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(Pro)renin receptor (PRR), a 350-amino acid receptor initially thought of as a receptor for the binding of renin and prorenin, is multifunctional. In addition to its role in the renin-angiotensin system (RAS), PRR transduces several intracellular signaling molecules and is a component of the vacuolar H + -ATPase that participates in autophagy. PRR is found in the kidney and particularly in great abundance in the cortical collecting duct. In the kidney, PRR participates in water and salt balance, acid-base balance, and autophagy and plays a role in development and progression of hypertension, diabetic retinopathy, and kidney fibrosis. This review highlights the role of PRR in the development and function of the kidney, namely, the macula densa, podocyte, proximal and distal convoluted tubule, and the principal cells of the collecting duct, and focuses on PRR function in body fluid volume homeostasis, blood pressure regulation, and acid-base balance. This review also explores new advances in the molecular mechanism involving PRR in normal renal health and pathophysiological states.

Adult rats exposed to maternal separation (MatSep) are normotensive but display lower glomerular filtration rate and increased renal neuroadrenergic drive. The aim of this study was to determine the renal α-adrenergic receptor density and the renal vascular responsiveness to adrenergic stimulation in male rats exposed to MatSep. In addition, baroreflex sensitivity was assessed to determine a component of neural control of the vasculature. Using tissue collected from 4-mo-old MatSep and control rats, α 1 -adrenergic receptors (α 1 -ARs) were measured in renal cortex and isolated renal vasculature using receptor binding assay, and the α-AR subtype gene expression was determined by RT-PCR. Renal cortical α 1 -AR density was similar between MatSep and control tissues (B max = 44 ± 1 vs. 42 ± 2 fmol/mg protein, respectively); however, MatSep reduced α 1 -AR density in renal vasculature (B max = 47 ± 4 vs. 62 ± 4 fmol/mg protein, P < 0.05, respectively). In a separate group of rats, the pressor, bradycardic, and renal vascular constrictor responses to acute norepinephrine injection (NE, 0.03-0.25 μg/μl) were determined under anesthesia. Attenuated NE-induced renal vasoconstriction was observed in rats exposed to MatSep compared with control ( P < 0.05). A third group of rats was infused at steady state with the α 1 agonist phenylephrine (10 μg/min iv) and vasodilator sodium nitroprusside (5 μg/min iv). The difference between the change in heart rate/mean arterial pressure slopes was indicative of reduced baroreflex sensitivity in MatSep vs. control rats (-0.45 ± 0.04 vs. -0.95 ± 0.07 beats·min -1 ·mmHg -1 , P < 0.05). These data support the notion that reduced α-adrenergic receptor expression and function in the renal vasculature could develop secondary to MatSep-induced overactivation of the renal neuroadrenergic tone., (Copyright © 2017 the American Physiological Society.)

Mitochondrial (Mt) dysfunction contributes to the pathophysiology of renal function and promotes cardiovascular disease such as hypertension. We hypothesize that renal Mt-genes derived from female spontaneously hypertensive rats (SHR) that exhibit hypertension have reduced expression specific to kidney cortex. After breeding a female Okamoto-Aoki SHR (SAP = 188mmHg) with Brown Norway (BN) males (SAP = 100 and 104 mmHg), hypertensive female progeny were backcrossed with founder BN for 5 consecutive generations in order to maintain the SHR mitochondrial genome in offspring that contain over increasing BN nuclear genome. Mt-protein coding genes (13 total) and nuclear transcription factors mediating Mt-gene transcription were evaluated in kidney, heart and liver of normotensive (NT: n = 20) vs. hypertensive (HT: n = 20) BN/SHR-mtSHR using quantitative real-time PCR. Kidney cortex, but not liver or heart Mt-gene expression was decreased ~2-5 fold in 12 of 13 protein encoding genes of HT BN/SHR-mtSHR. Kidney cortex but not liver mRNA expression of the nuclear transcription factors Tfam, NRF1, NRF2 and Pgc1α were also decreased in HT BN/SHR-mtSHR. Kidney cortical tissue of HT BN/SHR-mtSHR exhibited lower cytochrome oxidase histochemical staining, indicating a reduction in renal oxidative phosphorylation but not in liver or heart. These results support the hypothesis that renal cortex of rats with SHR mitochondrial genome has specifically altered renal expression of genes encoding mitochondrial proteins. This kidney-specific coordinated reduction of mitochondrial and nuclear oxidative metabolism genes may be associated with heritable hypertension in SHR.

Acute episodes of severe renal ischemia result in acute renal failure (ARF). These episodes are followed by a characteristic recovery and repair response, whereby tubular morphology and renal function appear completely restored within approximately 1 mo. However, the chronic effects of such an injury have not been well studied. Male rats were subjected to 60-min bilateral ischemia followed by reperfusion, yielding a characteristic injury. Postischemic animals manifested severe diuresis, peaking at 1 wk postinjury (volume: >45 ml/day, ARF vs. 18 ml/day, sham; P < 0.05). Urine flow subsequently declined but remained significantly elevated vs. sham animals for a 40-wk period. The prolonged alteration in urinary concentrating ability was attributable, in part, to a diminished capacity to generate a hypertonic medullary interstitium. By week 16, proteinuria developed in the post-ARF group and progressed for the duration of the study. Histological examination revealed essentially normal tubular morphology at 4 and 8 wk postinjury but the development of tubulointerstitial fibrosis at 40 wk. Transforming growth factor (TGF)-beta1 expression was elevated at 40 wk, but not at 4 and 8 wk postinjury. Microfil analysis revealed an approximately 30-50% reduction in peritubular capillary density in the inner stripe of the outer medulla at 4, 8, and 40 wk in post-ARF groups vs. sham animals. In addition, post-ARF rats manifested a significant pressor response to a low dose of ANG II (15 ng x kg(-1) x min(-1)). We hypothesize that severe ischemic injury results in a permanent alteration of renal capillary density, contributing to a urinary concentrating defect and the predisposition toward the development of renal fibrosis.

Chronic elevation of sodium intake may affect the sensitivity of the central nervous system to intracerebroventricular (I.C.V.) angiotensin II (Ang II) infusion. Experiments were conducted to determine the influence of raising Sprague-Dawley rats from 2 to 3 weeks of age on low (5.0 mmol/L per kg food), normal (50 mmol/L per kg food), or high (250 mmol/L per kg food) NaCl diets on renal and cardiovascular responses to low-dose I.C.V. Ang II infusion. At 12 weeks of age, Sprague-Dawley rats were instrumented for chronic study, including brain lateral ventricular cannulation. Artificial cerebrospinal fluid was infused (0.25 microL/min I.C.V.) during control and recovery, whereas Ang II (20 ng/min) was infused for 5 days. During the experiment, respective sodium intakes were infused intravenously over 24 hours. In rats fed high sodium, control mean arterial pressure was 115+/-2 mm Hg and increased to 132+/-4 mm Hg by day 5 of I.C.V. Ang II infusion. This increase in arterial pressure was associated with significant (P<.05) decreases in sodium excretion, leading to the retention of 5.4+/-0.6 mmol/L total sodium over the 5 days of Ang II infusion. In rats raised on low and normal sodium intakes from weaning and in 10-week-old rats exposed to a high sodium diet for only 2 weeks, arterial pressure was not increased and sodium was not retained during I.C.V. Ang II infusion at 20 ng/min. In rats raised on the high sodium diet, bilateral renal denervation abolished the arterial hypertension and reduced the sodium retention over 5 days of I.C.V. Ang II infusion. Thus, chronic elevation of sodium intake increases the hypertensive response to low-dose I.C.V. Ang II infusion, which is dependent on intact renal nerves. We conclude that elevated postnatal NaCl intake enhances the pressor sensitivity of the brain to Ang II.

Introduction: The spontaneously hypertensive rat (SHR) has been shown to possess elevated efferent sympathetic nerve activity, and renal denervation delays the development of hypertension in this genetic strain. Evidence that the renal sympathetic nerves have direct effects on tubular function suggests that one of the mechanisms for increasing arterial pressure in the SHR might involve neurally mediated sodium retention., Aims and Methods: The present study examined the relationships between renal sympathetic tone, daily sodium balance and the development of hypertension in SHR over a 4-week period. Conscious, unrestrained, 7-week-old SHR with innervated or denervated kidneys were placed on a fixed sodium intake by intravenous infusion (5.72 mumol/day per 100 g body weight). Urinary sodium excretion was determined once a day for 28 consecutive days; systolic blood pressure (SBP) and body weight were monitored twice a week., Results: Renal denervation delayed the onset of and retarded the development of hypertension. Despite the difference in SBP, daily sodium balance was equal in the innervated and the denervated SHR. The positive sodium balances exhibited by both groups are attributed to the rapid growth observed during the time course of the experiment. The growth rate was also similar in the two groups., Conclusion: The present data indicate that, although the renal nerves may mediate enhanced transient tubular sodium reabsorption, sodium retention does not contribute directly to the development of hypertension in the SHR. Rather, it appears that the elevation of arterial pressure might occur as a requirement to excrete excess sodium and thus maintain a daily sodium balance.

Renal sympathetic stimulation of plasma renin activity (PRA) and sodium reabsorption was examined in conscious dogs before and during intrarenal angiotensin II (ANG II)-type 1 receptor blockade with losartan (Dup-753) and converting enzyme inhibition. In uninephrectomized dogs, renal function and PRA responses to 14% blood volume depletion (BVD) were measured. BVD was utilized to activate renal sympathetic outflow in the absence of hypotension. In eight vehicle-treated dogs, 14% BVD increased PRA from 1.38 +/- 0.32 to 2.79 +/- 0.66 ng ANG I.ml-1 x h-1 and decreased urinary sodium excretion (UNaV) from 85.1 +/- 11.3 to 45.4 +/- 7.5 mueq/min. During losartan (n = 6) and captopril (n = 5) infusion, plasma renin responses were enhanced in response to 14% BVD (1.93 +/- 0.48 to 5.74 +/- 2.25 and 3.03 +/- 0.73 to 9.19 +/- 1.94 ng ANG I.ml-1 x h-1, respectively), whereas antinatriuretic responses were similar to vehicle-infused dogs. Thus, neurogenic antinatriuresis is not mediated by secondary generation of ANG II, since UNaV decreased similarly to control in all conditions of ANG II blockade. Tonic intrarenal and/or circulating ANG II synthesis of dogs on a normal sodium diet inhibit neurogenic stimulation of renin release, since PRA responses were enhanced after blockade of ANG II.

The spontaneously hypertensive rat (SHR) has an elevated efferent sympathetic nerve activity, suggesting that the renal handling of sodium and water may be altered. This study evaluated the renal neurogenic influence on the rate of achieving sodium balance in adult SHRs and Wistar-Kyoto (WKY) rats after either a step increase or step decrease in fixed sodium intake. Conscious, unrestrained rats with either innervated or denervated kidneys were initially placed on a low-sodium (0.3 mEq/d) or high-sodium (5.0 mEq/d) intake by intravenous infusion. Hourly urinary sodium excretion was determined 24 hours before and 72 hours after sodium intake had been increased from low to high or decreased from high to low. After either step change in fixed sodium intake, both innervated SHRs and innervated WKY rats achieved sodium balance within 24 hours. Similarly, the time course of achieving sodium balance was nearly identical between WKY rats with innervated and denervated kidneys after either switch in sodium intake. In SHRs receiving a step increase in sodium intake, both innervated and denervated kidneys increased urinary sodium excretion equally for 9 hours; however, at this time, innervated SHRs continued to increase sodium excretion rapidly, whereas denervated rats were delayed in a further response. Thus, innervated SHRs achieved sodium balance approximately 18 hours sooner than denervated SHRs. Differences in urinary sodium excretion did not result from concomitant changes in plasma renin activity or mean arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

The reflex control of plasma renin activity (PRA) and urinary sodium excretion (UNaV) was evaluated in 13 dogs instrumented for chronic study and maintained on a normal sodium intake (40 meq/day). Graded blood volume depletion of 14 (BVD1) and 21% (BVD2) of the estimated total blood volume was used to activate renal sympathetic nerve activity (RSNA), and experiments were conducted before and after bilateral renal denervation (DNX). In dogs with innervated kidneys, nonhypotensive BVD1 increased RSNA 40.9 +/- 10.9% (P < 0.05) above control. Blood volume depletion increased PRA from 1.95 +/- 0.52 to 3.5 +/- 0.57 ng.ml-1 x h-1 and decreased UNaV from 58.2 +/- 10.1 to 35.5 +/- 4.3 mu eq/min without changing renal blood flow or glomerular filtration rate. BVD2 failed to further activate RSNA (52.0 +/- 16.7%) but did increase PRA to 4.85 +/- 0.83 ng.ml-1 x h-1 and decreased UNaV to 17.9 +/- 2.7 mu eq/min. Renal DNX (n = 13) abolished both the PRA and antinatriuretic responses to BVD1 and BVD2. Thus volume-invoked reflex activation of RSNA, but not altered renal hemodynamics, mediates, activation of PRA and antinatriuresis. This neurogenic control of renal function may be critical to the rapid regulation of extracellular fluid volume, via alterations in urinary excretion.

Evidence that the renal sympathetic nerves have direct effects on renal tubular function suggests that neurogenic mechanisms may play an important role in the daily regulation of sodium balance. We evaluated the influence of the renal nerves on the rate of elevating urinary sodium excretion (UNaV) after a step increase in fixed sodium intake. Conscious rats with innervated (INN) or denervated (DNX) kidneys were placed on low-sodium intake (LNa = 0.3 meq/day) or a normal sodium intake (NNa = 1.0 meq/day) by intravenous infusion. Hourly changes in UNaV were determined 24 h before and 72 h after increasing sodium intake to either NNa or high-sodium intake (HNa = 5.0 meq/day). Switching from LNa to NNa, INN rats increased UNaV within 24 h; however, DNX rats did not begin to increase UNaV until hour 60. Cumulative sodium balance over 72 h was more positive in DNX rats (INN = 1.29 +/- 0.29 meq; DNX = 2.06 +/- 0.21 meq, P less than 0.05). During the LNa-to-HNa switch, both INN and DNX rats increased UNaV equally for 12 h; however, at this time INN rats continued to increase UNaV, whereas DNX rats did not. DNX rats had a net accumulation of 2.54 meq more sodium than INN rats over 72 h. Significant inhibition of plasma renin activity within the first 24 h occurred only in rats receiving the LNa-to-HNa switch in sodium intake, and this response was not different between rats with innervated and denervated kidneys. These data suggest that the renal nerves provide a rapid sodium excretory response to step increases in sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)

The long-term regulation of arterial pressure requires the maintenance of a balance between sodium and water intake and sodium and water excretion. Normal salt and water balance leads to stable body fluid volumes and the maintenance of normal renal function is critical to establishing extracellular fluid volume homeostasis. This review focuses on the role of the kidney in the long-term control of salt and water balance with particular emphasis on the relations between sodium intake, the renin-angiotensin-aldosterone system, renal sympathetic nerve activity, and the regulation of arterial pressure via renal sodium and water excretion. The accumulation of evidence in recent years demonstrates that low level elevation of renin release, circulating angiotensin II or aldosterone, or activation of renal sympathetic outflow may alter renal function such that normal natriuretic and diuretic responses to arterial pressure are significantly impeded. Under these circumstances, the maintenance of normal sodium and water excretion requires a significant elevation of arterial pressure. Thus, compromised renal function leads to elevation of arterial pressure to maintain adequate sodium and water balance during periods of increased sodium intake. The resultant chronic elevation of arterial pressure then becomes a compromise that is used by the kidneys to maintain normal extracellular body fluid volumes.

Low-frequency renal nerve stimulation (0.25 Hz) augments the renin secretion response to reduction of renal perfusion pressure to 50 mmHg by aortic constriction. The present experiments determined whether this modulating influence could be demonstrated when the macula densa receptor was inoperative. In 10 anesthetized dogs with a nonfiltering kidney and sectioned renal nerves, aortic constriction to 52 mmHg decreased renal blood flow and increased renin secretion from 126 +/- 94 to 192 +/- 55 ng/min. During low-frequency renal nerve stimulation and aortic constriction to 50 mmHg, renin secretion was not augmented (37 +/- 13 to 81 +/- 42 ng/min). In four anesthetized dogs with nonfiltering kidneys, aortic constriction to 52 mmHg increased renin secretion similarly before (16 +/- 8 to 68 +/- 17 ng/min) and after renal denervation (14 +/- 14 to 78 +/- 18 ng/min). Therefore, the augmentation of the renin secretion response to aortic constriction to 50 mmHg by low-frequency renal nerve stimulation in filtering kidneys does not result from an interaction with the renal vascular baroreceptor or the juxtaglomerular granular cells. Since neural augmentation of renin secretion during aortic constriction was not observed in the nonfiltering kidney where the macula densa is inoperative, we conclude that the macula densa is the probable site for the neural modulation of renin secretion.

1. Anaesthetized dogs were subjected to two 15 min periods of 60 degrees head-up tilt. Renal perfusion pressure was regulated to minimize changes during tilting. 2. In both intact and vagotomized animals there was a fall in systemic arterial pressure and a rise in heart rate. In both intact and vagotomized animals glomerular filtration rate fell slightly during the first tilt but remained unchanged in the second tilt period. Renal blood flow was unchanged throughout. 3. Both absolute and fractional excretions of sodium were reduced in intact animals subjected to the two consecutive periods of tilt. Following vagotomy these responses were as large as those observed in intact animals. 4. Tilting caused an increase in renin secretion from the kidney in both tilting periods to which the intact animals were subjected. In the vagotomized animals the increase in renin secretion was as large as that observed in intact animals. 5. The results of the present study show that, under the experimental conditions used, vagal afferent activity had no measurable effect on the decreases in sodium excretion or increases in renin secretion mediated by the renal nerves during short periods of 60 degrees head-up tilt.

To examine the interactions among the renal nerves, prostaglandins, and renal arterial pressure in the regulation of renin secretion, experiments using low-frequency renal nerve stimulation (LFRNS; supramaximal voltage, 0.5 ms, 0.5 Hz) were performed in anesthetized dogs. LFRNS, which did not affect renal hemodynamics or urinary sodium excretion, increased renin secretion rate before (79 +/- 16 ng/min) but significantly less after renal arterial administration of indomethacin or meclofenamate (26 +/- 7 ng/min). In a separate group of dogs, LFRNS increased both renin secretion rate (266 +/- 139 ng/min) and renal prostaglandin E2 secretion rate (2,080 +/- 635 ng/min). LFRNS does not alter input stimuli to the renal vascular baroreceptor or tubular macula densa receptor mechanisms for renin secretion and represents a direct neural stimulus for renin secretion; this also increases renal prostaglandin E2 secretion rate, which contributes to the increase in renin secretion rate. The renin secretion rate response of innervated and denervated kidneys to reduction in renal arterial pressure to 50 mmHg was examined before and after indomethacin/meclofenamate administration. The observation that indomethacin/meclofenamate decreased but did not abolish the renin secretion rate response to aortic constriction in innervated kidneys suggests the presence of a prostaglandin-independent mechanism that is mediated by an interaction between the renal nerves and the tubular macula densa receptor, as indomethacin/meclofenamate essentially abolished the renin secretion rate response to aortic constriction in denervated kidneys.

To investigate the influence of angiotensin II (AII) and renal prostaglandins on neonatal renal hemodynamics and sodium excretion, unanesthetized piglets 1-5, 18-20, and 45-50 days of age were treated with saralasin and indomethacin prior to volume expansion (VE) with isotonic saline. Saralasin did not affect basal renal blood flow (RBF) or the intrarenal distribution of blood flow as calculated as the ratio of outer-to-inner slice counts (O/I) in piglets 1-50 days of age. VE increased fractional sodium excretion equally in all animals. In 1- to 5-day-old piglets, saralasin blunted this natriuresis without affecting renal hemodynamics. Therefore, low neonatal RBF and O/I do not appear to be due to AII. In addition, indomethacin did not change renal hemodynamics in newborn piglets and did not affect the natriuresis after VE in any age group. Indomethacin decreased RBF and increased O/I of conscious 45- to 50-day-old animals. Renal prostaglandins do not appear to be a factor in control of renal hemodynamic in newborn pigs and do not influence the natriuresis in neonates following saline loading.

Renal nerve stimulation increases renal vascular resistance and decreases glomerular filtration rate and urinary sodium excretion. The purpose of this study was to determine whether neurally mediated changes in renal vascular resistance, glomerular filtration rate, and urinary sodium excretion at control renal perfusion pressure modified the autoregulation of renal blood flow and glomerular filtration rate and the antinatriuresis observed during reductions in renal perfusion pressure in pentobarbital-anesthetized dogs. Renal blood flow, glomerular filtration rate, and urinary sodium excretion were determined during stepwise reductions in renal perfusion pressure from 137 to 55 mm Hg (suprarenal aortic constriction) before and during electrical stimulation of the renal nerve at 0.5, 1.0, 2.0, and 4.0 Hz. In the absence of renal nerve stimulation, renal blood flow and glomerular filtration rate remained constant until renal perfusion pressure was reduced to 70 and 85 mm Hg, respectively. Urinary sodium excretion decreased linearly as renal perfusion pressure decreased. Renal nerve stimulation at 0.5, 1.0, 2.0, and 4.0 Hz increased renal vascular resistance and decreased glomerular filtration rate and urinary sodium excretion. These frequencies of renal nerve stimulation, however, did not alter the decreases in renal vascular resistance and glomerular filtration rate or the antinatriuretic response to stepwise reductions in renal perfusion pressure to 55 mm Hg. These data demonstrate that increased renal vascular resistance at either the afferent or efferent arteriole does not change the responses of these vessels to reductions in renal perfusion pressure. Renal nerve stimulation at frequencies which decrease urinary sodium excretion at control renal perfusion pressure also does not enhance the antinatriuretic response to reductions in renal perfusion pressure.

Experiments were conducted in conscious dogs to determine the relationships between postural position, arterial pressure, and renal sympathetic nerve activity. Observations of the changes in arterial pressure and renal nerve activity were made when animals spontaneously changed postural position from lying to sitting, sitting to standing, standing to sitting, and sitting to lying. Rising to sit from lying down increased arterial pressure from 109 +/- 5 to 125 +/- 3 mm Hg and increased renal nerve activity by 96 +/- 58 microV/sec (61% of control). Movement from the sitting to standing position decreased renal nerve activity by 90 +/- 39 microV/sec (48% of control) without changing mean arterial pressure. Sitting down from standing also did not change arterial pressure, whereas renal nerve activity increased by 56 +/- 17 microV/sec (33% of control). Returning to the lying position (from sitting) decreased arterial pressure, and this hypotension was associated with significant reductions in renal nerve activity. These results indicate that nonuniform changes in sympathetic outflow from the central nervous system must occur to various vascular beds during changes in postural position of conscious dogs. Thus, renal sympathetic outflow may or may not reflect changes in nerve traffic which contribute to alterations in arterial pressure.

To investigate blood flow autoregulation in filtering and nonfiltering kidneys, renal blood flow was determined during graded reductions in renal perfusion pressure in seven anesthetized dogs containing both a filtering and nonfiltering kidney. In each dog, one kidney was made nonfiltering by the method of EH Blaine, JO Davis, and RT Witty (Circ Res 27:1081-1089, 1970). Renal perfusion pressure was decreased from 129 to 115, 99, and 83 mm Hg by stepwise constriction of the suprarenal aorta. In filtering kidneys, the maximum decrease in renal perfusion pressure reduced renal blood flow only 20.1% of control whereas renal blood flow of nonfiltering kidneys decreased by 41.0% of control. During aortic constriction, renal vascular resistance of nonfiltering kidneys remained unchanged or slightly increased. These hemodynamic changes were associated with significantly greater autoregulation indices in nonfiltering kidneys. In eight dogs with nonfiltering kidneys, competitive inhibition of adenosine with theophylline (9 mg/kg iv) restored autoregulation of renal blood flow as shown by significant decreases in renal vascular resistance. These data indicate that in the nonfiltering kidney model, autoregulation of renal blood flow is impaired. It is suggested that this impaired autoregulatory response may result from renal ischemia and the vasoconstrictor influence of elevated intrarenal adenosine concentration.

Renal function was measured during the development of cardiac tamponade in anesthetized dogs. Tamponade was induced by infusion of isotonic saline (37 degrees C) into the pericardial space. Step increases in pericardial fluid volume in 20-ml increments from 0 to 160 ml increased renal efferent nerve activity by a total of 140 +/- 58% of control (from 205 +/- 70 microV/s). Since renal nerve traffic was elevated by pericardial fluid volume infusion prior to any changes in arterial pressure, renal function was determined before and after increasing pericardial pressure (PCP) by approximately 5 and 10 mmHg. Increasing PCP by 5 mmHg decreased urinary sodium excretion and increased renin secretion rate without changing mean arterial pressure, renal blood flow, or glomerular filtration rate (GFR). Further elevation of PCP to approximately 10 mmHg also decreased urinary sodium excretion as well as arterial pressure and GFR. Renal denervation prevented both of these antinatriuretic responses to elevated PCP. In a third group of dogs, similar antinatriuresis was induced by increasing PCP by approximately 5 and 10 mmHg. Bilateral cervical vagotomy abolished the antinatriuretic response to increased PCP by 5 mmHg but was ineffective when PCP was increased by 10 mmHg, which was accompanied by decreased arterial pressure. These results demonstrate that elevation of pericardial fluid volume, and consequently PCP, reflexly decreases urinary sodium excretion via activation of renal sympathetic outflow. Early reflex antinatriuresis results primarily from activation of cardiopulmonary or splanchnic receptors with vagal afferents, whereas, at larger PCP, reflex antinatriuresis may result from hypotension and unloading of high pressure baroreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

The increase in renin secretion resulting from low-frequency renal nerve stimulation (0.5 Hz) occurs in the absence of changes in urinary sodium excretion or renal blood flow and is apparently derived from a direct effect of renal sympathetic nerves on juxtaglomerular granular cells. We sought to determine the role of renal alpha-adrenoceptors in this neurally evoked renin secretion. The neurally evoked renin secretion was unaffected by renal alpha-adrenoceptor blockade with phentolamine or prazosin; however, two dose levels of phenoxybenzamine equally inhibited the renin secretion. The renal vasoconstrictor response to graded renal nerve stimulation was similarly diminished by phentolamine, prazosin, and the higher phenoxybenzamine dose, whereas the lower phenoxybenzamine dose was significantly less effective. Renal alpha-adrenoceptor stimulation with methoxamine infusion at doses that were just subthreshold for altering renal blood flow and urinary sodium excretion or at doses that just reduced urinary sodium excretion also did not change renin secretion. Higher doses of methoxamine that decreased both renal blood flow and sodium excretion increased renin secretion. Based on the inability of phentolamine and prazosin to prevent neurally mediated renin secretion and on the dose-response relationship between methoxamine and changes in renin secretion, renal blood flow, and urinary sodium excretion, we conclude that renal alpha-adrenoceptors do not mediate renin secretion elicited by direct neural activation of the juxtaglomerular granular cells. The data suggest that phenoxybenzamine inhibits neurally mediated renin secretion by a mechanism other than renal alpha-adrenoceptor blockade.

The purpose of this study was to determine if renin secretion resulting solely from low-frequency renal nerve stimulation (no change in renal blood flow or urinary sodium excretion) is mediated by activation of beta-1 (beta-1) or beta-2 (beta-2) adrenergic receptors. Beta-1 and beta-2 adrenergic receptor blockade were produced with atenolol and butoxamine, respectively. Low-frequency renal nerve stimulation (0.5 Hz) increased renin secretion without altering mean arterial pressure, renal blood flow, glomerular filtration rate or urinary sodium excretion. The increase in renin secretion in response to renal nerve stimulation was blocked by beta-1 blockade with intrarenal atenolol (2.0 micrograms/kg/min) infusion. This dose of atenolol reduced the renal vasodilator response to intrarenal isoproterenol by only 48%, thus indicating modest beta-2 receptor blockade. A lower dose of atenolol (30 micrograms/kg i.v.) markedly decreased the tachycardia in response to i.v. isoproterenol (2 micrograms) but had no effect on the renal vasodilator response to intrarenal isoproterenol injection (2 micrograms), thus indicating selective beta-1 blockade. This dose of atenolol abolished the increase in renin secretion during renal nerve stimulation. In contrast, beta-2 receptor blockade with butoxamine (20 micrograms/kg/min) did not alter the renin secretion response to renal nerve stimulation. This dose of butoxamine decreased the renal vasodilator response to intrarenal isoproterenol by 73%, thus demonstrating significant beta-2 receptor blockade. These results indicate the low-frequency renal nerve stimulation (0.5 Hz) increases renin secretion without altering renal hemodynamics or urinary sodium excretion. This neurally mediated renin secretion resulted from activation of beta-1 adrenergic receptors.

Relationships between frequency of renal nerve stimulation (RNS) and renal blood flow (RBF), glomerular filtration rate (GFR), and plasma renin activities (PRA) were evaluated in anesthetized dogs placed on low (5 meq/day)-, normal (40 meq/day)-, and high (200 meq/day)-sodium chloride diets. Arterial pressure, RBF, GFR, and renal venous and arterial PRA were determined before and during direct electrical RNS at 0.5, 1.0, and 2.0 Hz (15 V, 1.0 ms). Dogs on low sodium intakes increased renal venous PRA at 0.5, 1.0-, and 2.0-Hz RNS, whereas dogs on normal sodium intakes did not increase renal venous PRA until RNS reached 2.0 Hz. High sodium dogs did not increase PRA at any frequency of RNS tested. RNS at 0.5 Hz was not associated with any changes in GFR or RBF in any of the groups. Dogs on normal sodium and high sodium intakes decreased both GFR and RBF during 1.0- and 2.0-Hz RNS. Low-sodium dogs, however, only decreased GFR and RBF during 2.0-Hz RNS, and these hemodynamic responses were significantly less than 2.0-Hz GFR and RBF responses of high sodium dogs. These data indicate that renal vasoconstrictor responses to RNS are potentiated, and renin release responses to RNS are reduced by elevation of sodium chloride intake. We suggest that during low sodium intake, activation of sympathetic nerve activity elicits an enhanced renin release response, whereas the renal vasculature may be protected against neurogenic vasoconstriction.

The adrenoceptor mechanism that mediates the reduction of urinary sodium (UNa V) and bicarbonate (UHCO3 V) excretion during 1.0-Hz renal nerve stimulation (RNS) was evaluated in 21 anesthetized dogs. In each animal RNS decreased UNa V and UHCO3 V without changing mean arterial pressure, renal blood flow, or glomerular filtration rate. After these initial responses, dogs were administered phentolamine [2.0 micrograms.kg-1.min-1 intrarenal artery (ira); n = 7], prazosin (0.7 micrograms.kg-1.min-1 ira; n = 5), (+/- )-propranolol (2.0 micrograms.kg-1.min-1 ira; n = 4), or atenolol (50 mg/kg iv; n = 5) and the renal responses to RNS were again tested. Both the antinatriuretic response and reduction of UHCO3 V during RNS were abolished by alpha 1/alpha 2-adrenoceptor blockade with phentolamine and by alpha 1-adrenoceptor antagonism with prazosin. beta-Adrenoceptor blockade with (+/- )-propranolol (beta 1/beta 2) or atenolol (beta 1) did not alter either the decrease in UNa V or UHCO3 V after RNS. These results provide further evidence that, during low-frequency RNS, reduction of UNa V is mediated in part by carbonic anhydrase-dependent bicarbonate reabsorption. These antinatriuretic responses and decreases in UHCO3 V during 1.0-Hz RNS are mediated by adrenergic neurotransmitter stimulation of alpha 1-adrenoceptors.

Several experimental forms of hypertension require intact renal innervation for the development or maintenance (or both) of the elevated arterial pressure. We determined the relationships between urinary sodium and water excretion and arterial pressure in Dahl salt-sensitive rats (DS) with innervated (n = 6) and denervated (n = 7) kidneys after switching from a low to a high sodium diet. Arterial pressure significantly increased in both groups within 48 hours after they began to eat an 8% sodium chloride diet. This hypertension increased to 188 +/- 9 and 190 +/- 7 mm Hg, respectively, in rats with innervated and denervated kidneys after 12 days. Mean arterial pressures were not significantly different between groups on any day. The rise in arterial pressure of DS placed on a high sodium intake was associated with an elevation of urine flow rate and urinary sodium excretions in rats with either innervated or denervated kidneys. Urine flow rates and urinary sodium excretions were greater in denervated than in innervated rats on Days 4 through 7 after beginning the high sodium diet. This diuresis and natriuresis in rats with denervated kidneys were associated with greater water and sodium intakes on Days 4 to 7 of the high sodium diet when compared with rats with innervated kidneys. These results demonstrate that, following exposure to a high sodium intake, DS have increased arterial pressure within 24 hours. The development of this arterial hypertension is not dependent on intact renal innervation. In conscious DS, the renal innervation does participate in the regulation of urinary sodium excretion by promoting renal sodium and water reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)

This study evaluated the effects of increasing plasma endotoxin (Difco 055:B5) concentration by intravenous and intrarenal infusion on renal hemodynamics and renal function. Plasma endotoxin was increased to 130-150 ng/ml (infusion rate of 32 micrograms/min) in two groups of dogs and changes in plasma endotoxin concentration were correlated with arterial pressure (AP), glomerular filtration rate (GFR), renal blood flow (RBF), and urinary sodium excretion (UNaV) for 4 hr. In group 1, intrarenal endotoxin infusion decreased AP, GFR, RBF, and UNaV equally between infused and contralateral noninfused kidneys. In dogs with unilateral renal denervation (group 2), intravenous endotoxin maximally decreased AP, GFR, RBF, and UNaV in both kidneys by 90 min. Despite continued endotoxin infusion, RBF and GFR then spontaneously increased after 90 min, and by 240 min these values were significantly greater in the innervated kidneys compared with denervated kidneys (P less than 0.05). In both groups of dogs, the spontaneous increase in GFR and RBF was associated with a spontaneous increase in arterial pressure. These data suggest that renal dysfunction during moderate endotoxemia may be mediated by systemic hemodynamic changes rather than by direct intrarenal toxicity and that renal innervation may protect against endotoxin-induced reductions in RBF and GFR.

Renal transplantation studies have indicated that some form of renal dysfunction underlies the development of hypertension in Dahl salt-sensitive (S) rats. In the present study, we compared renal hemodynamic and tubular function of conscious Dahl S and salt-resistant (R) rats. Prehypertensive Dahl S rats had a blunted natriuretic response to an intravenous isotonic sodium chloride load compared with the responses of normotensive Dahl R or hypertensive Dahl S rats. This difference was probably not related to a generalized defect in renal tubular handling of sodium and water, since prehypertensive Dahl S rats excreted quantities of sodium comparable to those of R or hypertensive S rats when infused with hypertonic sodium chloride solutions. Dahl S rats also elevated free water clearance and lowered urine osmolality similar to R rats when challenged with a hypotonic saline load. Renal blood flows and glomerular filtration rates were similar in prehypertensive Dahl S, hypertensive Dahl S, and Dahl R rats. The possible link between sodium retention and the development of hypertension in Dahl S rats was examined further by measuring the changes in sodium and water balance, extracellular fluid volume (ECV), and blood pressure after exposure to an 8% sodium chloride diet. No differences could be detected in the salt and water balances of Dahl S and R rats exposed to a high-salt diet for 14 days. ECV increased significantly by 10% in Dahl S rats on the 1st day of a high-salt diet, whereas no change was observed in Dahl R animals.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of 1.0 Hz renal nerve stimulation (RNS) on the renal excretion of sodium and bicarbonate was determined in anesthetized dogs before and during inhibition of renal bicarbonate reabsorption. RNS decreased both urinary sodium and bicarbonate excretion without changing arterial pressure, renal blood flow, or glomerular filtration rate. Pharmacological blockade of bicarbonate reabsorption with acetazolamide prevented RNS-induced decreases in bicarbonate excretion and reduced the antinatriuretic response. Physiological blockade of tubular bicarbonate reabsorption with intrarenal sodium bicarbonate infusion (1 M) abolished both the antinatriuretic response to RNS and the decrease in bicarbonate excretion. This physiological blockade of neurogenic antinatriuresis resulted from alkalinization of the urine and/or peritubular blood rather than an increase in filtered sodium load, because during intrarenal infusion of 1 M sodium chloride RNS concomitantly decreased sodium and urinary bicarbonate excretion. Since antinatriuretic responses and the decrease in bicarbonate excretion response to RNS were significantly decreased by blockade of bicarbonate reabsorption (with acetazolamide and intrarenal sodium bicarbonate infusion), antinatriuresis during RNS is partly mediated by a mechanism dependent on intact bicarbonate reabsorption. The data suggest that renal nerve activity may participate in the normal regulation of acid-base balance via changes in bicarbonate excretion.

The neurogenic regulation of renal hormonal secretion has been the focus of numerous investigations since the anatomical identification of sympathetic innervation of structures within the kidney other than vascular smooth muscle. The major thrust of this research effort has been on the nature of the neurogenic signal in the regulation of renin and prostaglandin secretion from the kidney into the systemic circulation. Activation of renal sympathetic outflow increases both renin and prostaglandin release and these humoral responses are mediated by beta 1- and alpha-adrenoceptors, respectively. The mechanisms surrounding the release of each of these humoral factors are highly dependent upon the intensity of the neural signal since higher levels of sympathetic activation invoke both tubular and vascular signals which can summate to enhance both the renin and prostaglandin responses. Thus, the interactions which exist between renal sympathetic nerve activity, renin secretion and prostaglandin release can importantly influence renal function and the combination of these factors may alter the regulation of sodium and water balance and consequently the control of arterial pressure.