Prostaglandins and renal function II. The effect of prostaglandin inhibition on autoregulation of blood flow in the intact kidney of the dog

In order to evaluate the effect of prostaglandin release on renal autoregulation in the intact kidney of the dog, pressure-flow curves were obtained before and after the administration of either indomethacin or meclofenamate, two potent prostaglandin synthetase inhibitors. After drug administration renal venous prostaglandin E decreased in each of eight studies with a mean change from 286 to 141 pg/ml (p < .001). In addition, prostaglandin inhibition was associated with a 31 percent decrease in renal blood flow and a 58 percent increase in renal resistance. Yet, as renal perfusion pressure was decreased by aortic constriction, the change in flow per pressure reduction and the percent change in renal resistance were not significantly different after prostaglandin inhibition when compared to control values in the same animals. The magnitude of the pressure range over which autoregulation was maintained was also similar in the two groups although both the initial and lowest level of autoregulation were slightly higher after prostaglandin inhibition. It is concluded that the administration of these prostaglandin synthetase inhibitors does not significantly impair renal autoregulation in the intact dog kidney.     

Effects of indomethacin on fetal renal function, renal and umbilicoplacental blood flow and lung liquid production.

The effects of indomethacin (10 mg/kg i.v. to the ewe and 12 mg/kg i.v. to the fetus) were examined in 8 chronically catheterized fetal sheep (117-138 days gestation). These doses suppressed fetal 6-keto-prostaglandin F1 alpha and thromboxane B2 levels. Fetal arterial PO2 increased (P < 0.01); PCO2 (P < 0.001) and pH fell (P < 0.001) and arterial pressure did not change. Placental blood flow increased in 4 of the 5 fetuses in which blood flows were measured. Lung liquid flow rate fell (P < 0.001). Fetal renal blood flow did not change but its distribution did, i.e. flow to the inner part of the renal cortex decreased (P < 0.05). Urine flow rates did not change but there was a natriuresis (P < 0.02), kaliuresis (P < 0.02) and chloriuresis (P < 0.02). Urinary osmolality rose (P < 0.001) and free water clearance fell (P = 0.004). It is concluded that when indomethacin is administered to both ewe and fetus, the resulting fall in prostaglandin I2 and thromboxane A2 levels causes marked changes in fetal blood gas status, renal function and lung liquid production. These effects are more profound than those seen when indomethacin is given only to the fetus. They do not however, explain the reason why clinical use of indomethacin is associated with a reversible oligohydramnios.     

Effect of ACE inhibition on glomerular permselectivity and tubular albumin concentration in the renal ablation model

Despite the central role of tubular plasma proteins that characterize progressive kidney diseases, protein concentrations along the nephron in pathological conditions have not been quantified so far. We combined experimental techniques and theoretical analysis to estimate glomerular and tubular levels of albumin in the experimental model of 5/6 nephrectomy (Nx) in the rat, with or without angiotensin-converting enzyme (ACE) inhibition. We measured glomerular permselectivity by clearance of fluorescent Ficoll and albumin and used theoretical analysis to estimate tubular albumin. As expected, 5/6 Nx induced an elevation of the fractional clearance of the largest Ficoll molecules (radii >56 ?, P < 0.05), increasing the importance of the shunt pathway of the glomerular membrane and the albumin excretion rate (119 ± 41 vs. 0.6 ± 0.2 mg/24 h, P < 0.01). ACE inhibition normalized glomerular permselectivity and urinary albumin (0.5 ± 0.3 mg/24 h). Theoretical analysis indicates that with 5/6 Nx, an increased albumin filtration overcomes proximal tubule reabsorption, with a massive increase in average albumin concentration along the tubule, reaching the highest value of >2,500 μg/ml at the end of the collecting duct. ACE inhibition improved glomerular permselectivity, limiting albumin filtration under proximal tubule reabsorption capacity, with low albumin concentration along the entire nephron, averaging <13 μg/ml at the end of the collecting duct. These results reinforce our understanding of the mechanisms of renal disease progression and the effects of angiotensin II antagonism. They also suggest that evaluation of tubular protein concentration levels could help to identify patients at risk of kidney disease progression and to improve clinical management.     

Effects of blood flow on lung ACE kinetics: evidence for microvascular recruitment.

The parameter Amax/Km (product of reactant enzyme mass in perfused microvessels and the constant kcat/Km), calculated from in vivo assays of pulmonary endothelial ectoenzymes (e.g., angiotensin-converting enzyme, ACE), can provide estimates of the perfused pulmonary microvascular surface area (PMSA) in the absence of enzyme dysfunction. We examined the relationship between PMSA and pulmonary blood flow (Qb) in anesthetized rabbits placed on total heart bypass, using [3H]benzoyl-Phe-Ala-Pro (BPAP) as the ACE substrate. When Qb was increased from 250 to 1,100 ml/min, at zone 3 conditions, pulmonary arterial pressure increased, pulmonary vascular resistance (PVR) decreased, and Amax/Km increased linearly, reflecting increasing PMSA. When only the left lung was perfused, increasing Qb from 250 to 636 +/- 17 ml/min (the last value representing fully recruited and/or distended vascular bed), PVR decreased, while Amax/Km increased. When Qb was further increased to 791 +/- 44 ml/min, both PVR and Amax/Km remained unchanged, confirming the lack of additional changes in PMSA. We conclude that Amax/Km provides a sensitive indication of PMSA, because it 1) increases with increasing Qb and decreasing PVR, 2) reaches a maximum at Qb values that correspond to the minimal values in PVR, and 3) like PVR, did not change with further increases in Qb. Compared with predicted changes in PMSA produced by either microvascular recruitment alone or distension alone, our data indicate that recruitment is a larger contributor to the observed increase in PMSA.     

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.     

Measurement of human fetal blood flow.

Real-time B-mode ultrasonography was combined with a pulsed Doppler ultrasound technique for transcutaneous measurement of human fetal blood flow in the aorta and intra-abdominal part of the umbilical vein. The target vessel was located and its diameter measured in the two-dimensional real-time image. The pulsed Doppler transducer was attached to the real-time transducer at a fixed angle. By processing the Doppler shift signals the instrument estimated the mean and maximum blood velocities and the integral under the velocity curves. This permitted calculation of the blood flow. The method was applied to 26 fetuses in normal late pregnancies. Mean blood flow in the descending part of the fetal aorta based on maximum velocity was 191 ml/kg/min. Mean flow in the intra-abdominal part of the umbilical vein was 110 ml/kg/min. This method of measurement is non-invasive and opens new perspectives in studying fetal haemodynamics.     

Effects of reducing uterine blood flow on fetal blood flow distribution and oxygen delivery.

We examined the effect of graded reduction in uterine blood flow on distribution of cardiac output and oxygen delivery to fetal organs and venous blood flow patterns in 9 fetal sheep using the radionuclide-labeled microsphere technique. We reduced uterine blood flow in two steps, decreasing fetal oxygen delivery to 70% and 50% of normal, and compared the results with those from a similar study from our laboratory on graded umbilical cord compression. With 50% reduction in fetal oxygen delivery, blood flow and the fraction of the cardiac output distributed to the brain, heart, and adrenal gland increased and that to the lungs, carcass, skin, and scalp decreased. Oxygen delivery to the brain and myocardium was maintained, while that to the adrenal doubled, and that to the brain stem increased transiently. The decrease in oxygen delivery to both carcass and lower body segment correlated linearly with oxygen consumption (P less than 0.001). The proportion of umbilical venous blood passing through the ductus venosus increased from 44.6% to 53% (P less than 0.05). The preferential distribution of ductus venosus blood flow through the foramen ovale to the heart and brain increased, but that to the upper carcass decreased so that ductus venosus-derived blood flow to the upper body did not change. Hence, the oxygen delivered to the brain from the ductus venosus was maintained, and that to the heart increased 54% even though ductus venosus-derived oxygen delivery to the upper body fell 34%. Abdominal inferior vena caval blood flow and its contribution to cardiac output decreased, but the proportion of the abdominal inferior vena caval blood distributed through the foramen ovale also increased from 23.0 to 30.9%. However, the actual amount of inferior vena caval blood passing through the foramen ovale did not change. There was a 70% fall in oxygen delivery to the upper body segment from the inferior vena cava. A greater portion of superior vena caval blood was also shunted through the foramen ovale to the upper body, but the actual amounts of blood and oxygen delivered to the upper body from this source were small. Thus, graded reduction of uterine blood flow causes a redistribution of fetal oxygen delivery and of venous flow patterns, which is clearly different from that observed previously during graded umbilical cord occlusion.     

Effect of reduced uterine blood flow on fetal and maternal cortisol

We have measured the changes in fetal and maternal plasma concentrations of cortisol in relation to blood gases and percent oxygen saturation during 2- and 4-h episodes of reversibly reduced uterine blood flow in sheep between 120 days gestation and term. During that period of reduced uterine blood flow there was a significant decrease in fetal arterial percent oxygen saturation (SaO2), PO2 and pH. Fetal SaO2 decreased from 59.5 +/- 3.2% to 31.8% +/- 2.8% by 15 min, 32.9 +/- 2.9% by 60 min, and 33.5 +/- 2.9% by 120 min. Fetal PO2 decreased from 3.2 +/- 0.1 KPa to 2.0 +/- 0.2 KPa by 15 min, 2.2 +/- 0.2 KPa by 60 min and 2.3 +/- 0.1 KPa by 120 min. Fetal pH decreased from 7.36 +/- 0.01 to 7.30 +/- 0.03 by 15 min, 7.27 +/- 0.02 by 60 min and 7.25 +/- 0.03 by 120 min. During the period of reduced uterine blood flow, fetal plasma concentrations of cortisol increased from 37.1 +/- 10.8 nmol/l to 53.3 +/- 9.2 nmol/l by 15 min, 49.2 +/- 11.4 nmol/l by 60 min and 43.3 +/- 9.0 nmol/l by 120 min. The greatest percentage increase in fetal plasma concentrations of cortisol occurred in fetuses of 126-139 days gestation. There was no significant change in maternal blood gases, SaO2 or plasma concentrations of cortisol. These experiments demonstrate that there is a significant increase in fetal plasma concentrations of cortisol in response to reductions in uterine blood flow from as early as 120 days gestation.     

EDRF inhibition attenuates the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs.

At birth, pulmonary vasodilation occurs during rhythmic distension of the lungs and oxygenation. Inhibition of prostaglandin synthesis prevents pulmonary vasodilation during rhythmic distension of the lungs but not during oxygenation. Because endothelium-derived relaxing factor (EDRF) modulates pulmonary vascular tone at birth, at rest, and during hypoxia in older animals, we hypothesized that EDRF may modulate pulmonary vascular tone during oxygenation in fetal lambs. We studied the responses to N omega-nitro-L-arginine, a competitive inhibitor of EDRF synthesis, in nine near-term fetal lambs and to drug vehicle in six of these lambs and the subsequent responses to in utero ventilation with 95% O2 in these fetal lambs. In all fetal lambs, prostaglandin synthesis was prevented by meclofenamate. N omega-nitro-L-arginine increased pulmonary and systemic arterial pressures by 28% (P < 0.05) and 31% (P < 0.05), respectively, and decreased pulmonary blood flow by 83% (P < 0.05). In the controls, ventilation with 95% O2 increased pulmonary blood flow by 1,050% (P = 0.05) without changing pressures, thereby decreasing pulmonary vascular resistance by 88% (P = 0.05). During N omega-nitro-L-arginine infusion, ventilation with 95% O2 increased pulmonary blood flow by 162% (P = 0.05) and decreased pulmonary vascular resistance by 74% (P = 0.05). This suggests that EDRF may play an important role in modulating resting pulmonary vascular tone in fetal lambs and in the vasodilatory response to ventilation with O2 in utero.     

Polyuria and impaired renal blood flow after asphyxia in preterm fetal sheep

Renal impairment is common in preterm infants, often after exposure to hypoxia/asphyxia or other circulatory disturbances. We examined the hypothesis that this association is mediated by reduced renal blood flow (RBF), using a model of asphyxia induced by complete umbilical cord occlusion for 25 min (n = 13) or sham occlusion (n = 6) in chronically instrumented preterm fetal sheep (104 days, term is 147 days). During asphyxia there was a significant fall in RBF and urine output (UO). After asphyxia, RBF transiently recovered, followed within 30 min by a secondary period of hypoperfusion (P < 0.05). This was mediated by increased renal vascular resistance (RVR, P < 0.05); arterial blood pressure was mildly increased in the first 24 h (P < 0.05). RBF relatively normalized between 3 and 24 h, but hypoperfusion developed again from 24 to 60 h (P < 0.05, analysis of covariance). UO significantly increased to a peak of 249% of baseline between 3 and 12 h (P < 0.05), with increased fractional excretion of sodium, peak 10.5 +/- 1.4 vs. 2.6 +/- 0.6% (P < 0.001). Creatinine clearance returned to normal after 2 h; there was a transient reduction at 48 h to 0.32 +/- 0.02 ml.min(-1).g(-1) (vs. 0.45 +/- 0.04, P < 0.05) corresponding with the time of maximal depression of RBF. No renal injury was seen on histological examination at 72 h. In conclusion, severe asphyxia in the preterm fetus was associated with evolving renal tubular dysfunction, as shown by transient polyuria and natriuresis. Despite a prolonged increase in RVR, there was only a modest effect on glomerular function.     

Measurement of renal blood flow in the rat.

The radioactive microsphere technique is a simple method for measurement of RBF and intrarenal blood flow distribution in the rat that does not require surgical manipulation of the kidney or general anesthesia. The results are reproducible and compatible with other established techniques.     

Effect of aging on renal blood flow velocity during static exercise

During exercise, activation of the sympathetic nervous system causes reflex renal vasoconstriction. The effects of aging on this reflex are poorly understood. This study evaluated the effects of age on renal vasoconstrictor responses to handgrip. Seven older (65 +/- 9 yr) and nine younger (25 +/- 2 yr) subjects were studied. Beat-by-beat analyses of changes in renal blood flow velocity (RBV; duplex ultrasound) were performed during two handgrip paradigms. Arterial blood pressure (BP) and heart rate were also measured, and an index of renal vascular resistance (RVR) was calculated (BP/RBV). In protocol 1, fatiguing handgrip [40% of maximal voluntary contraction (MVC)] caused a greater increase in RVR in the older subjects (old 90% +/- 15 increase, young 52% +/- 4 increase; P = 0.03). During posthandgrip circulatory arrest (isolates muscle metaboreflex), the increases in RVR were only approximately 1/2 of the increase seen at end grip. In protocol 2, 15-s bouts of handgrip at graded intensities led to increases in RVR in both subject groups. This effect was not seen until 50% MVC workload (P < 0.05). RVR responses occurred early and were greater in older than in younger subjects at 50% MVC (32 +/- 6% vs. 16 +/- 5%; P = 0.02) and 70% MVC (39 +/- 11% vs. 24 +/- 8%; P = 0.02). Static exercise-induced renal vasoconstriction is enhanced with aging. Because the characteristics of this response suggest a predominant role for mechanoreceptor engagement, we hypothesize that mechanoreceptor responses are augmented with aging.     

Effects of renal denervation on cardiovascular and renal responses to ACE inhibition in conscious lambs

Smith, Francine G., Suzanne Chan, and Saskia N. De Wildt.Effects of renal denervation on cardiovascular and renal responsesto ACE inhibition in conscious lambs. J. Appl.Physiol. 83(2): 414-419, 1997.Cardiovascular andrenal effects of either the angiotensin-converting enzyme inhibitorcaptopril or vehicle were measured in chronically instrumented lambs inthe presence (intact; n = 6) andabsence of renal sympathetic nerves (denervated; n = 5) to determine whether there wasan interaction between the renin-angiotensin system and renalsympathetic nerves early in life. Captopril caused a similar decreasein mean arterial pressure (P < 0.001) in intact and denervated lambs, predominantly through a decreasein diastolic pressure. Heart rate was increased from 177 ± 34 to213 ± 22 (SD) beats/min during captopril compared with vehicleinfusion in intact lambs. In denervated lambs, basal heart rates wereelevated to 218 ± 33 beats/min; there was no further increase inheart rate during captopril compared with vehicle infusion. Captoprilinfusion caused a decrease in renal vascular resistance but only in theabsence of renal nerves. These findings provide evidence to suggestthat early in life there is an interaction between renal sympatheticnerves and the renin-angiotensin system in regulating renalhemodynamics and the baroreflex control of the heart.

     

Effect of nitric oxide synthase inhibition on regional blood flow during hyperthermia

The loss of compensatory splanchnic vasoconstriction during hyperthermia was assessed in rats after administration of either 0, 10, 30, or 100mg/kg N(w)-nitro-L-arginine methyl ester,L-NAME. Rectal temperature (T(re)), heart rate (HR), mean arterial blood pressure (MAP), breathing frequency (BF), and renal, mesenteric and caudal blood flows (Q(R), Q(M) and Q(C)) were measured until irreversible cardiovascular collapse occurred. HR, MAP and BF increased as T(re) rose to 42 degrees C, then fell as circulatory collapse occurred. As dose increased T(re) at collapse decreased. Q(M) decreased until a T(re) of 41.5-42 degrees C and then increased. Q(R) and Q(C) were unaffected by either hyperthermia orL-NAME. Inhibition of NO synthase did not prevent the circulatory collapse of heatstroke; the higher doses ofL-NAME may have exacerbated the onset of circulatory failure.