Endothelin resets renal blood flow autoregulatory efficiency during acute blockade of NO in the rat

First published August 15, 2001; 10.1152/ajprenal.00078.2001.—Renal blood flow (RBF) autoregulatory efficiency may be enhanced during NO inhibition in the rat, as recently reported. Under these conditions, endothelin (ET) synthesis and release may be increased. Our purpose was therefore to determine the role of ET in RBF autoregulatory changes induced by NO inhibition. To address this point, ETA/B receptors were blocked in anesthetized rats with bosentan, or selectively with BQ-610 or BQ-788. NO synthesis was inhibited with N G-nitro-l-arginine methyl ester (l-NAME). Mean arterial pressure (MAP) was decreased after bosentan (−10 mmHg; P < 0.01) or increased after l-NAME (25 mmHg; P < 0.001). RBF measured with an electromagnetic flow probe was reduced byl-NAME (−50%) and by BQ-788 (−24%). The pressure limits of the autoregulatory plateau (PA ∼100 mmHg) and of no RBF autoregulation (Po ∼80 mmHg) were significantly lowered by 15 mmHg after l-NAME but were unchanged after bosentan, BQ-610, or BQ-788. During NO inhibition, autoregulatory resetting was completely hindered by bosentan (PA ∼100 mmHg) and by ETB receptor blockade with BQ-788 (PA ∼106 mmHg), but not by ETA receptor blockade with BQ-610 (PA ∼85 mmHg). These results suggest that the involvement of ET in the RBF autoregulatory resetting occurs during NO inhibition, possibly by preferential activation of the ETB receptor. However, the relative contribution of ET receptor subtypes remains to be further specified.

Dynamics of flow, resistance, and intramural vascular volume in canine coronary circulation

Varying coronary volume will vary vascular resistance and thereby have an effect on coronary hemodynamics. Six ventricular septa were isolated from anesthetized dogs, dispersed in a biaxial stretch apparatus at diastolic stress, and perfused artificially with an oxygenated perfluorochemical emulsion at maximal vasodilation. Flow and thickness were measured continuously by an electromagnetic flow probe and sonomicrometer. Pressure was varied sinusoidally around 30, 50, and 70 mmHg with an amplitude of 7.5 mmHg; frequencies ranged between 0.015 and 7 Hz. Bode plots of admittance (flow/pressure) and capacitance (scaled thickness/pressure) were constructed. A two-compartment model was used in which the resistances vary with volume. Realistic values of microvascular compliance (∼0.3 ml ⋅ mmHg−1 ⋅ 100 g−1) were found. Values 10 times higher were then found when resistances were forced to be constant. We concluded that volume dependence of resistances have to be taken into account when dynamic or static pressure-flow relations are studied and conceal the effect of a large intramyocardial compliance on arterial hemodynamics.

Medullary blood flow responses to changes in arterial pressure in canine kidney

Although it is well recognized that whole kidney and cortical blood flow exhibit efficient autoregulation in response to alterations in renal arterial pressure (RAP), the autoregulatory behavior of medullary blood flow (MBF) has remained uncertain. We have evaluated MBF responses to stepwise reductions in RAP for both short-term (2 min, n = 6) and longer periods (15 min, n = 7) using single-fiber laser-Doppler flowmetry with needle probes inserted into the mid-medullary region in denervated kidneys of 13 anesthetized dogs. The changes in cortical blood flow (CBF) were assessed with either a surface probe or a needle probe inserted into the cortex. Control total renal blood flow (RBF), assessed by electromagnetic flow probe in these dogs, was 5.2 +/- 0.3 ml.min-1.g-1, and glomerular filtration rate was 0.97 +/- 0.05 ml.min-1.g-1 (n = 7). RBF, MBF, and CBF all exhibited efficient autoregulatory behavior during changes in RAP from 150 to 75 mmHg. The slopes of RAP vs. RBF, CBF, as well as MBF, were not significantly different from zero within this range of RAP. Below RAP of 75 mmHg, all indexes of blood flow showed linear decreases with reductions in pressure. The data indicate that blood flow in the renal medulla of dogs exhibits efficient autoregulatory behavior, similar to that in the cortex.

Left ventricular volumetric conductance catheter for rats

Left ventricular (LV) volume (V) is an essential parameter for assessment of the cardiac pump function. Measurement of LVV in situ by a conductance catheter method has been widely used in dogs and humans but not yet in small experimental animals such as rats. We instituted a miniaturized six-electrode conductance catheter (3-F) for rat LVV measurement and its signal processing apparatus. We compared stroke volumes (SVs) simultaneously measured with this conductance catheter introduced into the LV through the apex and an electromagnetic flow probe placed on the ascending aorta during gradual decreases in LVV by an inferior vena caval occlusion. A high and linear correlation (r = 0.982) was obtained between these differently measured by SVs pooled from six rats. In another group of three rats, LV pressure was simultaneously measured with a 3-F catheter-tip micromanometer introduced into the LV through the apex. We obtained the slope of the end-systolic pressure-volume (P-V) relationship (Emax) by a gradual ascending aortic occlusion. After administration of propranolol, Emax obviously decreased with no change in volume intercept of the P-V relationship. The conductance volumetry proved to be useful in rats.

Kinetics of amino acid and glucose absorption following pancreatic diversion in the pig

An experiment was conducted in the pig to determine the consequences of deprivation of exocrine pancreatic secretion on the composition and quantity of nutrients absorbed after intake of a balanced diet. Five growing pigs (53·8 kg body weight) were fitted with permanent catheters in the portal vein and the carotid artery and with an electromagnetic flow probe around the portal vein to measure the exchanges between the blood and the intestinal lumen. They were also fitted with a permanent catheter in the duct of Wirsung to educe the exocrine pancreatic secretion and another one in the duodenum in order to reintroduce it. In each animal, glucose, amino-N and amino acid absorption as well as insulin and glucagon production were measured over a period of 10 h after the meal (semi-purified diet based on purified starch and containing 180 g fish meal/kg, DM content of the meal 731 g), either in the presence of pancreatic juice (group C : immediate reintroduction), or in the absence of pancreatic juice (group D: deprivation). The deprivation of pancreatic juice provoked a marked depression in the absorption of glucose (D 67·9 (SEM 27·9) g/10 h, C 437·7 (SEM 39·5) g/10 h, P < 0·00l), and of amino-N (D 7·55 (SEM 0·54) g/10 h, C 15·80 (SEM 0·79) g/10 h, P < 0·001). The composition of the mixture of amino acids in the portal blood was only slightly modified: only the levels of histidine (P < 0·05) and of valine (P < 0·06, NS) decreased in the absence of pancreatic juice. Insulin production was much lower (by 64%, P < 0·05) in the absence of pancreatic juice whereas that of glucagon was not affected.

Renal responses to intra-arterial administration of adrenomedullin in dogs

The present study was undertaken to evaluate the renal responses to intra-arterial infusion (12.5 pmol.kg-1.min-1) for 30 min of adrenomedullin (ADM) in denervated kidneys of anesthetized dogs (n = 8). Total renal blood flow (RBF) was measured with an electromagnetic flow probe, and two single-fiber laser-Doppler needle flow probes were used to measure relative changes in cortical (CBF) and medullary blood flow (MBF). ADM administration resulted in decreases in renal vascular resistance (32.3 +/- 4.9 to 22.3 +/- 3.0 mmHg.ml-1.min.g) and increases in RBF (4.5 +/- 0.5 to 6.0 +/- 0.6 ml.min-1.g-1), CBF (33 +/- 1.3%, n = 41, and MBF (32 +/- 5.7%, n = 5) without changes in glomerular filtration rate. There were also substantial increases in urine flow (11.3 +/- 1.9 to 28 +/- 4.8 microliters.min-1.g-1), as well as in sodium excretion (1.8 +/- 0.2 to 4.2 +/- 0.6 microliter.min-1.g-1). After cessation of ADM infusion, partial recovery of these responses was observed within a 30-min period. Responses to ADM were attenuated during inhibition of nitric oxide (NO) synthesis by nitro-L-arginine (50 micrograms.kg-1.min-1). These findings indicate that renal vasodilator, diuretic, and natriuretic responses to ADM may be mediated by the release of endogenous NO and suggest that ADM could play a role in regulating water and electrolyte excretion by the kidney.

Intrapericardial denervation: responses to water immersion in rhesus monkeys

Eleven anesthetized rhesus monkeys were used to study cardiovascular, renal, and endocrine alterations associated with 120 min of head-out water immersion. Five animals underwent complete intrapericardial denervation using the Randall technique, while the remaining six monkeys served as intact controls. Each animal was chronically instrumented with an electromagnetic flow probe on the ascending aorta, a strain gauge pressure transducer implanted in the apex of the left ventricle (LV), and electrocardiogram leads anchored to the chest wall and LV. During immersion, LV end-diastolic pressure, urine flow, glomerular filtration rate, sodium excretion, and circulating atrial natriuretic peptide (ANP) each increased (P < 0.05) for intact and denervated monkeys. There were no alterations in free water clearance in either group during immersion, yet fractional excretion of free water increased (P < 0.05) in the intact monkeys. Plasma renin activity (PRA) decreased (P < 0.05) during immersion in intact monkeys but not the denervated animals. Plasma vasopressin (PVP) concentration decreased (P < 0.05) during the first 30 min of immersion in both groups but was not distinguishable from control by 60 min of immersion in denervated monkeys. These data demonstrate that complete cardiac denervation does not block the rise in plasma ANP or prevent the natriuresis associated with head-out water immersion. The suppression of PVP during the first minutes of immersion after complete cardiac denervation suggests that extracardiac sensing mechanisms associated with the induced fluid shifts may be responsible for the findings.

Effect of carotid sinus stimulation on resistance and critical closing pressure of the canine hindlimb

Sympathetically mediated changes in blood pressure are thought to occur through changes in arterial resistance (Ra). To test whether the critical closing pressure (Pcrit) could also play a role, we pump-perfused the vascularly isolated canine hindlimb at constant flow. Carotid sinuses were isolated and both vagus nerves cut. Carotid sinus (Pcar), arterial, perfusion (Pper), and venous (Pv) pressures and flow to the hindlimb (Q, electromagnetic flow probe) were measured. By decreasing pump flow to zero over time periods of 1-10 s and measuring the pressure at zero-flow, it was possible to estimate arterial compliance and Pcrit. Ra was calculated as (Pper - Pcrit)/Q. Venous resistance was calculated as (Pel - Pv)/Q, where Pel is the pressure in the compliant region obtained by the double-occlusion technique. Raising Pcar from 115 +/- 7 to 203 +/- 10 mmHg (n = 6) decreased Pcrit from 49.7 +/- 4.3 to 25.9 +/- 2.6 mmHg and Ra from 10.7 +/- 1.2 to 6.8 +/- 0.9 mmHg.min.100 g-1.ml-1 (P < 0.05). Lowering Pcar from 119 +/- 6 to 71 +/- 6 mmHg (n = 6) increased Pcrit from 37.0 +/- 3.3 to 61.0 +/- 8.5 mmHg and Ra from 10.0 +/- 1.6 to 14.0 +/- 2.4 mmHg.min.100 g.ml-1 (P < 0.05). Arterial compliance increased when Pcar was raised (P < 0.05) and decreased when Pcar was decreased (P < 0.1). Venous resistance did not change when Pcar was altered. In conclusion, changes in carotid sinus stimulation alters blood flow to the hindlimb through changes in both Pcrit and Ra.

Renal medullary interstitial infusion of diltiazem alters sodium and water excretion in rats

The role of renal papillary blood flow in regulation of fluid and electrolyte excretion was examined. The effects of an acute infusion of diltiazem (5 micrograms.kg-1 x min-1) into the renal medullary interstitium on papillary blood flow and sodium and water excretion were studied. Changes of renal blood flow were measured using an electromagnetic flow probe. Cortical and papillary blood flows were measured using laser-Doppler flowmetry. Renal and cortical blood flows were unchanged during medullary interstitial infusion of diltiazem, but papillary blood flow increased 26% (P < 0.05) and remained elevated for 1 h after diltiazem infusion was discontinued. Glomerular filtration rate (GFR) of the infused kidney increased by 21% from a control of 1.0 +/- 0.1 ml.min-1 x g-1 during infusion of diltiazem (P < 0.05), but it returned to control after diltiazem infusion was stopped. Urine flow and sodium excretion increased by 70% (P < 0.05), and fractional sodium excretion rose from 1.5 +/- 0.2 to 2.4 +/- 0.3% of the filtered load during the hour after diltiazem infusion. Renal blood flow, cortical and papillary blood flow, GFR, urine flow, and sodium excretion in the 0.9% sodium chloride vehicle-infused kidney were not significantly altered during the experiment. Intravenous infusion of the same dose of diltiazem (5 micrograms.kg-1 x min-1) increased GFR by 22%, but had no effect on urine flow and sodium excretion. These results indicate that renal medullary interstitial infusion of diltiazem selectively increased renal papillary blood flow, which was associated with an increase of sodium and water excretion.

The role of migrating myoelectric complexes in the regulation of digesta transport in the preruminant calf

Four calves were equipped with an electromagnetic flow probe inside the tranverse duodenum and with electrodes at intervals of 2 cm on either side of the probe. Amounts of 0.5, 2.0, 3.5, and 5.0 kg of whole milk were given according to a latin square design. Recordings of digesta flow and myoelectric activity were made during a 5.6-h period after feeding to quantify the influence of migrating myoelectric complexes on digesta flow through the transverse duodenum of preruminant calf under different levels of milk intake. Immediately after feeding, a phase of irregular spiking activity appeared; its length increasing linearly (p = 0.002) with the amount of milk fed. Increasing milk intake led to linear increases in duration (p = 0.001) and total electrical activity (p = 0.002) of the irregular activity phases, quadratic shortening of the quiescent phases (p = 0.021), and linear decrease (p = 0.006) in the numbers of migrating myoelectric complexes. Intermittent flows of digesta, each of them corresponding to a strong spike burst, appeared during irregular spiking activity phases. Augmentation of the milk ingested did not affect the volume of each gush of digesta but caused a cubic increase in the number of gushes (p = 0.023) and in the total volume of digesta (p = 0.009). These cubic effects implied that with increased intake of milk, the duodenum endeavoured to accelerate the flow of digesta in an attempt to return to an "empty state" in about the same time for all levels of milk consumed. This was achieved mainly through adjustments in the duration and activity of the irregular spiking activity phase.Key words: calf, myoelectric complex, digesta transport, milk intake.