors on juxtaglomerular cells function to restrain the secretion of renin induced by a variety of stimuli. The clinical significance of this is that caffeine, a widely consumed adenosine receptor antagonist, could augment renin release responses to diseases such as renovascular hypertension, liver cirrhosis and heart failure and to therapeutic maneuvers such as salt restriction, diuretics and vasodilators. Caffeine may be particularly troublesome in this regard because this methylxanthine has central nervous system effects and intracellular actions that also might contribute to the overall ability of caffeine to potentiate renin secretion. The purpose of this study was to document the effects of caffeine on renin release responses to a vasodilator and to investigate what mechanisms were responsible for any augmentation of vasodilator-induced renin secretion. Accordingly, we compared the effects of caffeine vs. 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX; a xanthine that we documented in this study not to significantly enter the brain or penetrate cell membranes) on base-line and hydralazine-induced renin release in both normal and beta adrenoceptor-blocked (propranolol, 15 mg/kg) rats. Both xanthines (at a dose of 10 mg/kg plus 150 micrograms/min) attenuated adenosine-mediated hypotension and bradycardia, and DPSPX was at least as effective as caffeine in antagonizing peripheral adenosine receptors. Caffeine and DPSPX increased base-line plasma renin activity to a similar extent regardless of whether the animals were pretreated with propranolol. In rats with an intact beta adrenergic system, caffeine, but not DPSPX, increased the renin release response to low-dose hydralazine (1 mg/kg). Although both xanthines augmented the renin release response to high-dose hydralazine (10 mg/kg), caffeine was more efficacious in this regard. In beta adrenoceptor-blocked rats, neither caffeine nor DPSPX augmented the renin release response to low-dose hydralazine, whereas both xanthines equally potentiated the renin release response to high-dose hydralazine. These data demonstrate that caffeine increases base-line renin release primarily by blocking peripheral (most likely renal), cell-surface adenosine receptors; however, caffeine potentiates vasodilator-induced renin secretion in part by blocking peripheral (most likely renal), cell-surface adenosine receptors and in part by additional central nervous system and/or intracellular mechanism(s) that involve the beta adrenergic system.     

A(1) receptor blockade induces natriuresis with a favorable renal hemodynamic profile in SHHF/Mcc-fa(cp) rats chronically treated with salt and furosemide.

Our goal was to test the hypothesis that A(1) receptor blockade induces diuresis/natriuresis with a favorable renal hemodynamic/cardiac profile in aged, lean SHHF/Mcc-fa(cp) rats, a rodent model of hypertensive dilated cardiomyopathy. Thirteen-month-old SHHF/Mcc-fa(cp) rats were pretreated for 72 h before experiments with furosemide (100 mg/kg by gavage 72, 48, and 24 h before experiments) to mimic the clinical setting of chronic diuretic therapy and were given 1% NaCl as drinking water to reduce dehydration/sodium depletion. Animals were instrumented for measurement of systemic and renal hemodynamics, renal excretory function, and cardiac performance, and baseline values were obtained during a 30-min clearance period. Animals then received either vehicle (n = 9), BG9719 [the S-enantiomer of 1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)] xanthine (also called CVT-124)] (highly selective A(1) receptor antagonist; 0.1 mg/kg bolus + 10 microg/kg/min; n = 9) or furosemide (loop diuretic; 30 mg/kg; n = 8) and measurements were repeated during four subsequent clearance periods. Both BG9719 and furosemide increased urine volume and absolute and fractional sodium excretion. BG9719 increased renal blood flow and glomerular filtration rate, but did not affect fractional potassium excretion. Furosemide decreased renal blood flow and glomerular filtration rate and increased fractional potassium excretion. Neither drug altered afterload; however, furosemide, but not BG9719, decreased preload (central venous pressure and ventricular end diastolic pressure). Neither drug altered systolic function (+dP/dt(max)); however, furosemide, but not BG9719, attenuated diastolic function (decreased -dP/dt(max), increased tau). In the setting of left ventricular dysfunction, chronic salt loading and prior loop diuretic treatment, selective A(1) receptor antagonists are effective diuretic/natriuretic agents with a favorable renal hemodynamic/cardiac performance profile.     

Additive diuretic effect of S-8666 during furosemide-induced diuresis in rats

In order to verify that the novel uricosuric loop-acting diuretic S-8666 has an additional site of action in the distal tubule, we investigated the additive diuretic effect of S-8666 during furosemide-induced diuresis in rats. Intravenous bolus injection of S-8666 (3-30 mg/kg) and trichlormethiazide (TCM) (1-10 mg/kg) caused dose-dependent increases in Na+ excretion during furosemide-induced diuresis (primary, 10 mg/kg i.v.; sustaining, 10 mg/kg/hr i.v.), whereas injection of furosemide (5 mg/kg) did not. Ca++ excretion was decreased by injection of each drug. A significant reduction in Ca++/Na+ was observed at all doses of S-8666 and TCM. Additional natriuretic and hypocalciuric effects were lower in the S-8666 than in the TCM group. From these observations we conclude that: 1) S-8666 has a natriuretic effect which is additive to that of furosemide; 2) S-8666 attenuates the calciuric effect of furosemide; and, 3) S-8666 may have an additional site of action in the distal tubule.     

Alpha-1 blockade inhibits compensatory sodium reabsorption in the proximal tubules during furosemide-induced volume contraction.

The renal effects of alpha-1 adrenoceptor blockade (i.v. infusion of doxazosin, 50 micrograms/kg prime; 30 micrograms/kg/h) on tubular sodium reabsorption during acute furosemide-induced volume contraction (i.v. infusion of furosemide, 7.5 mg/kg/h for 3 h) was investigated by clearance technique in conscious rats. By measuring inulin clearance, lithium clearance and urinary excretion rates of sodium and water, the changes in proximal and distal tubular sodium handling were dissociated. In furosemide-infused rats given doxazosin (n = 11) or volume replacement (n = 9), the fractional lithium excretion increased from 30% (control) to a steady-state value of 51% (last hour of furosemide infusion), whereas in rats infused with furosemide only (n = 9), the fractional lithium excretion increased transiently to a peak value of 52% and then declined to a steady-state value of 39%. Doxazosin attenuated the acute natriuretic response to furosemide by 54%, mainly due to increased sodium reabsorption in the distal nephron segment. This effect was associated with a significant lower mean arterial pressure compared with rats given furosemide only. The results are compatible with a contributory role of proximal tubular alpha-1 adrenoceptors in mediating compensatory Na reabsorption during furosemide-induced volume contraction.     

Mechanisms of Renin Secretion during Hemorrhage in the Dog

The importance of renal perfusion pressure (RPP), the sympathetic beta adrenergic nervous system and renal prostaglandins (PG) on renin release during a uniform 15-17% reduction in blood pressure by hemorrhage (HH) was studied systematically in anesthetized dogs. All groups of animals had similar decrements in systemic and renal hemodynamics with HH. In control dogs (n = 7), both plasma renin activity (PRA, 4.1-9.0 ng angiotensin I/ml per h, P < 0.05) and renin secretory rate (RSR, 26-228 ng/ml per h.min, P < 0.005) increased significantly with HH. This increase in renin release during HH was not abolished by any single maneuver alone including beta adrenergic blockade with d,l-propranolol (n = 6), renal PG inhibition with indomethacin (n = 7), or control of RPP (n = 6). However, when beta adrenergic blockade was combined with control of RPP (n = 7) during HH, neither PRA (1.9-2.7 ng/ml per h, NS) nor RSR (16-53 ng/ml per h.min, NS) increased significantly. Similarly, a combination of beta adrenergic blockade and PG inhibition (n = 6) also abolished the increase in PRA (1.5-1.4 ng/ml per h, NS) and RSR (14-55 ng/ml per h.min, NS) during HH despite significant decreases in sodium excretion. Finally, a combination of PG inhibition and RPP control was associated with significant increases in PRA and RSR during HH. These results support a multifactorial mechanism in renin release during HH and implicate both the beta adrenergic receptors, renal baroreceptors, and possibly the macula densa as constituting the primary pathways of renin release during HH of this magnitude. Because either constant RPP or PG inhibition blunted renin release during HH in the setting of beta adrenergic blockade, the present results strongly suggest that the renal baroreceptor, and probably the macula densa mechanism are PG mediated.     

Pharmacokinetics and dynamics of furosemide in the newborn piglet

Furosemide was administered as either an i.v. bolus (6 mg/kg) or primed continuous infusion (4 mg/kg/hr) with quantitative fluid replacement to 10 3-day-old and 9 18-day old piglets. Total and unbound plasma as well as urinary furosemide concentrations were measured for up to 6 hr and drug disposition and renal sodium excretory dynamics were compared at the two ages. The plasma clearance of furosemide was concentration-independent over the range studied (0.1-10 mg/l). Steady-state volume of distribution and unbound fraction of furosemide in plasma were both considerably higher in the younger piglets (618 +/- 320 vs. 201 +/- 71 ml/kg, p less than .01 and 0.22 +/- 0.08 vs. 0.06 +/- 0.02 ml/kg, p less than .001, respectively) while unbound secretory clearance was several-fold lower in this age group (49.2 +/- 23 vs. 107 +/- 55 ml/min/kg, P less than .01). A log-logistic equation was fitted to sigmoidal plots of sodium excretion rate vs. log furosemide excretion rate. While basal response and slope parameters did not differ significantly, maximal response and stimulus required for half-maximal response were both reduced in the younger piglets (0.70 +/- 0.24 vs. 1.18 +/- 0.30 mmol/min and 0.06 +/- 0.04 vs. 0.14 +/- 0.06 mumol/min, respectively, P less than 0.05). Thus, younger piglets were more sensitive to the natriuretic effects of the drug. While term piglets were useful for studying the maturation of protein binding and renal drug excretory processes for furosemide, drug disposition was not comparable to that in human premature infants because of the higher secretory capability of the piglet.     

Caffeine potentiates the renin response to diazoxide in man. Evidence for a regulatory role of endogenous adenosine

In the rat and dog, exogenous adenosine inhibits renin release and adenosine receptor blockade augments stimulated renin release, suggesting that endogenous adenosine contributes to the regulation of renin release. The present study examines the role of endogenous adenosine in the regulation of renin in humans. The ability of the adenosine receptor blocker, caffeine, to augment renin release in response to the vasodilator, diazoxide, has been investigated in eight normal subjects in a double-blind, placebo-controlled, cross-over study. During each arm of the study, subjects on a 150 mEq of sodium, xanthine-free diet received caffeine (250 mg 3 times daily) or placebo for 3 days before and on the study day, when they were given an i.v. loading dose of diazoxide (4 mg/kg) followed by a 3-hr continuous infusion (0.67 mg/kg/hour). PRA, caffeine and diazoxide levels were measured before, during and after the diazoxide infusion. PRA measurements were repeated with subjects standing, 6 hr after starting diazoxide. Administration of diazoxide resulted in a modest tachycardia and a small, but significant, decrease in BP. Supine PRA was elevated during and after the diazoxide infusion and rose further with standing. Although there was no difference in plasma diazoxide levels, maximal pulse or BP response to diazoxide between the two arms of the study, the renin response was significantly greater in the presence of caffeine. These data confirm that caffeine augments the PRA response to diazoxide and suggest that endogenous adenosine inhibits stimulated renin response in humans.     

Macula densa control of renin release and glomerular hemodynamics.

In each nephron of the mammalian kidney, the tubule returns to the hilus of the parent glomerulus, forming the juxtaglomerular apparatus (JGA). The JGA displays a unique arrangement of afferent and efferent arterioles, interstitial cells and macula densa (a specialized plaque of tubular epithelial cells). Because of this intimate anatomical relationship, it has long been suggested that the macula densa may somehow sense changes in the composition of the tubular fluid and control both the glomerular filtration rate and renin release. Despite extensive investigation, attempts to obtain direct evidence of this have been hindered by the anatomical complexity of the JGA. However, recent technical developments now permit direct assessment of the role of the macula densa in the control of both renin release and glomerular hemodynamics. These developments include microdissection/perfusion of the afferent arteriole, the macula densa or both, as well as a sensitive renin assay which permits measurement of renin release from a single JGA. Observations resulting from such developments are discussed in this article.     

Ouabain inhibits renin release by a direct renal haemodynamic effect

The effect of intrarenal infusion of ouabain (90 micrograms/kg) on renin release was examined in the anaesthetized dog. Ouabain reduced cortical Na-K-ATPase activity to 23% and outer medullary activity to 18% of the control level. During renal arterial constriction to a perfusion pressure below the autoregulatory range, renin release rose from 1.2 +/- 0.4 to 47.4 +/- 6.9 micrograms/min (P less than 0.001). This response was abolished by ouabain. When superimposed on renal arterial constriction, beta-adrenergic stimulation enhanced renin release from 25.6 +/- 10.7 to 56.9 +/- 9.5 micrograms/min (P = 0.02) at a urinary sodium excretion of 2 +/- 1 mumol/min. After ouabain, the corresponding increment substantially decreased since release rose from 5.6 +/- 2.0 to 19.9 +/- 5.3 micrograms/min only (P = 0.02), at a urinary sodium excretion of 140 +/- 67 mumol/min. When glomerular filtration was reduced to zero by ureteral occlusion in one series, renin release increased to 22.6 +/- 5.1 but was reduced (P less than 0.05) by ouabain to 13.5 +/- 5.5 micrograms/min and superimposed isoproterenol had no effect. According to these observations, ouabain inhibits renin release by a direct effect on the afferent arteriole through constriction of the autoregulating renin-secreting segment.