Split intrarenal hemodynamics in renovascular hypertension.

Split intrarenal hemodynamics in stenotic and contralateral kidneys of unilateral renovascular hypertension (RVH) were estimated by Gomez's formulae. Ten patients with RVH were studied. Split para-amino hippurate and inulin clearances were measured by ureteral catheterization as indexes for renal plasma flow and glomerular filtration rates, allowing the estimation of intrarenal hemodynamics such as preglomerular arteriolar resistance, postglomerular arteriolar resistance and glomerular hydrostatic pressure in each kidney. Renal plasma flow and glomerular filtration rates were lower in the stenotic kidney (83 +/- 12, 19 +/- 2 ml/min/m2) than in the contralateral kidney (170 +/- 19, 43 +/- 4). Preglomerular arteriolar resistance was elevated due to the stenotic lesion in the stenotic kidney (30,900 +/- 4,500 dyns.sec.cm-5) while the elevation in the contralateral kidney (11,300 +/- 1,000) was less. Postglomerular arteriolar resistance was high in both kidneys. Glomerular pressure was lowered in the stenotic kidney (54 +/- 1 mmHg), while elevated in the contralateral kidney (71 +/- 3). Although the stenotic kidney of RVH was protected from systemic hypertension (138 +/- 6 mmHg) by stenosis of the renal artery, the increase in preglomerular arteriolar resistance in the contralateral kidney was not sufficient, making glomerular pressure elevated. Thus, glomerular hypertension and hyperfiltration were demonstrated in the contralateral kidney of RVH.     

Effects of verapamil and converting enzyme inhibition on bilateral renal function of two-kidney, one-clip hypertensive rats

Experiments were conducted in two-kidney, one-clip renal vascular hypertensive rats (GHR) to assess the responses of each kidney to acute treatment with the antihypertensive calcium channel blocking agent verapamil in the presence and in the absence of converting enzyme inhibitor (CEI). One group of GHR (0.2 mm inner diam. clip 3 weeks before study) were examined during a control period, and during a second period of infusion of verapamil (600 micrograms h-1 kg-1). A second group of GHR were examined during a control period, during CEI (teprotide, 3 mg h-1 kg-1) infusion and during a third period of verapamil (600 micrograms h-1 kg-1) infusion superimposed on CEI infusion. Although systemic blood pressure (BP) decreased from 175 +/- 4 to 149 +/- 5 mmHg (mean +/- SEM) in response to verapamil alone, renal blood flow for non-clipped kidneys increased from 5.9 +/- 0.4 to 6.5 +/- 0.3 ml/min, indicating a 30% reduction of renal vascular resistance (P values less than or equal to 0.01; n = 9). Glomerular filtration rate (GFR) for non-clipped kidneys (n = 24) increased from 0.91 +/- 0.09 to 1.47 +/- 0.14 ml/min and filtration fraction increased from 0.32 +/- 0.04 to 0.47 +/- 0.03 (P values less than or equal to 0.05). Urine flow rate and absolute and fractional sodium excretion for non-clipped kidneys increased. GFR for clipped kidneys decreased during verapamil. Treatment with CEI alone resulted in nearly identical responses of BP and function of the non-clipped kidney, except filtration fraction was unchanged. The addition of verapamil to ongoing converting enzyme blockade tended to augment the increased GFR of the non-clipped kidney. Plasma renin activity (PRA) increased from 30 +/- 3 to 59 +/- 7 ng of angiotensin (ANG) I h-1 ml-1 with verapamil alone, a significantly larger increment than the increase of PRA from 27 +/- 5 to 39 +/- 9 ng of ANG I h-1 ml-1 in GHR subjected to comparable blood pressure reduction by mechanical aortic constriction. Verapamil resulted in many similar effects on renal function to those observed during blockade of converting enzyme. The increased filtration fraction observed in response to verapamil may be the result of vasodilatation of the afferent arteriole or of an increase in the glomerular ultrafiltration coefficient.     

Dissociation of systemic and renal effects in endotoxemia. Prostaglandin inhibition uncovers an important role of renal nerves.

To elucidate the mechanisms responsible for systemic and renal hemodynamic changes in early endotoxemia, the roles of prostaglandins (PG) and renal nerves were investigated. Endotoxin (E, 3 micrograms/kg i.v.) was given to two groups of anesthetized dogs that had undergone unilateral renal denervation: Group I (n = 9) E only; Group II (n = 11) E + indomethacin (10 mg/kg i.v.) or meclofenamate (5 mg/kg i.v.). A third group of dogs (Group III, n = 5) received indomethacin (10 mg/kg i.v.) only. 1 h after E group I dogs, mean arterial pressure (MAP) decreased from 126 to 94 mm Hg (P less than 0.001), and prostacyclin (6-keto-Fl alpha metabolite, PGI2) increased (from 0.64 to 2.08 ng/ml, P less than 0.005). Glomerular filtration rate (GFR) and renal blood flow (RBF) declined comparably both in innervated and denervated kidneys. In marked contrast, group II dogs had a stable MAP (136-144 mm Hg, NS) and no increase in PGI2 levels. Plasma renin activity (0.7-2.5 ng/ml per h, P less than 0.005) increased, and renin secretion was greater in innervated compared with denervated kidneys (255 vs. 74 U/min, P less than 0.01) in these PG-inhibited dogs. In addition, denervated kidneys in group II dogs had a greater GFR (42 vs. 34 ml/min, P less than 0.01) and RFB (241 vs. 182 ml/min, P less than 0.01) than innervated kidneys after E. Group III animals had no significant changes in systemic or renal hemodynamics, plasma renin activity or PGI2 during the study. These results suggest that PGI2 mediates the systemic hypotension of early endotoxemia in the PG-intact animal. Moreover, PG inhibition uncovers an important effect of E to increase efferent renal nerve activity with a consequent decline in GFR and RBF independent of changes in MAP. Finally, the results demonstrate that renal nerves are important stimuli to renin secretion in early endotoxemia via pathways that are PG-independent.     

Effect of Volume Expansion on Hemodynamics of the Hypoperfused Rat Kidney

The hemodynamics of the rat kidney were studied during reduction of renal arterial pressure to 35-40 mm Hg (H), and after volume expansion at that pressure with 0.9% NaCl (IS), 1.7% NaCl (HS), 5% mannitol in 0.9% NaCl (MS), 5% mannitol in water (MW), or 50 mM mannitol + 125 mM NaCl. During H, left renal blood flow (RBF) was 0.8+/-0.1 ml/min. Expansion with IS did not alter RBF, but expansion with HS, MS, MW, and 50 + 125 mM NaCl elevated RBF to 200-250% of hypoperfusion values. Glomerular capillary pressure rose significantly from 15.7+/-0.7 mm Hg during H to 22.3+/-1.1, 24.4+/-0.7, and 26.6+/-0.7 mm Hg following expansion with HS, MS, or MW, respectively. Efferent arteriolar pressure also rose significantly to 6.9+/-0.5, 9.7+/-0.8, and 9.5+/-0.9 mm Hg, respectively. Preglomerular resistance fell to 18-24% of H values, and postglomerular resistance fell to 58-74% of H values after expansion with HS, MS, or MW. Glomerular filtration (GFR) could not be detected during H or after IS expansion. HS and mannitol-containing solutions restored GFR to 0.10+/-0.02-0.15+/-0.02 ml/min, and single nephron glomerular filtration to 6-12 nl/min. Papaverine, acetylcholine, and kinins had no effect on RBF or GFR at a perfusion pressure of 35-40 mm Hg. We conclude that mannitol and HS have the capacity to augment RBF during hypoperfusion by reducing arteriolar resistance. The mechanism of the rise in RBF is uncertain; it may be due to changes in effective osmolality of the extracellular fluid or to a direct action of mannitol on vascular smooth muscle. Other potent vasodilators were ineffective during hypoperfusion. Restoration of GFR occurs as a result of the combined effects of augmented RBF and elevated net filtration pressure.     

Aminophylline inhibits renal vasoconstriction produced by intrarenal hypertonic saline

An intrarenal infusion of hypertonic saline to sodium-depleted dogs causes an acute reduction in renal blood flow (RBF) which has been postulated to be due to tubuloglomerular feedback (TGF). Adenosine has been suggested as a mediator of TGF, as adenosine receptor blockade with methylxanthines inhibits TGF. In order to test further the hypothesis that the renal response to hypertonic saline is mediated by TGF, the RBF response to intrarenal hypertonic saline infusions have been investigated in sodium-depleted dogs before and after either an infusion of vehicle or an intrarenal infusion of aminophylline. Aminophylline (2.5 mg/min), at a dose which did not change basal RBF or responses to bolus doses of angiotensin II, inhibited the responses to intrarenal bolus doses of adenosine. In control dogs (n = 5), a 10-min intrarenal infusion of hypertonic saline significantly (P less than .05) reduced RBF both before (-27 +/- 4%) and during (-16 +/- 9%) an infusion with aminophylline vehicle. In a second group of animals (n = 5), an intrarenal hypertonic saline infusion reduced RBF before (-33 +/- 8%; P less than .05), but not during an intrarenal aminophylline infusion (2.5 mg/min). We conclude that aminophylline inhibits the renal vascular response to hypertonic saline and that the renal response to hypertonic saline might be mediated by intrarenal adenosine release.     

Effect of sodium orthovanadate on renal renin secretion in vivo

The effect of vanadate (0.5 mumol/min) on renin secretory rate (RSR) of the kidney has been studied in nembutal-anesthetized, volume-expanded dogs. Intrarenal vanadate infusion caused a 69.3 +/- 8.8% decrease in RSR. This was accompanied by marked decreases in renal blood flow (RBF), glomerular filtration rate (GFR) and fractional excretion of sodium (FENa). Renal vascular resistance rose from 1.3 +/- 0.09 to 6.1 +/- 2.3 mm Hg/ml/min (P less than .0005). Papaverine infusion partially blunted the effect of vanadate on RSR (RSR only fell to 42. +/- 10% of basal values). The decreases in RBF and GFR were also less and FENa slightly higher than normal. Acetylcholine prevented the effects of vanadate more fully. There was no fall in RBF, GFR or FENa and it basically abolished the fall in RSR which fell only 19.4 +/- 25.3 of control (P = N.S.). Nifedipine (a slow Ca++ channels blocker) also prevented the fall in RBF, GFR and FENa induced by vanadate. RSR did not change significantly (7.8 +/- 10.9%). These results clearly demonstrate that vanadate is a potent inhibitor of renin secretion and suggest that inhibition of smooth muscle Na+, K+, adenasine triphosphatase and changes in the cystosolic concentration of Na and Ca are involved in its mechanism. Changes in perfusion pressure and sodium delivery to the macula densa appear to have little if any role in the inhibition.     

Some determinants of the effects of VAL-5-angiotensin II amide on glomerular filtration rate and sodium excretion in dogs

In 12 dogs anesthetized with chloralose, angiotensin (angiotensin II amide) given intravenously increased the glomerular filtration rate (GFR) of an ischemic kidney while simultaneously having little effect on the GFR of the contralateral kidney. In the ischemic kidney, in 14 of 30 observations, increments of GFR greater than 100% of mean control GFR (9 ml/min) occurred in response to angiotensin. The magnitude of the increase in GFR produced by angiotensin was independent of dose (range 0.005-0.050 mug/kg per min), the degree of accompanying pressor response, and alterations in renal blood flow (RBF) (electromagnetic flow-meter). In the ischemic kidney, increments of GFR could be produced by sub-pressor doses of angiotensin.Dissociations between increments of GFR and sodium excretion occurred. Equivalent increments of GFR in the ischemic kidney in dogs receiving either 5% glucose in water or 10% mannitol in 0.3% saline were associated with natriuresis only in the latter group: a) as an initial response of the contralateral kidney to renal arterial constriction (RAC) in spite of a concomitant reduction in RBF and an unchanged GFR; b) in the ischemic kidney on giving angiotensin. The natriuresis produced by angiotensin was independent of the magnitude of elevations in blood pressure, altered filtration fraction, and was associated with a further reduction in RBF. After release of RAC in the dogs receiving mannitol, an antinatriuresis was again observed in response to angiotensin.The presence of unilateral renal ischemia allowed the demonstration of a differential action of angiotensin on the GFR of an ischemic and nonischemic kidney. The natriuresis in response to angiotensin requires, in addition to mannitol, the participation of undefined factors invoked by unilateral renal ischemia.     

Regional blood flows and cardiac function changes induced by angiotensin II in conscious dogs

Hemodynamic properties of angiotensin (ANG) II 1, 5, 10 and 100 ng/kg i.v. and 10, 100 and 1000 ng/kg i.v.t. were assessed in conscious dogs. ANG II i.v. produced a dose-dependent pressor response (59 +/- 5-124 +/- 16 mmHg) and renal vasoconstriction (1.3 +/- 0.4-96 +/- 32 mmHg/ml/min). Ganglionic blockade (chlorisondamine 2 mg/kg i.v.) diminished mean arterial responses without altering peptide effects on renal circulation. At the highest dose, ANG II i.v. induced cardiac stimulation: increased heart rate (75 +/- 4-115 +/- 6 beats/min), cardiac output (2.0 +/- 0.1-2.4 +/- 0.2 l/min), dP/dt (2308 +/- 181-2773 +/- 173 mmHg/sec) and coronary blood flow (49 +/- 10-96 +/- 23 ml/min). Although with chlorisondamine cardiac response was more pronounced, subsequent beta blockade abolished it. Concomitantly, an isolated increase in plasma epinephrine was recorded (63 +/- 8-1505 +/- 354 pg/ml). A pressor response (59 +/- 8-89 +/- 13 mmHg) and renal vasoconstriction (1.1 +/- 0.1-2.2 +/- 0.5 mmHg/ml/min) were also produced by ANG II i.v.t. at the highest dose. These centrally mediated changes were prevented by chlorisondamine. Our study demonstrates 1) i.v. ANG II-mediated pressor responses are dependent on direct and indirect components, the relative contribution of each being dependent on the regional circulation; ANG II i.v. also produced a biphasic cardiac response--an initial centrally mediated depression and a secondary stimulation dependent on epinephrine via cardiac beta receptors and 2) i.v.t. ANG II-mediated pressor effects are essentially indirect. Finally, no evidence was found to support the role of vasopressin in ANG II effects.     

Acute kidney injury: new concepts. Hepatorenal syndrome: the role of vasopressors

Type 1 hepatorenal syndrome (HRS) is prerenal failure specific to decompensated cirrhosis. In patients with HRS, there is marked splanchnic/systemic vasodilation resulting in arterial hypotension, arterial baroreceptor unloading, overstimulation of the sympathetic nervous and renin-angiotensin systems. This reflex neurohumoral hyperactivity via endogenous vasoconstrictors/vasopressors such as angiotensin II and noradrenaline induces arterial vasoconstriction in different extrasplanchnic vascular beds (including preglomerular arteries in the kidneys). Decreased arterial pressure (i.e. low renal perfusion pressure) and preglomerular vasoconstriction are thought to play a major role in the decline of the glomerular filtration rate (GFR). Nonrandomized studies in patients with HRS have shown that the administration of a splanchnic vasoconstrictor (vasopressin analogue or alpha(1)-adrenoceptor agonist), usually combined with intravenous albumin, causes increases in arterial pressure, arterial baroreceptor uploading, decreased neurohumoral activity, decreased renal vascular resistance, and increased GFR. Randomized clinical trials have shown that treatment with a combination of the vasopressin analogue terlipressin and intravenous albumin improves renal function in patients with type 1 HRS. Vasopressor therapy with terlipressin plus intravenous albumin is the medical treatment of choice for type 1 HRS.     

Role for intrarenal adenosine in the renal hemodynamic response to contrast media

The intrarenal injection of contrast media results in a transient fall in renal blood flow (RBF) and a decrease in glomerular filtration rate (GFR). These effects are enhanced by dietary sodium restriction and attenuated by sodium loading. A similar sodium-dependent response of RBF and GFR occurs with the intrarenal injection of adenosine. In view of these similarities, we sought to determine whether endogenous adenosine is involved in the renal hemodynamic response to contrast media. The intrarenal injection of contrast media (meglumine-Na diatrizoate, 76%) in six sodium-depleted, anesthetized dogs resulted in a 17% +/- 4% decrease in RBF and a 31% +/- 5% decrease in GFR. The infusion of the adenosine receptor antagonist, theophylline (5 mumol/min), reduced the decrease in RBF to 6% +/- 2% and in GFR to 12% +/- 3% of control values. During the intrarenal infusion of dipyridamole (24 micrograms/kg/min), a potentiator of adenosine through its action to inhibit the cellular uptake of nucleosides, the hemodynamic response to contrast media was greater; RBF fell 25% +/- 4% and GFR fell 44% +/- 7%. In addition, the urinary excretion of endogenous adenosine increased after the injection of contrast media (388 +/- 79 vs. 830 +/- 231 nmol/min). In summary, the contrast media-induced fall in RBF and GFR was attenuated by theophylline and augmented by dipyridamole, and the administration of contrast media resulted in an increase in the excretion of endogenous adenosine. These results support the hypothesis that endogenous adenosine is involved in the renal hemodynamic response to contrast media.     

Feedback-mediated reduction in glomerular filtration during acetazolamide infusion in insulin-dependent diabetic patients.

1. A sustained high glomerular filtration rate in diabetes mellitus is associated with increased proximal reabsorption, suggesting alterations in the tubuloglomerular feedback system. To test this hypothesis, renal function was studied in eight control subjects and 14 recent-onset euglycaemic insulin-dependent diabetic patients before and after infusion of the carbonic anhydrase inhibitor, acetazolamide (5 mg/kg body weight). 2. Acetazolamide induced a dramatic fall in glomerular filtration rate in both diabetic patients and control subjects (from 138 +/- 5 to 114 +/- 4 and from 127 +/- 3 to 113 +/- 2 ml min-1 1.73 m-2, respectively, P less than 0.0001). This fall in glomerular filtration rate was strongly correlated with the acetazolamide-induced decrease in absolute proximal reabsorption calculated by using lithium clearance. 3. To further assess the potential role of angiotensin II in the acetazolamide-induced tubulo-glomerular feedback response, 11 additional diabetic patients were investigated before and after the administration of acetazolamide plus the angiotensin-converting enzyme inhibitor, enalaprilat (1.25 mg intravenously). Despite the effective blockade of angiotensin II formation and a slight decrease in renal vascular resistance, the glomerular filtration rate fell significantly and by a similar magnitude as seen with acetazolamide alone. 4. These results indirectly suggest that there is an altered basal tubulo-glomerular feedback system in diabetic patients but a normal response to the increase in distal delivery. No convincing role for an angiotensin II-mediated effect on the afferent limb of the tubuloglomerular feedback response could be demonstrated.     

Effect of captopril and the nonpeptide angiotensin II antagonists, SK&F 108566 and EXP3174, on renal function in dogs with a renal artery stenosis.

Treatment with an angiotensin converting enzyme (ACE) inhibitor can result in acute renal failure in patients with a renal artery stenosis. In the present study the effects of the selective nonpeptide angiotensin II antagonists, SK&F 108566 ((E)-alpha-[[2-Butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl] methylene]-2-thiophenepropanoic acid) and EXP3174 (2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]imidazole-5-carboxylic acid hydrochloride) (the active metabolite of DuP 753, losartan) were compared with the ACE inhibitor, captopril, in the anesthetized dog which had been uninephrectomized and the remaining renal artery clamped to reduce renal blood flow (RBF) by approximately 50%. All three agents resulted in dose-dependent reductions in mean arterial pressure (MAP), glomerular filtration rate (GFR) and RBF. The maximum responses to captopril and SK&F 108566 were similar with MAP, RBF and GFR all decreasing approximately 30%. EXP3174 also resulted in decreases in GFR and RBF of approximately 30%; however, there was a smaller (approximately 17%) decrease in MAP. The data indicate that the possible bradykinin enhancing activity of ACE inhibitors may not provide any moderating activity of ACE inhibitor-induced reduction in GFR observed in dogs with a renal artery stenosis.     

The Role of Renal Nerves and Prostaglandins in Control of Renal Hemodynamics and Plasma Renin Activity during Hypotensive Hemorrhage in the Dog

The effects of hypotensive hemorrhage (HH) on renal hemodynamics and plasma renin activity (PRA) during prostaglandin (PG) synthesis inhibition were examined in three groups of dogs. In each group of animals arterial blood pressure was lowered by a 30% decrement. In the first group of eight control animals, HH was not associated with a significant change in glomerular filtration rate (GFR, 42-36 ml/min, NS); renal blood flow (RBF) declined significantly, from 234 to 171 ml/min, P < 0.05. In the second group of eight animals, pretreated with RO 20-5720 (RO, 2 mg/kg), a competitive inhibitor of PG synthesis, HH was associated with a significant fall in GFR (43-17 ml/min, P < 0.001) and RBF (195-89 ml/min, P < 0.001). In the third group of eight animals, pretreatment with indomethacin (IN, 10 mg/kg), a chemically dissimilar PG inhibitor, HH was also associated with a significant fall in GFR (38-8 ml/min, P < 0.001) and RBF (150-30 ml/min, P < 0.001). Renal denervation attenuated this renal ischemic effect of HH in the presence of PG inhibition. In the RO group, GFR (34 vs. 17 ml/min, P < 0.005) and RBF (145 vs. 89 ml/min, P < 0.025) were significantly greater in denervated vs. innervated kidneys during HH. Similarly, in animals treated with IN, a significantly higher GFR (28 vs. 8 ml/min, P < 0.005) and RBF (101 vs. 30 ml/min, P < 0.005) occurred in denervated as compared to innervated kidneys during HH. With HH, the increase in PRA in the control group (3.34-11.68 ng/ml per h, P < 0.005) was no different than that observed in the RO group (4.96-18.9 ng/ml per h, P < 0.001) or IN group (4.71-17.8 ng/ml per h, P < 0.001). In summary, the present results indicate that renal PG significantly attenuate the effect of HH to decrease GFR and RBF. Furthermore, renal denervation exerts a protective effect against the enhanced renal ischemic effects which occur in the presence of PG inhibition during HH. Finally, PG inhibition does not alter the effect of HH to cause an increase in PRA.     

Pharmacological doses of atrial natriuretic peptide ameliorate the acute renal dysfunction induced by systemic hypoxemia

The acute renal effects of systemic hypoxemia and the ability of atrial natriuretic peptide (ANP) to reverse these effects were assessed in seven anesthetized and mechanically ventilated adult rabbits. Throughout the experiment, arterial pH, PaCO2 and HCO3 remained unchanged. Hypoxemia induced a significant increase in rabbit-ANP plasma levels from 151 +/- 26 to 246 +/- 65 pg/ml. During the normoxemic period (PaO2 = 131 +/- 12 mm Hg), glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR) and urinary sodium excretion (UNaV) were similar in both kidneys. The subsequent hypoxemic period (PaO2 = 30 +/- 1 mm Hg) caused a decrease in right and left kidney function: GFR, -26 +/- 5 and -29 +/- 6%; RBF, -17 +/- 9 and -29 +/- 8%; RVR, +28 +/- 16 and +59 +/- 30%; urine flow rate, -38 +/- 6 and -36 +/- 6%; and UNaV, -51 +/- 7 and -50 +/- 7%, respectively. Human-ANP infusion in the left renal artery (100 ng/min) during sustained systemic hypoxemia induced a significant improvement in GFR (+57 +/- 18%), RBF (+21 +/- 8%), RVR (-20 +/- 7%), urine flow rate (+151 +/- 27%) and UNaV (+270 +/- 48%) in the left experimental kidney, as compared with the preceding hypoxemic period. In contrast, the function of the right control kidney remained impaired.     

Mechanisms of portal hypertension-induced alterations in renal hemodynamics, renal water excretion, and renin secretion.

Clinical states with portal venous hypertension are frequently associated with impairment in renal hemodynamics and water excretion, as well as increased renin secretion. In the present investigation, portal venous pressure (PVP) was increased in anesthetized dogs undergoing a water diuresis. Renal arterial pressure was maintained constant in all studies. As PVP was increased from 6 to 20 mm Hg, decreases in cardiac output (2.5-2.0 liter/min, P less than 0.05) and mean arterial pressure (140-131 mm Hg, P less than 0.05) were observed. Increases in PVP were also associated with decreases in glomerular filtration rate (GFR, 40-31 ml/min, P less than 0.001), renal blood flow (RBF, 276-193 ml/min, P less than 0.001), and increases in renin secretion (232-939 U/min, P less than 0.025) in innervated kidneys. No significant change in either GFR or RBF and a decrease in renin secretion occurred with increases in PVP in denervated kidneys. To dissociate the changes in cardiac output and mean arterial pressure induced by increase PVP from the observed decreases in GFR and RBF, studies were performed on animals undergoing constriction of the thoracic inferior vena cava. In these studies, similar decreases in cardiac output and mean arterial pressure were not associated with significant changes in GFR or RBF. Increases in PVP also were associated with an antidiuresis as urine osmolality increased from 101 to 446 mosmol/kg H2O (P less than 0.001). This antidiuresis was significantly blunted but not abolished by acute hypophysectomy. In hypophysectomized animals, changes in free water clearance and urine flow were linearly correlated as PVP was increased. These studies indicate that increases in PVP result in decreases in GFR and RBF and increases in renin secretion mediated by increased renal adrenergic tone. Increased PVP is also associated with antidiuresis; this antidiuresis is mediated both by vasopressin release and by diminished tubular fluid delivery to the distal nephron.     

Glomerular function and morphology after renal mass reduction in dogs

To determine whether the proteinuria, glomerular sclerosis, and decline in glomerular filtration rate (GFR) described in rodents after renal mass reduction develop in another species, 24-hour proteinuria, glomerular structure, and fasting and postfeeding GFR were examined in dogs subjected to seven-eighths reduction in renal mass. All dogs were fed a diet containing 26% protein. Six dogs with a GFR less than 10 ml/min (8% to 17% of control two-kidney GFR) were killed within 6 months after renal mass reduction. Twenty-four-hour urinary protein excretion was modestly although definitely increased (236 +/- 26 mg/24 hr, P less than 0.01). All remnant kidneys demonstrated structural changes of mesangial hyperplasia or focal glomerular sclerosis. Ten dogs with a remnant kidney and early GFRs 16% to 39% of control values were followed for 18 to 39 months. In seven dogs, GFR showed little tendency to decrease with time. In one of them, proteinuria was 106 mg/24 hr with normal-appearing glomeruli at 14 months. In three dogs, proteinuria was progressive, averaging about 1 gm/24 hr at 18 months and 2 gm/24 hr at 24 to 34 months; glomerular pathologic findings progressed from focal mesangial hyperplasia or focal glomerular sclerosis at 8 to 16 months to focal and segmental sclerosis or diffuse glomerular obsolescence at 25 to 34 months; and fasting GFR progressively declined starting at 21 to 24 months after renal mass reduction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for luminal uptake of gentamicin in the perfused rat kidney.

Gentamicin nephrotoxicity is preceded by proximal tubular accumulation of the drug. To determine whether gentamicin enters cells from the peritubular surface or from the tubular lumen after filtration, we studied filtering and non-filtering isolated perfused rat kidneys. Filtering kidneys were perfused with 6 g/dl of albumin, non-filtering kidneys with 11 g/dl of albumin and a lower perfusion pressure after ureteral occlusion. Accumulation of [14C]gentamicin in filtering or non-filtering kidneys was compared to that of [14C]cephaloridine, which is taken up primarily at the antiluminal cell surface. Renal accumulation of gentamicin was approximately 4 times greater in filtering than in non-filtering kidneys after 1 hr of perfusion. In contrast, accumulation of [14C]cephaloridine was 38% greater in the non-filtering model. Gentamicin did not significantly change sodium reabsorption or glomerular filtration rate during the 60-min study. Fractional potassium excretion, however, was slightly but significantly increased by perfusion with gentamicin. Our results indicate that 1) renal tubular gentamicin uptake is primarily by filtration and subsequent reabsorption and 2) the non-filtering and filtering isolated perfused rat kidney may be used to investigate mechanisms of renal accumulation of other nephrotoxic agents.     

Depression of proximal tubular sodium reabsorption in the dog in response to renal beta adrenergic stimulation by isoproterenol

Water diuresis was produced in anesthetized hypophysectomized, cortisone-treated dogs by infusion of 2.5% dextrose. Alpha adrenergic blockade of the left kidney produced by infusion of phenoxybenzamine in the left renal artery was associated with a significantly (P < 0.05) greater rate of urine flow (V) and free water excretion (C(H2O)) in the left kidney than in the right despite similar glomerular filtration rates (GFR) (17 +/- 1.3 ml/min, left; 18 +/-0.9 ml/min, right). Sodium excretion (U(Na)V) was similar in the two kidneys (3 and 5 muEq/min).When beta adrenergic stimulation of the left kidney was superimposed on alpha blockade by the addition of isoproterenol to the left renal artery infusate, GFR remained unchanged and similar in the two kidneys, as V and C(H2O) increased significantly (P < 0.01) in the left kidney but not in the right. When isoproterenol was discontinued, V and C(H2O) returned towards control in the left kidney and remained unchanged in the right. The ratios of the left kidney to the right during control, isoproterenol, and postcontrol were 1.22, 1.65, and 1.35, respectively, for V and 1.36, 1.90, and 1.44, respectively, for C(H2O). Sodium excretion remained unchanged and similar in the two kidneys throughout the study.The results indicate that blockade of alpha adrenergic activity inhibits the increased proximal tubular sodium reabsorption which anesthesia induces in the dog.Beta adrenergic stimulation appears to decrease proximal tubular sodium reabsorption but does not prevent virtually complete reabsorption of the increased quantity of delivered sodium by the ascending limb of the loop of Henle and the distal tubule. These changes in sodium reabsorption presumably are not associated with changes in colloid osmotic pressure or hydrostatic pressure in the peritubular capillary inasmuch as cortical and non-cortical plasma flow, filtration fraction, and mean arterial pressure in the left kidney were unchanged. Thus, isoproterenol probably produced its effects through a direct action on the renal tubule, possibly through the mediation of the adenyl cyclase system.     

La modification du débit sanguin rénal influe-t-elle sur le débit de filtration glomérulaire ?

The glomerular filtration rate (GFR) and the renal blood flow (RBF) correspond to the filtered volume by the kidneys and the blood volume delivered by the renal arteries per unit of time, respectively. The relationship between GFR and RBF is complex. A better understanding of renal physiology is needed to delineate the impact of modifications in renal hemodynamics on GFR. In each glomerulus, ultrafiltration is determined by the difference between the hydrostatic pressures in the glomerular capillary and the Bowman’s space, the coefficient of ultrafiltration (K_f) and the oncotic pressure in the afferent arteriole. The relationship between GFR and RBF depends on the renal autoregulation, allowing the maintenance of a constant GFR over a large range of perfusion pressures. In animals, at the early stages of sepsis, GFR is correlated with cardiac output. In contrast, at later stages, a decline in GFR is observed in animals and humans along with the development of renal vascular damage. After renal vascular damage has occurred, the reduction in GFR is much greater in comparison to the reduction in RBF. The complexity of the mechanisms involved in the relationship between GFR and RBF and the progression in this relationship over time likely explains the repeated failures of hemodynamic interventions in rescuing renal function after end-organ insult.     

Endothelin B receptors preserve renal blood flow in a normotensive model of endotoxin-induced acute kidney dysfunction

The aim was to investigate the role of endothelin 1 receptor subtypes in the early renal response to lipopolysaccharide (LPS) during normotensive endotoxemia with acute kidney dysfunction. Endotoxemia was induced in thiobutabarbital-anesthetized rats (n = 9 per group) by infusion of LPS (dosage, 1 mg/kg per hour i.v.). The study groups (1) sham-saline, (2) LPS-saline, (3) LPS-BQ123, (4) LPS-BQ788 and (5) LPS-BQ123 + BQ788 received isotonic saline, the ETA receptor antagonist BQ-123 (dosage, 30 nmol/kg per minute i.v.), and/or the ETB receptor antagonist BQ-788 (dosage, 30 nmol/kg per minute i.v.) before and during 2 h of LPS infusion. Renal clearance measurements, renal blood flow (RBF), and cortical and outer medullary perfusion (laser-Doppler flowmetry) and oxygen tension (Clark-type microelectrodes) were analyzed throughout. Before LPS administration, there were no significant differences between groups in glomerular filtration rate (GFR), RBF, or in cortical (CLDF) and outer medullary perfusion. However, mean arterial pressure (MAP) was elevated in LPS-BQ788 group compared with LPS-BQ123 + BQ788 group (P < 0.05). In saline-treated rats, endotoxin induced an approximate 35% reduction in GFR (P < 0.05), without significant effects on MAP, RBF, or on CLDF and cortical PO2. In addition, LPS increased outer medullary perfusion and PO2 (P < 0.05). The fractional urinary excretion rates of sodium, potassium, and water were not significantly different in LPS-saline group compared with sham-saline group. Neither selective nor combined ETA and ETB receptor blockade improved GFR. In BQ-788-infused rats, endotoxin produced marked reductions in RBF (-18% +/- 4% [P < 0.05]) and CLDF (-18% +/- 2% [P < 0.05]). Similarly, endotoxin decreased RBF (-14% +/- 3% [P < 0.05]) and CLDF (-10% +/- 2% [P < 0.05]) in LPS-BQ123 + BQ788 group. Endotoxin reduced MAP (-22% +/- 4% [P < 0.05]) in BQ-123-treated rats but did not significantly influence MAP in other groups. We conclude that in early normotensive endotoxemia, ETB receptors exert a renal vasodilator influence and contribute to maintain normal RBF.