Glomerular haemodynamic profile of patients with Type 1 diabetes compared with healthy control subjects.

AIMS: To evaluate the glomerular haemodynamic profile of patients with Type 1 diabetes with either renal hyperfiltration (GFR ≥ 135 ml/min/1.73 m2 ) or renal normofiltration (GFR 90-134 ml/min/1.73 m2 ) during euglycaemic and hyperglycaemic conditions, and to compare this profile with that of a similar group of healthy control subjects. METHODS: Gomez's equations were used to derive afferent and efferent arteriolar resistances, glomerular hydrostatic pressure and filtration pressure. RESULTS: At baseline, during clamped euglycaemia, patients with Type 1 diabetes and hyperfiltration had lower mean ± sd afferent arteriolar resistance than both those with Type 1 diabetes and normofiltration (914 ± 494 vs. 2065 ± 597 dyne/s/cm5 ; P < 0.001) and healthy control subjects (1676 ± 707 dyne/s/cm(5) ; p < 0.001). By contrast, efferent arteriolar resistance was similar in the three groups. Patients with Type 1 diabetes and hyperfiltration also had higher mean ± sd glomerular hydrostatic pressure than both healthy control subjects and patients with Type 1 diabetes and normofiltration (66 ± 6 vs. 60 ± 3 vs. 55 ± 3 mmHg; P < 0.05). Similar findings for afferent arteriolar resistance, efferent arteriolar resistance, glomerular hydrostatic pressure and filtration pressure were observed during clamped hyperglycaemia. CONCLUSION: Hyperfiltration in Type 1 diabetes is primarily driven by alterations in afferent arteriolar resistance rather than efferent arteriolar resistance. Renal protective therapies should focus on afferent renal arteriolar mechanisms through the use of pharmacological agents that target tubuloglomerular feedback, including sodium-glucose cotransporter 2 inhibitors and incretins.

Involvement of renal sympathetic nerve activation on the progression of ischemic acute kidney injury in the mouse.

Renal ischemia produces renal sympathoexcitation that is responsible for the development of ischemic acute kidney injury. The present study examined changes in the sympathetic nerve function in mice. Ischemic acute kidney injury was induced by occlusion of both renal pedicles. Renal ischemia/reperfusion increased blood urea nitrogen and plasma creatinine and expression of tyrosine hydroxylase, a rate-limiting enzyme for the biosynthesis of noradrenaline, in the kidney. Renal immunoreactivity of tyrosine hydroxylase was observed along with vessel and tubular structure both in the sham-operated and the ischemic acute kidney injury mice. The prominent morphological change was that tyrosine hydroxylase immunoreactivity was observed in the glomeruli of the ischemic acute kidney injury mice, whereas there are almost no tyrosine hydroxylase immunoreactivity signals in the glomeruli of the sham-operated mice. This tyrosine hydroxylase immunoreactivity in the glomeruli is colocalized with synapsin I immunoreactivity in the ischemic acute kidney injury mice. Intraperitoneal pretreatment with DSP-4 (50 mg/kg) attenuated these changes induced by renal ischemia/reperfusion. These results suggest that morphological and functional changes of glomerulus adrenergic nerve terminal are involved in the pathophysiology of ischemia/reperfusion-induced ischemic acute kidney injury.

Glomerular haemodynamics, the renal sympathetic nervous system and sepsis-induced acute kidney injury.

BACKGROUND: To describe recent insights into glomerular haemodynamics in septic acute kidney injury (AKI). METHODS: We reviewed the literature with particular emphasis on recent findings in animal experiments and human studies in relation to renal macro- and micro-renal haemodynamics during septic AKI. RESULTS: The dominant paradigm is that septic AKI is due to decreased renal perfusion with ischaemic loss of glomerular filtration rate (GFR), ischaemic tubular cell injury and acute tubular necrosis (ATN). However, recent experimental and human studies challenge this view of the pathogenesis of septic AKI. In addition, rapid post-mortem and experimental histological studies do not support ATN as the histological substrate of septic AKI. Finally, more recent experimental evidence suggests that changes in the glomerular and peri-glomerular haemodynamics provide a more likely explanation for the loss of GFR seen in the early phases of septic AKI. CONCLUSIONS: Despite a long-standing paradigm that septic AKI is due to renal hypo-perfusion and associated ATN, experimental and human studies increasingly suggest that changes in the state of the glomerular and peri-glomerular micro-vasculature are a more likely additional explanation for this condition.

Topology of Schwann cells and sympathetic innervation along preglomerular vessels: a confocal microscopic study in protein S100B/EGFP transgenic mice.

Schwann cells (Sc), associated axons, and nearby vascular endothelium constitute a functional trilogy of major importance during the development and regrowth of peripheral vascular nerves. The goal of the present study is to provide a technique of triple fluorescence confocal imaging of these cell types along renal preglomerular vessels. We took advantage of a protein S100B/EGFP transgenic mouse to visualize Sc. The endothelium was labeled with an intravenous injection of fluorescently tagged lectin, and after tissue processing, adrenergic nerves were revealed with an antibody against the marker protein synaptophysin. As a validation step, we found that EGFP-positive perivascular cells with prominent cell bodies and extensive, multidirectional cell processes were protein S100B positive. They were identified as Sc and indirectly assumed to be unmyelinated Sc. By contrast, we found strong EGFP expression in proximal epithelial cells and in the epithelium lining thin limbs of Henle. This epithelial fluorescence was not associated with immunoreactive protein S100B and thus corresponded to ectopic EGFP expressions in this mouse strain. Sc were organized in bundles or as a meshwork surrounding the preglomerular vasculature from arcuate arteries to afferent arterioles. No Sc were detected in the medulla. Although most Sc were closely apposed to adrenergic varicosities, many varicosities were not associated with detectable Sc processes. The present technique, and the capacity of confocal microscopy to yield three-dimensional imaging, allow the study of the microtopology of Sc and related sympathetic axons in the renal perivascular interstitium.

Differential neural control of glomerular ultrafiltration.

The renal nerves constrict the renal vasculature, causing decreases in renal blood flow (RBF) and glomerular filtration rate (GFR). Whether renal haemodynamics are influenced by changes in renal nerve activity within the physiological range is a matter of debate. We have identified two morphologically distinct populations of nerves within the kidney, which are differentially distributed to the renal afferent and efferent arterioles. Type I nerves almost exclusively innervate the afferent arteriole whereas type II nerves are distributed equally on the afferent and efferent arterioles. We have also demonstrated that type II nerves are immunoreactive for neuropeptide Y, whereas type I nerves are not. This led us to hypothesize that, in the kidney, distinct populations of nerves innervate specific effector tissues and that these nerves may be selectively activated, setting the basis for the differential neural control of GFR. In physiological studies, we demonstrated that differential changes in glomerular capillary pressure occurred in response to graded reflex activation of the renal nerves, compatible with our hypothesis. Thus, sympathetic outflow may be capable of selectively increasing or decreasing glomerular capillary pressure and, hence, GFR by differentially activating separate populations of renal nerves. This has important implications for our understanding of the neural control of body fluid balance in health and disease.

ATP release in human kidney cortex and its mitogenic effects in visceral glomerular epithelial cells.

BACKGROUND: In chronic renal failure the sympathetic nervous system is activated. Sympathetic cotransmitters released within the kidney may contribute to the progression of renal disease through receptor-mediated proliferative mechanisms. METHODS: In human renal cortex electrical stimulation induced adenosine 5'-triphosphate (ATP; luciferin-luciferase-assay) and norepinephrine (HPLC) release was measured. ATP release also was induced by alpha1- and alpha2-adrenergic agonists. [3H]-thymidine uptake was tested in human visceral glomerular epithelial cells (vGEC) and mitogen-activated protein kinase (MAPK42/44) activation in vGEC and kidney cortex. The involved P2-receptors were characterized pharmacologically and by RT-PCR. RESULTS: Sympathetic nerve stimulation and alpha-adrenergic agonists induced release of ATP from human kidney cortex. Seventy-five percent of the ATP released originated from non-neuronal sources, mainly through activation of alpha2-adrenergic receptors. ATP (1 to 100 micromol/L) and related nucleotides (1 to 100 micromol/L) increased [3H]-thymidine uptake. The adenine nucleotides ATP, ATPgammaS, ADP and ADPbetaS were about equally potent. UTP, UDP and alpha,beta-methylene ATP had no effect. ATP, ADPbetaS but not alpha,beta-methylene ATP activated MAPK42/44. ATP induced MAPK42/44 activation, and [3H]-thymidine uptake was abolished in the presence of the MAPK inhibitor PD 98059 (100 micromol/L). mRNA for P2X4,5,6,7 and P2Y1,2,4,6,11 were detected in human vGEC by RT-PCR. CONCLUSIONS: In human renal cortex, adrenergic stimulation releases ATP from neuronal and non-neuronal sources. ATP has mitogenic effects in vGEC and therefore the potential to contribute to progression in chronic renal disease. The pattern of purinoceptor agonist effects on DNA synthesis together with the mRNA expression suggests a major contribution of a P2Y1-like receptor.

Preglomerular and postglomerular resistance responses to different levels of sympathetic activation by hypoxia.

This study investigated the effects of graded reflex increases in renal sympathetic nerve activity (RSNA) on renal preglomerular and postglomerular vascular resistances. With the use of hypoxia to reflexly elicit increases in RSNA without affecting mean arterial pressure, renal function and stop-flow pressures were measured in three groups of rabbits before and after exposure to room air and moderate (14% O2) or severe (10% O2) hypoxia. Moderate and severe hypoxia increased RSNA, primarily by increasing the amplitude of the sympathetic bursts rather than their frequency. RSNA amplitude increased by 20 +/- 6% (P < 0.05) and 60 +/- 16% (P < 0.05), respectively. Moderate hypoxia decreased estimated renal blood flow (ERBF; 26 +/- 7%; P = 0.07), whereas estimated glomerular capillary pressure (32 +/- 1 versus 34 +/- 1 mmHg; P < 0.05) and filtration fraction (FF; P < 0.01) increased. In response to moderate hypoxia, calculated preglomerular (approximately 20%) and postglomerular (approximately 70%) resistance both increased, but only the increase in postglomerular resistance was significant (P < 0.05). In contrast, severe hypoxia decreased ERBF (56 +/- 8%; P < 0.01), GFR (55 +/- 9%; P < 0.001), and glomerular capillary pressure (32 +/- 1 versus 29 +/- 1 mmHg; P < 0.001), with no change in FF, reflecting similar preglomerular (approximately 240%; P < 0.05) and postglomerular ( approximately 250%; P < 0.05) contributions to the vasoconstriction and a decrease in calculated K(f) (P < 0.05). These results provide evidence that reflexly induced increases in RSNA amplitude may differentially control preglomerular and postglomerular vascular resistances.

Sympathetic modulation of renal blood flow by rilmenidine and captopril: central vs. peripheral effects.

Renal blood flow (RBF) is modulated by renal sympathetic nerve activity (RSNA). However, agents that are supposed to reduce sympathetic tone, such as rilmenidine and captopril, influence RBF also by direct arteriolar effects. The present study was designed to test to what extent the renal nerves contribute to the renal hemodynamic response to rilmenidine and captopril. We used a technique that allows simultaneous recording of RBF and RSNA to the same kidney in conscious rabbits. We compared the dose-dependent effects of rilmenidine (0.01-1 mg/kg) and captopril (0.03-3 mg/kg) on RBF and RSNA in intact and renal denervated (RNX) rabbits. Because rilmenidine and captopril lower blood pressure, studies were also performed in sinoaortically denervated (SAD) rabbits to determine the role of the baroreflex in the renal hemodynamic response. Rilmenidine reduced arterial pressure, RBF, and RSNA dose dependently. In intact rabbits (n = 10), renal conductance (RC) remained unaltered (3 +/- 5%), even after the 1-mg/kg dose, which completely abolished RSNA. In RNX rabbits (n = 6), RC fell by 18 +/- 5%, whereas in SAD rabbits (n = 7) RC increased by 30 +/- 20% after rilmenidine. In intact rabbits, captopril increased RSNA maximally by 64 +/- 8%. RSNA did not rise in SAD rabbits. Despite the differential response or absence of RSNA, captopril increased RC to a comparable degree (maximally 40-50%) in all three groups. Using spectral analysis techniques, we found that in all groups, independently of ongoing RSNA, captopril, but not rilmenidine, attenuated both myogenic (0.07-0.25 Hz) and tubuloglomerular feedback (0.01-0.07 Hz) related fluctuations in RC. We conclude that, in conscious rabbits, the renal vasodilator effect of rilmenidine depends on the level of ongoing RSNA. Its sympatholytic effect is, however, blunted by a direct arteriolar vasoconstrictor effect. In contrast, the renal vasodilator effect of captopril is not modulated by ongoing RSNA and is associated with impairment of autoregulation of RBF.

Renal nerve stimulation restores tubuloglomerular feedback after acute renal denervation.

Renal nerves play an important role in the setting of the sensitivity of the tubuloglomerular feedback (TGF) mechanism. We recently reported a time-dependent resetting of TGF to a lower sensitivity 3-4 h after acute unilateral renal denervation (aDNX). This effect persisted after 1 week, but was then less pronounced. To determine whether normal TGF sensitivity could be restored in aDNX kidneys by low-frequency renal nerve stimulation (RNS), the following experiments were performed. Rats with aDNX were prepared for micropuncture. In one experimental group proximal tubular free flow (Pt) and stop flow pressures (Psf) were measured during RNS at frequencies of 2, 4 and 6 Hz. In another series of experiments the TGF sensitivity was evaluated from the Psf responses at different loop perfusion rates after 20 min of RNS at a frequency of 2 Hz. The maximal drop in Psf (delta Psf) and the tubular flow rate at which half the maximal response in delta Psf was observed (turning point, TP), were recorded. At RNS frequencies of 2, 4 and 6 Hz, Pt decreased from the control level of 14.1 +/- 0.8-13.1 +/- 1.0, 12.4 +/- 1.1 and 11.2 +/- 0.8 mmHg (decrease 21%, P < 0.05), respectively, while at zero perfusion and during RNS at 2 and 4 Hz Psf decreased from 42.5 +/- 1.6 to 38.2 +/- 1.4 and 32.8 +/- 4.3 mmHg (decrease 23%, P < 0.05), respectively. The TGF characteristics were found to be reset from the normal sensitivity with TP of 19.0 +/- 1.1 nL min-1 and delta Psf of 8.7 +/- 0.9 mmHg to TP of 28.3 +/- 2.4 nL min-1 (increase 49%, P < 0.05) and delta Psf of 5.8 +/- 1.2 mmHg (decrease 33%) after aDNX. After 20 min of RNS at 2 Hz TP was normalized and delta Psf was 33% higher. Thus the present findings indicate that the resetting of the TGF sensitivity that occurred 2-3 h after aDNX could be partially restored by 20 min of RNS at a frequency of 2 Hz. These results imply that renal nerves have an important impact on the setting of the sensitivity of the TGF mechanism.

Alpha 2-adrenoceptors determine the response to nitric oxide inhibition in the rat glomerulus and proximal tubule.

Arginine-derived nitric oxide exerts control over the processes of glomerular filtration and tubular reabsorption. The tonic influence of nitric oxide over both of these is eliminated by renal denervation. The hypothesis that the renal nerves function, in this regard, via the activation of alpha 2-adrenoceptors was tested by renal micropuncture. The physical determinants of glomerular filtration and proximal tubular reabsorption were assessed in Munich-Wistar rats before and during the administration of the nitric oxide synthase inhibitor NG-monomethyl L-arginine (L-NMMA). In one set of studies, the systemic infusion of the alpha 2-agonist B-HT 933 rendered nephron GFR, nephron plasma flow, and proximal reabsorption sensitive to reduction by L-NMMA after renal denervation. In a second set of studies, the infusion of the alpha 2 receptor antagonist, yohimbine, to rats with renal nerves intact was found to suppress the effects of L-NMMA on nephron plasma flow and proximal reabsorption. The effects of L-NMMA on nephron GFR and nephron plasma flow, afferent and efferent arteriolar resistances, and proximal reabsorption correlated with the level of underlying alpha 2-adrenergic activity. The activation of renal alpha 2-adrenoceptors increases the influence of arginine-derived nitric oxide in the glomerulus and proximal tubule.

Effects of beta-adrenergic blockade on the glomerular and tubular response to acute renal denervation.

Using micropuncture techniques in euvolemic adult male Munich-Wistar rats, we assessed the functional role of renal beta-adrenoceptors in mediating neural control of glomerular filtration and proximal tubular reabsorption. The determinants of nephron filtration and rate of proximal tubular reabsorption were measured in two groups of animals before and after acute surgical renal denervation (DNX). Group A animals (n = 6) were pretreated with the beta-adrenoceptor antagonist propranolol (25 mg/kg body weight per day for 4-6 days). Group B animals (n = 7) served as non-beta-blocked controls. Acute renal DNX resulted in no significant change in nephron filtration rate or any of its determinants in either group. Acute DNX caused similar decrements in the rate of fluid reabsorption from the proximal convoluted tubule of beta-blocked and control rats. Loop of Henle fluid reabsorption did not appear to be affected by DNX in either group. Because the effect of denervation on proximal tubular reabsorption was not conditioned by prior beta-blockade, the beta-adrenoceptors present within the proximal convoluted tubule do not appear to be the primary mediators of the adrenergic influence on fluid transport in that segment of the nephron.

Neuropeptide Y (NPY)-like immunoreactive nerve fibers in the human and monkey (Macaca fascicularis) kidney.

Nerve fibers immunoreactive for neuropeptide Y (NPY) are demonstrated for the first time by the indirect immunofluorescence technique in the human and monkey kidney. NPY-like immunoactivity (NPY-LI) is shown in a bundle of nerve fibers in the surrounding connective tissue of arteries and to a lesser extent, veins, mainly at the juxtamedullary region. Varicose nerve terminals are shown associated with blood vessels and passing between tubules in the mid and lower cortex. NPY-LI nerve fibers are also seen surrounding afferent and occasionally efferent arterioles at the vascular pole of the glomeruli. The distribution of NPY-LI nerve fibers in the monkey and human kidneys is similar to that of other species, only the quantity of the nerve fibers varies.

Morphologic demonstration of adrenergic influences on the glomerulus.

Previous micropuncture studies found that increasing the adrenergic nerve activity to the kidneys elevates the pre- and postglomerular arteriolar resistances and decreases the glomerular capillary ultrafiltration coefficient (product of the filtration surface area and the hydraulic conductivity to water). To define the morphologic expression of this adrenergic effect on the glomerular capillaries the authors compared the microscopic vascular casts of entire glomeruli from right and left kidneys that were simultaneously perfusion-fixed during selective stimulation of only the left renal nerves. The maximum cross-sectional diameter of ten randomly chosen glomeruli from each stimulated and contralateral kidneys of eight rats averaged 123.7 +/- 4.1 mu in stimulated kidneys compared with a maximum diameter of 136.3 +/- 6.4 in the contralateral kidneys (P less than 0.001). The average perpendicular diameter of 100.4 +/- 1.5 mu in the stimulated kidneys was also significantly smaller than the average diameter of 110.7 +/- 1.9 mu in the contralateral kidneys (P less than 0.005). To examine if morphologic changes analogous to those found in whole glomeruli can be demonstrated at the single cell level, the authors assessed the size of mesangial cells in vitro before, during, and after exposure to the adrenergic neurotransmitter, norepinephrine. First passage mesangial cells approximately 4 weeks after explantation were studied by phase-contrast microscopy and recorded on time-lapse video recorder. The planar surface area of individual mesangial cells was measured by electronic planimeter from photographs of the video images. In response to norepinephrine (1 microM), the surface area decreased significantly on average, from 3.58 +/- 0.28 X 10(-6) sq mm to 3.38 +/- 0.27 (P less than 0.005). Washout of norepinephrine and replacement with hormone-free media in other cells led an increase in the surface area (from 2.47 +/- 0.43 X 10(-6) sq mm to 2.61 +/- 0.40, P less than 0.005). No changes were observed in cells initially bathed in hormone-free media. Thus, the morphologic equivalent of the adrenergic nerve-induced reduction in the ultrafiltration coefficient is a contraction of the glomerular corpuscle. By regulating the configuration of mesangial cells that anchor the glomerular capillary network to the vascular pole, the adrenergic nerve may concurrently determine the number of capillary channels available for filtration as well as the glomerular corpuscular volume.

[Monoaminergic innervation of the kidney of the carp (Cyprinus carpio L.)]. / Monoaminergicheskaia innervatsiia pochki karpa (Cyprinus carpio L.).

By means of fluorescent-histochemical method distribution of monoaminergic structures has been studied in the sympatho-adrenal system of the carp (Cyprinus carpio L.) mesonephros. Catecholaminergic nervous fibers are revealed in the walls of adrenal and venous vessels and glomerular arterioles. In the glomerular capillaries they are not found. In the walls of the venous vessels, besides catecholamine-containing nervous fibers, chromaffin cells with long processes running along the vessel are observed. Some contacts of catecholamine-containing structures of the mesonephric vascular wall with the proximal and, very seldom, with distal parts of the nephron canaliculi are demonstrated. Structures containing indolamines are not revealed.

Localization of beta adrenoceptor subtypes in rat kidney by light microscopic autoradiography.

The characteristics and localization of beta adrenoceptor subtypes in rat kidney sections have been examined using [125I]cyanopindolol and in vitro labeling combined with autoradiography. Binding was stereoselective since the (-)-isomers of propranolol and pindolol were some two orders of magnitude more effective as competitors than the (+)-isomers. Competition curves obtained using the subtype selective antagonists ICI 118,551 (beta-2) and betaxolol (beta-1) had low pseudo Hill coefficients and were resolved into two distinct components representing beta-1 (63%) and beta-2 adrenoceptors (37%). Combined autoradiographic and histochemical studies using nuclear emulsion-coated coverslips and alkaline phosphatase staining showed that the majority of receptors were in the renal cortex and in the outer band of the medulla with fewer receptors associated with the inner medulla, papilla and renal blood vessels. Delineation of beta-1 and beta-2 adrenoceptor subtypes with the selective antagonists betaxolol and ICI 118,551 indicated that the highly localized receptors were predominately of the beta-1 subtype, associated with glomeruli and with tubules that from their staining characteristics and topography represent distal and cortical collecting tubules with few if any receptors associated with proximal tubules. Beta-2 adrenoceptors were more diffusely distributed in the cortex and there were minor areas of localization in the inner medulla. Although some glomerular beta adrenoceptors probably play a role in control of renin release, their distribution throughout this structure indicates that they also control other functions. The distribution of beta adrenoceptors in tubules corresponds well with the known distribution of beta adrenoceptor-stimulated adenylate cyclase in rat kidney and indicates that these receptors subserve a physiological function.

Hormonal regulation of glomerular filtration.

Technological advances within the last decade now permit examination of the effects of various vasoactive substances on glomerular hemodynamics and the filtration process. By modulating the vasomotor tone of the preglomerular and postglomerular arterioles, these substances influence the rate of plasma entering the glomerulus and the pressure within the glomerular capillaries. In addition, hormones appear to influence the permeability of glomerular capillaries by altering the surface area available for filtration.

Angiotensin II in adrenergic-induced alterations in glomerular hemodynamics.

UNLABELLED: Micropuncture analysis of glomerular ultrafiltration (SNGFR) was conducted in Munich-Wistar rats to assess the functional responses to moderate-frequency (3-Hz) renal nerve stimulation. Angiotensin II inhibition (ANG II-inhib) was produced by the intravenous administration of [Sar1, Ala8] angiotensin II or MK 421 to investigate whether it modulates the effects of renal nerve stimulation. Micropuncture measurements were obtained before and during renal nerve stimulation. Renal nerve stimulation decreased SNGFR approximately 25% (from 49.9 +/- 2.3 to 38.0 +/- 1.4 nl X min-1 X g kidney wt-1), the result of decreased glomerular capillary hydrostatic pressure gradient and nephron plasma flow. These decreases were due to increased afferent (approximately 43%) and efferent (approximately 30%) arteriolar resistances, since the glomerular ultrafiltration coefficient remained unaffected. The effects of renal nerve stimulation during ANG II-inhib were less in magnitude than in renal nerve stimulation alone: SNGFR decreased from 48.0 +/- 1.5 to 44.8 +/- 2.0 nl X min-1 X g kidney wt-1 after renal nerve stimulation. The net renal production of norepinephrine was augmented by renal nerve stimulation but it was not influenced by ANG II-inhib. IN CONCLUSION: renal nerve stimulation can regulate glomerular ultrafiltration by altering vascular resistances, and angiotensin II appears to be a critical factor for the full functional expression of renal nerve stimulation at the glomerulus.

Glomerular mesangium as an effector locus for the tubuloglomerular feedback system and renal sympathetic innervation.

To define the effector loci for the tubuloglomerular feedback system, the determinants of the single-nephron glomerular filtration rate (SNGFR) were assessed in Munich-Wistar rats by direct glomerular puncture during perfusion of Henle's loop with isotonic Ringer's solution at rates of 0 and 40 nl/min. At the higher flow rate, SNGFR averaged only approximately 65% that measured during the lower flow rate. Whereas mean glomerular capillary hydraulic pressure was unaffected, both glomerular plasma flow rate and ultrafiltration coefficient Kf were found to decrease significantly in response to increase in loop perfusion rate, thereby accounting for the measured reduction in SNGFR. These changes were associated with increased afferent (RA) and efferent (RE) arteriolar resistances. Based on the close anatomic contact between mesangial cells and these arterioles, a single effector mechanism channeled through mesangial contractility is suggested to account for the observed reduction in Kf and increase in RA and RE. Mesangial contractility appears to be under sympathetic nerve control. In our recent micropuncture study with Munich-Wistar rats, a marked reduction in SNGFR was observed during high-frequency stimulation (5 Hz) of the renal nerve. This reduction in SNGFR was accompanied by a marked fall in Kf and increase in RA and RE. When kidneys were perfusion-fixed during high-frequency stimulation, a marked reduction in the number of open channels was demonstrated together with marked narrowing of afferent and efferent arterioles. These observations are consistent with the view that sympathetic innervation of mesangium may modulate GFR through its ability to regulate mesangial contractility.

Endocrine and neural control of amphibian renal functions.

Three aspects of amphibian renal functions were considered. 1) The neurohypophysial hormone, arginine vasotocin (AVT), is diuretic in lungfishes, but is antidiuretic in amphibians. AVT probably produces diuresis in fishes by increasing systemic blood pressure and, hence, glomerular filtration rate. Receptors for AVT in early amphibians may have become more numerous or sensitive in the preglomerular circulation than in the peripheral vasculature. AVT could then produce glomerular antidiuresis. Tubular receptors to AVT also developed to provide better control of urine volume during terrestrial adaptation. In our investigations only glomerular antidiuresis was produced by AVT in the mud puppy whereas bullfrogs responded to AVT with both glomerular and tubular antidiuresis. 2) Although exogenous AVT can produce antidiuresis in amphibians, alpha-adrenergic neural mechanisms also appeared to play an important role in glomerular and tubular functions in the bullfrog. 3) Mesotocin, the amphibian neutral neurohypophysial hormone, produces glomerular diuresis in the amphibians studied. However, whether it has a physiological role in regulating amphibian renal function remains unclear.