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.     

Effect of sympathetic blocking agents on the antinatriuresis of reflex renal nerve stimulation.

To evaluate the effects of reflex renal sympathetic nerve stimulation on renal tubular sodium handling, clearance studies were performed in anesthetized dogs. With renal perfusion pressure held constant, baroreceptor reflex renal sympathetic nerve stimulation was produced by controlled arterial hemorrhage or carotid sinus perfusion. Significant decreases in urinary sodium excretion occurred in the presence of minor insignificant alterations in renal blood flow and no changes in glomerular filtration rate. Renal alpha adrenergic receptor blockade (phenoxybenzamine) or adrenergic blockade (guanethidine) completely reversed the fall in urinary sodium excretion; this could not be attributed to alterations in glomerular filtration rate or renal blood flow. These studies support the interpretation that adrenergic innervation of the renal tubules is involved in the regulation of renal tubular sodium reabsorption.     

Renin, aldosterone and renal haemodynamics in cirrhosis with ascites

The interrelationships between the renin-angiotensin-aldosterone system, renal haemodynamics and urinary sodium excretion were investigated in fifty-six non-azotaemic cirrhotics with ascites. In twelve additional patients the renal renin secretion rate was also studied. Plasma renin activity and concentration and plasma aldosterone ranged from normal to very high values. There was a significant inverse relationship between plasma aldosterone and the urinary sodium excretion. Plasma aldosterone showed a highly significant direct correlation with plasma renin activity, and plasma renin concentration was closely and directly related to the estimated renin secretion rate. Neither plasma renin activity, plasma renin concnetration nor the estimated renin secretion rate correlated with the renal plasma flow or the glomerular filtration rate. These results suggest that in non-azotaemic cirrhosis with ascites the renin-angiotensin-aldosterone system is an important factor influencing sodium excretion, increased plasma renin and aldosterone concentrations are mainly due to an increased secretion rate, and total renal perfusion is not a major factor influencing renin secretion.     

Effects of packed cell volume reduction on renal haemodynamics and the renin-angiotensin-aldosterone system in patients with secondary polycythaemia and hypoxic cor pulmonale

Polycythaemia was corrected by erythrapheresis in ten patients with hypoxic cor pulmonale who were stable on regular diuretic therapy. Renal haemodynamics, renal function and the renin-angiotensin-aldosterone system were assessed before and afterwards. Before erythrapheresis effective renal plasma flow (ERPF) was reduced (63% predicted) but glomerular filtration rate (GFR) was preserved (88% predicted) by a rise in filtration fraction (FF) (138% predicted). A negative correlation existed between ERPF and packed cell volume (r = -0.723; P less than 0.02) and also between ERPF and PaCO2 (r = -0.710; P less than 0.05). Polycythaemia was sufficient to maintain renal oxygen delivery (97% predicted). After erythrapheresis systemic blood pressure, blood volume and blood viscosity all decreased. ERPF increased by 18% (P less than 0.02). FF fell by 11% (P less than 0.05) and GFR was unchanged. Renal oxygen delivery diminished by 25% (P less than 0.001). Plasma renin activity was increased in five patients and plasma aldosterone increased in two patients before erythrapheresis. No sustained fall occurred in plasma renin activity or plasma aldosterone, possibly because the haemodynamic consequences of the procedure had opposing actions on renin secretion. Although the reduction in FF would per se tend to enhance renal sodium and water excretion, a diuresis or natriuresis did not occur consistently.     

Phenylbutazone-induced decrease in renal blood flow

Phenylbutazone (Butazolidin), and anti-inflammatory agent, has been reported to decrease renal excretion of sodium and water. Whether or not an alteration in renal hemodynamics could be involved in producing these effects was tested in anesthetized dogs. Renal blood flow (RBF) was monitored with electromagnetic flow probes. After i.v. administration of phenylbutazone, 2 mg/kg, RBF fell by 20%. Glomerular filtration rate, sodium and water excretion were also decreased and blood pressure increased slightly. The reduction of RBF and glomerular filtration rate by phenylbutazone indicates that a hemodynamic mechanism could be involved in the retention of sodium and water induced by this agent. The decreased blood flow was correlated with a depressed renal secretion of prostaglandin E. Also, in animals pretreated with indomethacin, another inhibitor of prostaglandin synthesis, administration of phenylbutazone did not result in any additional changes in renal hemodynamics or excretion of sodium and water. In addition, phenylbutazone antagonized the ability of furosemide to increase RBF, an inhibition which has previously been shown to occur with indomethacin. Thus, phenylbutazone appears to alter renal mechanisms in a manner similar to indomethacin.     

Effect of renal denervation on the antinatriuretic response to morphine administration in conscious rats

The effect of surgical denervation on the antinatriuretic response to morphine was assessed in conscious rats prepared with arterial and venous catheters and bladder cannulas. In sham-operated animals, morphine sulfate (4 mg/kg i.v. plus 2 mg/kg X hr) caused a marked reduction in sodium excretion (650 +/- 218 vs. 2394 +/- 265 nEq/100 g X min in vehicle-treated animals; P less than .05). Although glomerular filtration rate was reduced, fractional excretion of sodium, expressed as a percentage of the filtered load, was also markedly decreased by morphine (0.62 +/- 0.18 vs. 1.51 +/- 0.15% in the vehicle group; P less than .05). The changes in sodium excretion were readily reversed by naloxone. In rats subjected to the renal denervation procedure, morphine had no effect on sodium excretion (1614 +/- 261 vs. 1926 +/- 520 nEq/100 g X min) or on fractional sodium excretion (1.92 +/- 0.50 vs. 1.41 +/- 0.37%). However, glomerular filtration rate was reduced by morphine as in the sham-denervated rats. Blood pressure and heart rate were not significantly affected by morphine in either group. The results suggest that morphine enhances renal tubular sodium reabsorption, at least in part, by a mechanism dependent on intact renal nerves. Because there was no evidence of generalized sympathetic activation (as judged by blood pressure and heart rate changes), the effect may be selective for the renal innervation.     

Genetic co-segregation of renal haemodynamics and blood pressure in the spontaneously hypertensive rat

1. To determine the relevance of renal circulatory abnormalities found in the immature spontaneously hypertensive rat (SHR) to the genetic hypertensive process, glomerular filtration rate and renal blood flow were measured in conscious F2 rats, derived from cross-breeding SHR and normotensive Wistar-Kyoto rats (WKY), at 4, 11 and 16 weeks of age by determining the renal clearances of 51Cr-ethylenediaminetetra-acetate and 125I-hippuran respectively. Plasma renin activity was measured at 11 and 16 weeks of age. 2. Mean arterial pressure, glomerular filtration rate and renal blood flow increased between 4 and 11 weeks of age. Between 11 and 16 weeks the mean glomerular filtration rate and renal blood flow did not alter, although the mean arterial pressure rose significantly. At 11 weeks of age, during the developmental phase of hypertension, a significant negative correlation between mean arterial pressure and both glomerular filtration rate and renal blood flow was noted. However, by 16 weeks when the manifestations of genetic hypertension were more fully expressed, no correlation between mean arterial pressure and renal blood flow or glomerular filtration rate was observed. Plasma renin activity was negatively correlated with both glomerular filtration rate and renal blood flow, but the relationship was stronger at 11 than at 16 weeks of age. 3. These results suggest that the reduction in renal blood flow and glomerular filtration rate, found in immature SHR, is genetically linked to the hypertension and may be of primary pathogenetic importance. It is proposed that the increased renal vascular resistance in these young animals stimulates the rise of systemic arterial pressure which returns renal blood flow and glomerular filtration rate to normal.     

Denervation Diuresis and Renin Secretion in the Anaesthetized Dog

Abstract Simultaneous determinations of renal sodium excretion and renin secretion have been performed on 10 anaesthetized dogs, 1–2 weeks after unilateral splanchnicotomy ("renal denervation"). Under basal conditions, urine flow and sodium excretion were increased, renal venous renin activity (RVRA) and secretion decreased on the denervated side. During isotonic volume expansion a quantitative increase in denervation diuresis and natriuresis occurred while RVRA in denervated kidneys decreased further and the secretion rate became negative. Regardless of the absolute differences in water and sodium excretion between intact and denervated kidneys, RVRA and the output of the latter amounted to about 60 per cent of the intact kidney values. Both sodium reabsorption and renin production seem to be neurally regulated; their interrelationship is discussed.     

Effects of renal denervation on sodium balance and renal function during chronic furosemide administration in rats.

In order to investigate whether the renal nerves are involved in the compensatory response of increased renal tubular Na reabsorption, which limits the natriuretic response during chronic furosemide treatment (the "braking phenomenon"), daily Na balance measurements were performed in rats with either renal denervation (DNX) or sham denervation (Sham-DNX) infused i.p. for 5 days with furosemide (Fur) (0.5 mg/hr) or vehicle (Veh) (10 microliters/hr) (n = 8 in each group). Renal denervation reduced renal norepinephrine concentration by 98 to 99%. Average daily Na and water excretion was similar in Fur/DNX and Fur/Sham-DNX animals. Fur treatment increased daily sodium excretion by 75% and daily urine production by 150%. Cumulative Na balance during Fur infusion was significantly lower than in Veh-treated animals. All rats were chronically instrumented and, in order to study intrarenal adjustments to chronic Fur treatment, clearance experiments were performed before and after 5 days of Fur infusion. In comparison with Fur/Sham-DNX, Fur/DNX animals showed no significant changes in mean arterial pressure, heart rate, renal plasma flow, glomerular filtration rate or renal tubular handling of sodium, potassium or lithium. A test dose of amiloride produced no changes in lithium clearance, and the natriuretic and antikaliuretic responses to amiloride were unaltered after 5 days of treatment with either Fur or Veh. In both of the Fur-infused groups, there was a significant increase in hematocrit, as compared with the Veh-treated animals, and a significant reduction in plasma potassium concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of fenoldopam on the acute and subacute nephrotoxicity produced by amphotericin B in the dog.

The effect of the selective dopamine DA1 receptor agonist fenoldopam (1 microgram/kg/min i.v.) on the acute nephrotoxic response to amphotericin B (2 mg/kg i.v.) has been studied in the anesthetized dog. Animals were prepared for the measurement of blood pressure, renal blood flow, urine flow, glomerular filtration rate and sodium and potassium excretion. Amphotericin B was given over 20 min and the animals were followed for an additional 160 min. The fenoldopam infusion was started 20 min before amphotericin B and was continued for the duration of the experiment. In control animals, amphotericin B markedly increased renal vascular resistance without affecting blood pressure and thus produced a significant reduction in renal blood flow. The renal vasoconstrictor response to amphotericin B was not attenuated by fenoldopam. Concomitant with the renal vasoconstriction produced by amphotericin B was a marked reduction in glomerular filtration rate, sodium excretion and urine flow rate, which lasted for at least 160 min after amphotericin B treatment. Fenoldopam did not have any effect on the initial reductions in glomerular filtration rate, sodium excretion and urine flow rate but did produce a significant return of these parameters toward control levels by 160 min, despite the continued renal vasoconstriction. The effect of fenoldopam (0.5 microgram/kg/min) given continuously by i.v. infusion on the subacute nephrotoxic response produced by amphotericin B given every other day for 8 days was also investigated. One day after the start of the fenoldopam infusion, venous samples were drawn for the analysis of serum creatinine and blood urea nitrogen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrarenal actions of the new adenosine agonist CGS 21680A, selective for the A2 receptor

The purpose of this study was to define the direct intrarenal actions of the new adenosine agonist CGS 21680A (hydrochloride "A" salt of (2-[p-2-carboxyethyl)phenethylamino]5'-N-ethyl-carboxamido adenosine), which is selective for the A2 receptor. CGS 21680A was infused into the left renal artery, while simultaneously measuring blood pressure (BP) and parameters of renal function from both the left and right kidneys. At doses higher than 0.05 micrograms/kg/min, CGS 21680A appeared to leak from the circulation of the infused kidney in pharmacologically significant quantities, inasmuch as BP fell and renal blood flow was increased and renal vascular resistance decreased in the noninfused contralateral kidney. At doses of 0.025 to 0.05 micrograms/kg/min, CGS 21680A appeared localized to the renal circulation, because neither BP nor any measured parameter of contralateral renal function was altered. Intrarenal infusion of 0.025 to 0.05 micrograms/kg/min of CGS 21680A increased renal blood flow but not glomerular filtration rate leading to a fall in the filtration fraction. Urine volume and urinary sodium excretion were unaffected by selective intrarenal infusion of CGS 21680A. Plasma renin activity and renin secretion rate were also not altered significantly by intrarenal infusion of 0.05 micrograms/kg/min of CGS 21680A. In contrast plasma renin activity increased significantly in response to the intrarenal infusion of 0.075 micrograms/kg/min of CGS 21680A, a dose which leaked from the kidney and lowered BP. The results presented suggest that the new adenosine agonist CGS 21680A exerts a direct intrarenal effect on renal hemodynamics, but does not affect urine volume or sodium excretion or directly influence renin release.     

Renal effects of methoxyverapamil in anesthetized rats

The purpose of these experiments was to determine the renal effects of methoxyverapamil (D-600). Three groups of rats were anesthetized with sodium pentobarbital and given 0, 0.85 or 1.69 nmol/min of methoxyverapamil i.v. Increases in urine flow and Na, K and Ca excretory rates occurred, in an apparently dose-dependent manner. Plasma Na and arterial renin concentration decreased at both doses and, at the higher dose, mean arterial blood pressure and effective renal plasma flow decreased while plasma K increased. Plasma Ca, glomerular filtration rate, filtration fraction and total renal plasma flow were not affected. The findings that methoxyverapamil increased urine flow and electrolyte excretion without changing glomerular filtration rate are consistent with the hypothesis that methoxyverapamil acts directly on tubular reabsorptive mechanisms. These effects, and the effect on plasma renin concentration, could contribute to the beneficial effects of this and other Ca entry antagonists in the treatment of hypertension.     

Chronic effects of oral sulindac on renal haemodynamics and hormones in subjects with chronic renal disease

The effects of oral sulindac, 600 mg daily, on renal function and plasma hormones were studied in eight subjects with chronic renal failure. Renal function and plasma hormones were measured before drug administration and then after taking sulindac for 28 days. Effective renal plasma flow was reduced in all subjects after 28 days but the glomerular filtration rate did not change. Plasma renin activity, potassium and aldosterone concentrations and urinary sodium excretion did not change but urinary prostaglandin E2 excretion fell significantly. Sulindac may be a relatively renal-sparing drug in its effects on the hormonal control of glomerular function.     

Further studies on the mechanism of the natriuretic response to low-dose dopamine in man: effect on lithium clearance and nephrogenic cAMP formation

The effect of intravenous infusion of low-dose dopamine on electrolyte excretion, lithium clearance, nephrogenous cAMP formation and renal haemodynamics was investigated in healthy volunteers. Dopamine significantly increased the urine flow rate by 70.6% and urinary sodium excretion by 72%, but did not change creatinine clearance, PRA or plasma levels of AVP, ANP and cAMP. Renal plasma flow significantly increased by 48.6%; the glomerular filtration rate was not changed. Lithium per se increased basal PRA, but had no effect on the increments of urine flow rate, sodium excretion and renal blood flow induced by dopamine. Dopamine significantly increased the fractional excretion of lithium (representing fractional excretion of sodium at the proximal level). The increase in urinary sodium excretion during dopamine infusion, significantly correlated with the increase in fractional excretion of lithium (r = 0.94; P less than 0.01) and the increase in nephrogenous cAMP formation (r = 0.96; P less than 0.01). No correlation was found between the increase in urinary sodium excretion and the increase in renal blood flow. In conclusion, this study confirms that low-dose dopamine increases renal blood flow and urinary sodium excretion in healthy volunteers. This natriuretic response appears to be due to interaction with proximal tubular dopamine receptors, which are positively coupled to adenylate cyclase.     

Renal effects of acute calcium blockade with nifedipine in hypertensive patients receiving beta-adrenoceptor-blocking drugs

The effects on blood pressure and renal function of a single 20-mg sublingual dose of nifedipine were investigated in 10 patients with mild to moderate arterial hypertension insufficiently treated on beta-blocker monotherapy. Nifedipine induced a prompt and marked reduction of both systolic and diastolic blood pressure (average maximal reduction 30/22 mm Hg, P less than 0.001). Despite the beta blockade, heart rate rose 25%. Only insignificant increments of glomerular filtration (RVR) was markedly reduced (P less than 0.001). Urinary excretion rate of albumin and beta-2 microglobulin rose after nifedipine, reflecting changes in glomerular as well as tubular function. Mean blood pressure seemed to be a major determinant of the excretion of proteins. There was a marked increase in the excretion of sodium after nifedipine and urine volume rose from a mean of 8.2 +/- 1.3 to 12.5 +/- 1.8 ml/min (P less than 0.01). The changes in sodium excretion rate correlated with the renal hemodynamic changes. Uric acid excretion rate rose remarkably after nifedipine and the magnitude of the changes seemed intimately related to the basal level of RVR. The results indicate that nifedipine therapy may be advantageous in patients whose hypertension is insufficiently controlled with beta blockers alone. Renal blood flow is maintained and there is a desirable diuretic action and enhancement of uric acid excretion.     

An effect of extrarenal beta adrenergic stimulation on the release of renin

The present study was undertaken to examine whether the beta adrenergic agonist, isoproterenol, increases plasma renin activity (PRA) by activation of intrarenal or extrarenal pathways. The effects of intravenous (i.v.) and renal arterial infusion of isoproterenol on PRA and renin secretion rate (RSR) were compared in anesthetized dogs. In 12 studies in 9 dogs i.v. infusion of isoproterenol (0.009-0.018 mug/kg per min) was associated with an increase in PRA from 14.7 to 35.7 ng/ml per 3 hr (P < 0.001). PRA decreased to 19.4 ng/ml per 3 hr (P < 0.001) after cessation of the infusion. In innervated kidneys RSR increased from 1640 to 5062 U/min (P < 0.02) and decreased to 2132 U/min after cessation of the infusion (P < 0.05). In denervated kidneys the control RSR was significantly lower (455 U/min) but still increased during i.v. infusion of isoproterenol to 2762 U/min (P < 0.001) and decreased to 935 U/min (P < 0.001) after the infusion was stopped. These changes in PRA and RSR were associated with an increase in cardiac output averaging 49% and a large decrease in total peripheral resistance. These effects of i.v. isoproterenol to increase RSR were not mediated by changes in renal perfusion pressure since this was held constant by adjusting a suprarenal aortic clamp. In addition, there were no changes in glomerular filtration rate, renal plasma flow, or electrolyte excretion in either denervated or innervated kidneys during i.v. infusion of isoproterenol, and the concentration of potassium in plasma was unchanged. Prior hypophysectomy abolished the antidiuretic effect of i.v. isoproterenol but did not prevent the effect on RSR. In contrast, renal arterial infusion of isoproterenol at the same dose had no apparent effect on PRA and RSR in seven studies in five dogs and also did not produce changes in cardiac output, peripheral resistance or renal hemodynamics. These results do not provide evidence for a role of intrarenal beta adrenergic receptors in the control of renin release and indicate that the effect of beta adrenergic stimulation with isoproterenol to increase the release of renin is mediated by an extrarenal mechanism. Since the effect of i.v. isoproterenol occurred in the absence of changes in plasma potassium concentration, renal perfusion pressure, glomerular filtration rate, renal plasma flow, and electrolyte excretion and was not abolished by renal denervation, the possibility must be considered that the effect on renin secretion is mediated by circulatory factors. The changes in systemic hemodynamics which occurred with i.v. but not renal arterial infusion of isoproterenol may be involved in the initiation of such a pathway.     

Renal tubular site of action of felodipine

The renal tubular site of action of felodipine was localized using renal clearance and recollection micropuncture techniques in the anesthetized rat. In initial renal clearance experiments, felodipine (2.75 nM/kg/min i.v. X 60 min) had no effect on mean arterial pressure or glomerular filtration but significantly increased urinary flow rate, sodium and potassium excretion. In subsequent recollection micropuncture experiments, felodipine decreased mean arterial pressure but did not affect renal blood flow or renal vascular resistance or glomerular filtration rate; absolute and fractional urinary excretion of sodium and water, but not potassium, were increased. Proximal tubular and loop of Henle sodium, potassium and water reabsorption were not affected but distal tubular and collecting duct sodium and water (not potassium) reabsorption were decreased by felodipine. Felodipine is a vasodilator antihypertensive agent which, in doses which decrease mean arterial pressure in normotensive rats, increases urinary flow rate and sodium excretion by inhibiting distal tubular and collecting duct sodium and water reabsorption; potassium reabsorption or excretion is not affected. As a vasodilator antihypertensive agent, felodipine possesses beneficial natriuretic rather than detrimental sodium retaining properties.     

Integrated cardiac, renal, and endocrine actions of endothelin.

Endothelin, a newly discovered endothelial-derived peptide, has been demonstrated in vitro to have potent vasocontractile properties and has been speculated to play a role in vivo in arterial pressure-volume homeostasis. The present studies in anesthetized dogs were designed to determine the action of endothelin on cardiovascular-renal and endocrine function in vivo as in acute arterial pressure-volume regulation. Intravenous infusion of endothelin (50 ng/kg per min) increases arterial pressure by increasing peripheral vascular resistance but in association with an increase in coronary vascular resistance and decreases in cardiac output. Renal blood flow and glomerular filtration rate were markedly reduced in association with a sustained reduction in sodium excretion and an increase in plasma renin activity. Atrial natriuretic factor, vasopressin, and aldosterone were also elevated. These results indicate that endothelin is a potent vasoconstrictor that elevates systemic blood pressure in association with marked decreases in cardiovascular and renal function. This peptide may function as a counterregulatory hormone to the effects of endothelial-derived vasodilator agent(s).     

Effect of a kinin antagonist on renal function and haemodynamics during alterations in sodium balance in conscious normotensive rats

1. To evaluate whether sodium intake can modulate the action of endogenous kinins on renal function and haemodynamics, a receptor antagonist of bradykinin was infused in conscious normotensive rats maintained on either a normal or a low sodium diet. 2. The antagonist inhibited the hypotensive effect of exogenously administered bradykinin. It did not change the vasodepressor effect of acetylcholine, dopamine or prostaglandin E2. 3. The antagonist did not affect mean blood pressure, glomerular filtration rate, renal blood flow or urinary sodium excretion, in rats on sodium restriction. It did not change mean blood pressure, glomerular filtration rate or urinary sodium excretion, but decreased renal blood flow, in rats on a normal sodium intake. 4. The kallikrein-kinin system has a role in the regulation of renal blood flow in rats on a normal sodium diet.