The effect of parathormone on the reactivity of renal blood flow to vasopressin in normotensive and spontaneously hypertensive rats

It has been shown that after parathyroid hormone (PTG) administration vasopressin increases the falling rate of the renal cortical blood flow and decreases the falling rate of the renal medullary blood flow in normotensive rats. In spontaneously hypertensive rats (SHR) the PTG decreases the falling rate of the cortical and medullary blood flow after vasopressin administration. PTG-induced hypercalcemia in SHR followed by vasopressin administration leads to the renal blood flow redistribution reaction due to which the medullary blood flow dominates over the cortical one.     

Intrarenal blood flow distribution: effect of carotid occlusion.

In this study we have examined the influence of bilateral carotid occlusion on intrarenal blood flow distribution. Using labeled microspheres to determine intrarenal hemodynamics, bilateral carotid ligation in mannitol or saline expanded dogs resulted in an increase in outer cortical blood flow and a decrease in inner cortical flow. Total renal blood flow and glomerular filtration rate did not change significantly during carotid occlusion whereas the average mean arterial blood pressure rose from 130 to 166 mmHg. Inner cortical flow resistance increased substantially after carotid occlusion; outer cortical resistance was unchanged. These results suggest that bilateral carotid occlusion selectively activates inner cortical renal sympathetic fibers.     

Role of prostaglandins in the cortical distribution of renal blood flow following reductions in renal perfusion pressure

The purpose of this study was to examine the role of prostaglandins in the redistribution of renal cortical blood flow that occurs following reductions in renal perfusion pressure. The distribution of blood flow to the renal cortex was examined using radio-labeled microspheres (15 +/- 1 micron). It was found that in animals not treated with a prostaglandin synthesis inhibitor a decrease in renal perfusion pressure to the limit of renal blood flow autoregulation was associated with a decrease in fractional flow to the outer cortex (Zone I) and an increase in fractional flow to the inner cortex (Zones III and IV). A further decrease in renal perfusion pressure below the limit of autoregulation produced a further decrease in the fractional flow to Zone I and a further increase in fractional flow to Zones III and IV. In contrast, in animals treated with the prostaglandin synthesis inhibitor meclofenamate (5 mg/kg, i.v. bolus) a reduction in renal perfusion pressure to the limit of renal blood flow autoregulation produced no change in fractional blood flow to any of the 4 cortical zones. A further decrease in renal perfusion pressure, however, did produce a fall in fractional blood flow to Zone I and an increase in fractional flow to Zones III and IV. In conclusion, the results of this study indicate that within, but not below, the limit of renal blood flow autoregulation prostaglandin synthesis is an important factor in the regulation of renal cortical blood flow distribution.     

Early effect of Crotalus durissus terrificus venom on kidney circulation

Local blood flow was measured in renal cortex (1 mm below cortical surface) by means of the hydrogen clearance method in urethanized rats. Recording of blood pressure from femoral artery was performed. Crotalus durissus terrificus venom injection (one mg/kg i.v.) significantly decreased cortical blood flow at 10 min, without a significant arterial pressure modification. Posterior injection of mannitol 200 mg induced a significant increase in cortical blood flow, although initial values were not reached. Electron microscopy showed thromboses in the glomerular capillaries 35 minutes after venom injection. It is suggested that the precocious effect of this venom on renal cortical blood flow may be instrumental in the development of the renal acute insufficiency induced by Crotalus durissus terrificus venom.     

Role of prostagalandins in the cortical distribution of renal blood flow following reductions in renal perfusion pressure

The purpose of this study was to examine the role of prostaglandins in the redistribution of renal cortical blood flow that occurs following reductions in renal perfusion pressure. The distribution of blood flow to the renal cortex was examined using radio-labeled microspheres (15 ± 1 μm). It was found that in animals not treated with a prostaglandin synthesis inhibition a decrease in renal perfusion pressure to the limit of renal blood flow autoregulation was associated with a decrease in fractional flow to the outer cortex (Zone I) and an increase in fractional flow to the inner cortex (Zones III and IV). A further decrease in renal perfusion pressure below the limit of autoregulation produced a further decrease in the fractional flow to Zone I and a further increase in fractional flow to Zones III and IV. In contrast, in animals treated with the prostaglandin synthesis inhibitor meclofenamate (5 mg/kg, i.v. bolus) a reduction in renal perfusion pressure to the limit of renal blood flow autoregulation produced no change in fractional blood flow to any of the 4 cortical zones. A further decrease in renal perfusion pressure, however, did produce a fall in fractional blood flow to Zone I and an increase in fractional flow to Zones III and IV. In conclusion, the results of this study indicate that within, but not below, the limit of renal blood flow autoregulation prostaglandin synthesis is an important factor in the regulation of renal cortical blood flow distribution.     

Morphofunctional reorganization of the kidneys in lymphatic outflow disturbance

In 115 Wistar male rats structures and rates of tissue blood flow have been studied in the cortical and medullary renal substance histologically, polarographically (estimation of the volumetric tissue blood flow by hydrogen clearance). Systemic arterial (peritoneal aorta), venous (caudal vena cava) and lymphatic (renal lymph nodes) pressures have been measured, normal and after ligation of the thoracic duct at early (1-3 days), middle (1 month) and late (2-3 months) periods. In 1-3 days edema and dystrophy of the renal parenchyma, decrease of the blood flow rate in the cortical and its increase in the renal medullary substance, as well as a sharp elevation of pressure in the lymph nodes are observed. In 1 month of the experiment together with dystrophy and edema moderate sclerosis, decreasing blood flow rate in the cortical and medullary substance are noted. Increase of the systemic arterial and venous pressure and decreasing pressure in the lymph nodes, as well as a sharp increase of the renal nodes mass are revealed. In 2-3 months of the experiment, together with sclerosis of the renal parenchyma, elevated blood flow rate is observed in the kidneys and decreasing pressure in the lymph nodes up to its initial value takes place.     

Effects of alfa-receptor and adrenergic neuron blockade on indomethacin-induced changes of renal haemodynamics

The effect of prostaglandin synthesis inhibitor indomethacin was studied on renal haemodynamics by radioactive microspheres in untreated control dogs and in animals treated by the alfa-adrenergic receptor blocking agent phentolamine or by the adrenergic neuron blocking agent guanethidine. RBF was reduced by indomethacin. The reduction of blood flow was more pronounced in the inner cortical zones, which resulted in a blood flow redistribution towards the superficial cortical regions. Urine flow, osmotic concentration and electrolyte excretion did not change significantly. Pretreatment by phentolamine or by guanethidine did not influence the effect of indomethacin on renal haemodynamics or renal function. These data suggest that the sympathetic nervous system is not involved in the renal effects of indomethacin.     

A role for the angiotensin IV/AT4 system in mediating natriuresis in the rat

Angiotensin II (AngII) or Angiotensin IV (AngIV) was infused into the renal artery of anesthetized rats while renal cortical blood flow was measured via laser Doppler flowmetry. The infusion of AngII produced a significant elevation in mean arterial pressure (MAP) with an accompanying decrease in cortical blood flow, glomerular filtration rate (GFR), urine volume, and urine sodium excretion. The infusion of AngIV induced significant increases in renal cortical blood flow and urine sodium excretion, without altering MAP, GFR, and urine volume. Pretreatment infusion with a specific AT1 receptor antagonist, DuP 753, blocked or attenuated the subsequent AngII effects, while pretreatment infusion with the specific AT4 receptor antagonist, Divalinal-AngIV, blocked the AngIV effects. These results support distinct and opposite roles for AngII and AngIV, i.e. AngII acts as an anti-natriuretic agent, while AngIV acts as a natriuretic agent.     

Renal cortical and medullary blood flow responses to L-NAME and ANG II in wild-type, nNOS null mutant, and eNOS null mutant mice

Experiments in wild-type (WT; C57BL/6J) mice, endothelial nitric oxide synthase null mutant [eNOS(-/-)] mice, and neuronal NOS null mutant [nNOS(-/-)] mice were performed to determine which NOS isoform regulates renal cortical and medullary blood flow under basal conditions and during the infusion of ANG II. Inhibition of NOS with N(omega)-nitro-l-arginine methyl ester (l-NAME; 50 mg/kg iv) in Inactin-anesthetized WT and nNOS(-/-) mice increased arterial blood pressure by 28-31 mmHg and significantly decreased blood flow in the renal cortex (18-24%) and the renal medulla (13-18%). In contrast, blood pressure and renal cortical and medullary blood flow were unaltered after l-NAME administration to eNOS(-/-) mice, indicating that NO derived from eNOS regulates baseline vascular resistance in mice. In subsequent experiments, intravenous ANG II (20 ng x kg(-1) x min(-1)) significantly decreased renal cortical blood flow (by 15-25%) in WT, eNOS(-/-), nNOS(-/-), and WT mice treated with l-NAME. The infusion of ANG II, however, led to a significant increase in medullary blood flow (12-15%) in WT and eNOS(-/-) mice. The increase in medullary blood flow following ANG II infusion was not observed in nNOS(-/-) mice, in WT or eNOS(-/-) mice pretreated with l-NAME, or in WT mice administered the nNOS inhibitor 5-(1-imino-3-butenyl)-l-ornithine (1 mg x kg(-1) x h(-1)). These data demonstrate that NO from eNOS regulates baseline blood flow in the mouse renal cortex and medulla, while NO produced by nNOS mediates an increase in medullary blood flow in response to ANG II.     

Influence of antidiuretic hormone on intrarenal blood flow distribution in diabetes insipidus dogs and rats.

The distribution of labeled microspheres within the renal cortex was used to evaluate the influence of physiological amounts of antidiuretic hormone on intrarenal blood flow distribution in hypophysectomized dogs and in rats with hereditary diabetes insipidus. In both species, intravenous infusions of ADH caused a significant decrease in the ratio of inner to outer cortical blood flow. The change in blood flow distribution observed in the hypophysectomized dog with ADH was primarily a consequence of a decrease in inner cortical blood flow. No consistent changes in outer cortical blood flow were found. Also in the dog, glomerular filtration rates and electrolyte excretion rates (Na and K) increased following ADH. In contrast, ADH infusion into Brattleboro rats caused no change in glomerular filtration or excretion of Na and K.     

Studies on the mechanism of non-oliguric experimental acute renal failure.

Although acute renal failure, caused either by renal ischemia or nephrotoxic agents, is usually characterized by oliguria, a severe fall in glomerular filtration rate, and a fall in renal blood flow, some patients and experimental models display a non-oliguric pattern of renal injury. The present study was designed to evaluate the mechanism of preservation of high urinary flow rate under this condition. Following the administration of the aminoglycoside gentamicin to rats for five days, a decrease in concentrating ability was demonstrated, caused by impaired vasopressin-mediated water transport. Further treatment resulted in a fall in Cin to 15 percent of control, although RBF was reduced to only 67 percent of control, and urine flow rate rose above control levels. Induction of acute and renal failure with dichromate was associated with variable high or low urinary flow rates according to pre-injury intake of sodium. Urine volume correlated directly with cortical blood flow. These data suggest that the non-oliguric pattern of acute renal injury is caused by preservation of cortical perfusion in the setting of severe tubular injury.     

A mathematical model of diffusional shunting of oxygen from arteries to veins in the kidney

To understand how arterial-to-venous (AV) oxygen shunting influences kidney oxygenation, a mathematical model of oxygen transport in the renal cortex was created. The model consists of a multiscale hierarchy of 11 countercurrent systems representing the various branch levels of the cortical vasculature. At each level, equations describing the reactive-advection-diffusion of oxygen are solved. Factors critical in renal oxygen transport incorporated into the model include the parallel geometry of arteries and veins and their respective sizes, variation in blood velocity in each vessel, oxygen transport (along the vessels, between the vessels and between vessel and parenchyma), nonlinear binding of oxygen to hemoglobin, and the consumption of oxygen by renal tissue. The model is calibrated using published measurements of cortical vascular geometry and microvascular Po(2). The model predicts that AV oxygen shunting is quantitatively significant and estimates how much kidney Vo(2) must change, in the face of altered renal blood flow, to maintain cortical tissue Po(2) at a stable level. It is demonstrated that oxygen shunting increases as renal Vo(2) or arterial Po(2) increases. Oxygen shunting also increases as renal blood flow is reduced within the physiological range or during mild hemodilution. In severe ischemia or anemia, or when kidney Vo(2) increases, AV oxygen shunting in proximal vascular elements may reduce the oxygen content of blood destined for the medullary circulation, thereby exacerbating the development of tissue hypoxia. That is, cortical ischemia could cause medullary hypoxia even when medullary perfusion is maintained. Cortical AV oxygen shunting limits the change in oxygen delivery to cortical tissue and stabilizes tissue Po(2) when arterial Po(2) changes, but renders the cortex and perhaps also the medulla susceptible to hypoxia when oxygen delivery falls or consumption increases.     

Prostaglandin D2, another renal prostaglandin?

Prostaglandin (PG) D₂ was biosynthesized by rabbit renal papillae incubates in vitro. Quantification of the renal prostaglandins by gas chromatography-mass spectroscopy demonstrated that the concentration of PGD₂ generated by renal papillae was to the amount of PGE₂ or about 1 μg/g tissue/30 min. Infusion of the sodium salt of PGD₂ into the renal artery of the dog produced a dose related increase in renal blood flow and urine flow, free water clearance, sodium excretion and potassium excretion without changes in systemic hemodynamics. At low doses PGD₂ increased renal blood flow to all cortical zones. Higher concentrations of PGD₂ produced a shift in the intrarenal distribution of blood flow toward the juxtamedullary nephrons.     

Effect of metabolic acidosis on fetal renal haemodynamics

The effects of metabolic acidosis on renal haemodynamics and intrarenal blood flow distribution was studied in two groups of chronically-catheterized fetal sheep between 122 and 130 days of gestation. One group (experimental group) was studied before and during infusion of 1.1 M lactic acid, whereas the second group received on infusion of dextrose 5% (w/v) in water and served as a time-control group. Infusion of lactic acid for 2 h decreased fetal arterial pH from 7.37 +/- 0.01 to 6.95 +/- 0.02, did not change arterial blood pressure, but produced a significant decrease in renal blood flow (41 +/- 3 to 33 +/- 7 ml/min, P less than 0.05) and a significant increase in renal vascular resistance (1.42 +/- 0.13 to 1.86 +/- 0.18 mmHg/ml/min, P less than 0.05). Moreover, a significant decline in cortical blood flow was also observed in the outer portion of the renal cortex during lactic acidosis. Taken together, these results suggest that metabolic acidosis produces significant changes in fetal renal haemodynamics not associated with changes in arterial blood pressure.     

Modulation of V1-receptor-mediated renal vasoconstriction by epoxyeicosatrienoic acids

This study examined the effects of renal arterial infusion of a selective cytochrome P-450 epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 2 mg/kg plus 1.5 mg.kg(-1).h(-1)), on renal hemodynamic responses to infusions of [Phe(2),Ile(3),Orn(8)]vasopressin and ANG II into the renal artery of anesthetized rabbits. MS-PPOH did not affect basal renal blood flow (RBF) or cortical or medullary blood flow measured by laser-Doppler flowmetry (CLDF/MLDF). In vehicle-treated rabbits, [Phe(2),Ile(3),Orn(8)]vasopressin (30 ng.kg(-1).min(-1)) reduced MLDF by 62 +/- 7% but CLDF and RBF were unaltered. In MS-PPOH-treated rabbits, RBF and CLDF fell by 51 +/- 8 and 59 +/- 13%, respectively, when [Phe(2),Ile(3),Orn(8)]vasopressin was infused. MS-PPOH had no significant effects on the MLDF response to [Phe(2),Ile(3),Orn(8)]vasopressin (43 +/- 9% reduction). ANG II (20 ng.kg(-1).min(-1)) reduced RBF by 45 +/- 10% and CLDF by 41 +/- 14%, but MLDF was not significantly altered. MS-PPOH did not affect blood flow responses to ANG II. Formation of epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DiHETEs) was 49% lower in homogenates prepared from the renal cortex of MS-PPOH-treated rabbits than from vehicle-treated rabbits. MS-PPOH had no effect on the renal formation of 20-hydroxyeicosatetraenoic acid (20-HETE). Incubation of renal cortical homogenates from untreated rabbits with [Phe(2),Ile(3),Orn(8)]vasopressin (0.2-20 ng/ml) did not affect formation of EETs, DiHETEs, or 20-HETE. These results do not support a role for de novo EET synthesis in modulating renal hemodynamic responses to ANG II. However, EETs appear to selectively oppose V(1)-receptor-mediated vasoconstriction in the renal cortex but not in the medullary circulation and contribute to the relative insensitivity of cortical blood flow to V(1)-receptor activation [corrected].     

Effect of renal vasodilatation on intrarenal blood flow distribution

Total renal blood flow (TRBF) and its intrarenal and intracortical distribution were measured before and during renal vasodilatation induced by acetylcholine infusion using the 133Xe washout, 86Rb uptake and radioactive microspheres distribution techniques. A good agreement was observed between TRBF calculated from 133Xe washout and measured with the electromagnetic flowmeter (FM). 86Rb-TRBF was lower than FM-TRBF and, due to the progressive reduction of renal 86Rb uptake, the difference increased with the increase of flow. With the alteration of TRBF the intrarenal distribution of 86Rb uptake did, however, not change significantly and, accordingly there was no redistribution of RBF either between the cortex and medulla, or among the individual cortical zones. The intracortical distribution of labelled microspheres showed, however, moderate flow dependent changes: with the rise of TRBF, due probably to the reduction of the steric hindrance, the estimated fractional perfusion of the inner cortical zones increased. The sum of the per cent 86Rb content of the innermost cortical zone (C4) and of the medulla exceeded the per cent microsphere content of zone C4. It is concluded that the medulla is perfused not exclusively with blood flowing from the juxtamedullar glomeruli. The regional flow values obtained from the 133Xe curves are not comparable with the results obtained by other methods and cannot be attributed to well defined areas of the kidney.     

The influence of nitric oxide synthase 1 on blood flow and interstitial nitric oxide in the kidney

The role of nitric oxide (NO) produced by NO synthase 1 (NOS1) in the renal vasculature remains undetermined. In the present study, we investigated the influence of systemic inhibition of NOS1 by intravenous administration of N(omega)-propyl-L-arginine (L-NPA; 1 mg. kg(-1). h(-1)) and N(5)-(1-imino-3-butenyl)-L-ornithine (v-NIO; 1 mg. kg(-1). h(-1)), highly selective NOS1 inhibitors, on renal cortical and medullary blood flow and interstitial NO concentration in Sprague-Dawley rats. Arterial blood pressure was significantly decreased by administration of both NOS1-selective inhibitors (-11 +/- 1 mmHg with L-NPA and -7 +/- 1 mmHg with v-NIO; n = 9/group). Laser-Doppler flowmetry experiments demonstrated that blood flow in the renal cortex and medulla was not significantly altered following administration of either NOS1-selective inhibitor. In contrast, the renal interstitial level of NO assessed by an in vivo microdialysis oxyhemoglobin-trapping technique was significantly decreased in both the renal cortex (by 36-42%) and medulla (by 32-40%) following administration of L-NPA (n = 8) or v-NIO (n = 8). Subsequent infusion of the nonspecific NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 50 mg. kg(-1). h(-1)) to rats pretreated with either of the NOS1-selective inhibitors significantly increased mean arterial pressure by 38-45 mmHg and significantly decreased cortical (25-29%) and medullary (37-43%) blood flow. In addition, L-NAME further decreased NO in the renal cortex (73-77%) and medulla (62-71%). To determine if a 40% decrease in NO could alter renal blood flow, a lower dose of L-NAME (5 mg. kg(-1). h(-1); n = 8) was administered to a separate group of rats. The low dose of L-NAME reduced interstitial NO (cortex 39%, medulla 38%) and significantly decreased blood flow (cortex 23-24%, medulla 31-33%). These results suggest that NOS1 does not regulate basal blood flow in the renal cortex or medulla, despite the observation that a considerable portion of NO in the renal interstitial space appears to be produced by NOS1.     

Endothelin receptor A antagonism attenuates renal medullary blood flow impairment in endotoxemic pigs

Background

Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors.

Methods and Findings

A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg⁻¹, n = 8) or served as endotoxin-treated controls (n = 8). Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002). Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05) measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02) and increased medullary pyruvate levels (p = 0.03). Decreased creatinine clearance and oliguria were present in both groups without any significant difference.

Conclusions

These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury.     

Cardiac output distribution and intrarenal haemodynamics: role of thromboxanes.

The effects of imidazole, an inhibitor of thromboxane synthesis, were studied on the distribution of cardiac output and on the intrarenal haemodynamics in anaesthetized, furthermore on the salt and water excretion in conscious rats. Imidazole treatment (10 mg/100 g b.m., intraperitoneally, twice a day for two days) failed to influence the arterial blood pressure, the cardiac output and its distribution in organs investigated (heart, muscle, lung [bronchial fraction], skin, liver, spleen, small intestine, adrenal gland and kidneys). The medullary blood flow increased, while cortical blood flow remained unchanged, but the intrarenal percentile blood flow shifted towards the medulla. Imidazole elevated the water turnover in the animals, but no change in sodium and potassium excretion occurred. It is supposed that thromboxanes may affect the renal medullary vascular tone without altering the vascular smooth muscle activity in other organs.     

Biphasic changes in phospholipid hydroperoxide levels during renal ischemia/reperfusion.

The involvement of lipid peroxidation in renal ischemia/reperfusion was explored by measuring changes in the cortical content of specific primary lipid hydroperoxides (using chemluminescent detection with HPLC) following ischemia and reperfusion and by correlating the changes in hydroperoxide content with measurements of renal blood flow. Phosphatidylcholine and phosphatidylethanolamine hydroperoxide concentrations were significantly lowered during 30 or 60 min of ischemia (to levels less than 50% of control at 60 min). Following 30 min of renal ischemia, reperfusion resulted in a rebound of phospholipid hydroperoxide tissue content to levels higher than controls. Increased phospholipid hydroperoxide formation was not, however, observed in response to reperfusion following long-term (60 min) ischemia. In separate animals it was demonstrated that following 30 min ischemia and reperfusion, renal blood flow recovers to about 65% of control in 1 h. In contrast, following 60 min ischemia and reperfusion, the renal blood flow remains more highly impaired (less than 25% recovery for periods up to 24 h). These results imply that phospholipid hydroperoxides are produced and accumulate in the kidneys under normal aerobic conditions and that lipid peroxidative activity increases during renal ischemia/reperfusion to an extent dependent on the degree of local blood perfusion.