Vagal afferent activity and renal nerve release of dopamine

To investigate the involvement of vagal afferents in renal nerve release of catecholamines, we compared norepinephrine, dopamine, and epinephrine excretion from innervated and chronically denervated kidneys in the same rat. The difference between innervated and denervated kidney excretion rates was taken as a measure of neurotransmitter release from renal nerves. During saline expansion, norepinephrine excretion from the innervated kidney was not statistically greater than from denervated kidneys. Vagotomy increased norepinephrine release from renal nerves. Thus vagal afferents participated in the suppression of renal sympathetic nerve activity during saline expansion. No significant vagal control of dopamine release by renal nerves was detected under these conditions. Bilateral carotid ligation stimulated renal nerve release of both norepinephrine and dopamine in saline-expanded rats. The effects of carotid ligation and vagotomy were not additive with respect to norepinephrine release by renal nerves. However, the baroreflex-stimulated renal nerve release of dopamine was abolished by vagotomy. Electrical stimulation of the left cervical vagus with a square wave electrical pulse (0.5 ms duration, 10 V, 2 Hz) increased dopamine excretion exclusively from the innervated kidney of hydropenic rats. No significant change in norepinephrine excretion was observed during vagal stimulation. Increased dopamine excretion during vagal stimulation was associated with a larger natriuretic response from the innervated kidney than from its denervated mate (p less than 0.05). We conclude that under appropriate conditions vagal afferents stimulate renal release of dopamine and produce a neurogenically mediated natriuresis.     

Role of the renal nerves and angiotensin II in the renal function curve.

The relationship between renal perfusion pressure and urinary sodium is involved in arterial pressure regulation. The aim of this study was to investigate the role of renal nerves and angiotensin II in the pressure-natriuresis relationship. Experiments were performed in anaesthetised cats in which one kidney was surgically denervated. Renal perfusion pressure (RPP), renal blood flow (RBF) glomerular filtration rate (GFR, creatinine clearance), urinary volume (V) and sodium excretion (Una + V) were separately measured from both kidneys. RPP was progressively reduced in two consecutive steps by a suprarenal aortic snare. Two groups of animals were studied: the first without any pharmacological treatment (Untreated), the second during treatment with an angiotensin converting enzyme inhibitor (Captopril, 0.4 mg/Kg intravenously followed by an infusion of 0.4 mg/Kg/h). In the Untreated group RPP was reduced from 152.4 +/- 7.3 to 113.6 +/- 5.8 and 83.0 +/- 4.4 mmHg during the first and second step respectively. RBF and GFR were only slightly reduced during the second step of reduced RPP. In control conditions V and UNa + V were greater in the denervated compared to the innervated kidney. The graded decrease in RPP reduced both V and UNa + V in the innervated as well as in the denervated kidney. In the Captopril group V and UNa + V were larger than in the Untreated group in both the innervated and the denervated kidney. A decrease of RPP similar to that observed in the Untreated group, produced similar haemodynamic changes. Also in the Captopril group the graded decrease in RPP reduced both V and UNa + V in the innervated as well as in the denervated kidney. Matching UNa + V against RPP values significant correlations were found in the innervated and denervated kidneys of both groups. Both renal denervation and ACE inhibition were accompanied by an increased gain of the pressure-natriuresis curve, but only renal denervation shifted the crossing of the pressure axis to the left. In the ACE inhibited animals renal denervation only shifted the curve to the left. In conclusion our data suggest that i) at each level of RPP renal nerves and angiotensin II decrease renal sodium excretion, ii) renal nerves and angiotensin II increase the slope of the renal function curve, iii) renal nerves shift to the right the renal function curve.     

Effect of acute and chronic renal denervation on renal function after release of unilateral ureteral obstruction in the rat.

The role of the renal nerves in determining renal function after relief of 24-h unilateral ureteral obstruction (UUO) was studied using clearance techniques in anaesthetized rats. Acute renal denervation during the first 1--2 h after relief of UUO resulted in a significant increase in glomerular filtration rate (GFR), renal plasma flow (RPF), urine flow, and sodium and potassium excretion, changes which were not seen in the sham-denervated postobstructive kidney. Acute denervation of sham-operated normal kidneys caused a similar natriuresis and diuresis but with no change in GFR or RPF. Chronic renal denervation 4--5 days before UUO denervated postobstructive controls, while chronic denervation alone was associated with a significantly higher urine flow and sodium excretion rate from the denervated kidney. The effectiveness of renal denervation was confirmed by demonstrating marked depletion of tissue catecholamines in the denervated kidney. It was concluded that renal nerve activity plays a significant but not a major role in the functional changes present after relief of UUO. Chronic renal denervation did not protect against the functional effects of unilateral ureteral obstruction.     

Effect of ventilation on sodium excretion in the anesthetized dog with unilateral renal denervation

We studied if the effect of mechanical ventilation induced to keep arterial blood gas values within normal physiological limits has any influence on renal sodium excretion in anesthetized dogs (n = 17) subjected to acute unilateral renal denervation. Compared to the control and the postcontrol periods, ventilation elevated arterial pO2 from 86 +/- 5 to 96 +/- 5 mmHg and blood pH from 7.37 +/- 0.02 to 7.41 +/- 0.01 while arterial pCO2 was decreased from 38 +/- 2 to 33 +/- 1 mmHg (p less than 0.05 in all cases). Compared to the innervated kidney urine flow, urinary sodium and potassium excretion from the denervated kidney were markedly elevated both during spontaneous respiration and during mechanical ventilation but GFR and cPAH were similar on the two sides. Ventilation decreased sodium excretion by the denervated kidney from 314 +/- 26 to 252 +/- 31 mumols/min/100 g k. w. (p less than 0.05). No other excretory changes were noted either in the innervated or in the denervated kidneys. Difference in sodium excretion between innervated and denervated kidneys was decreased from 209 +/- 19 to 126 +/- 20 mumole/min/100 g k. w. (p less than 0.001), due to the ventilation induced diminution of sodium excretion from the denervated kidney. It is concluded that mechanical ventilation of anesthetized dogs modifies sodium excretion, and this phenomenon can be demonstrated only in the denervated kidney.     

Role of adrenergic innervation in experimental renal hypertension

Renal hypertension was induced by ligation of the aorta between renal arteries in rats sympathectomized with 6-hydroxydopamine. In the early phase, equally severe hypertension developed in the denervated group as compared to innervated controls. Later, blood pressure was lower in the denervated rats. Initially, increases in plasma renin were seen in both groups; the levels, however, were markedly lower in the denervated rats. Later, the renin levels were similar and not different from baseline. It is concluded that adrenergic neural activity is not essential in the development of renal hypertension; the maintenance of the chronic state, however, depends in part on adrenergic innervation.     

Pressor responsiveness in renal prehypertensive rabbits with a denervated kidney

Norepinephrine was infused iv at several doses into four groups of conscious rabbits (six per group), and the pressor responses were recorded. The groups were 3-day sham-operated rabbits; 3-day, two-kidney rabbits with unilateral renal artery stenosis (RAS); 3-day, two-kidney rabbits with unilateral renal denervation; and 3-day, two-kidney rabbits with unilateral renal denervation plus RAS of the denervated kidney. The rabbits with RAS of an innervated kidney and those with RAS of a denervated kidney had the same pressor responses to norepinephrine, which were greater than the pressor responses in the sham-operated rabbits or in the rabbits with a denervated kidney but without RAS. Four additional groups of similarly prepared rabbits were infused with norepinephrine at 800 ng/min/kg body wt, and mean arterial pressure and cardiac output were determined before and during norepinephrine infusion. The rabbits with RAS of an innervated or of a denervated kidney had greater increases in total peripheral resistance as well as in mean arterial pressure during norepinephrine infusion than did the two groups of rabbits without RAS. This indicated that the rabbits with RAS also had increased vascular responses to norepinephrine. The concentration of norepinephrine in six denervated kidneys was extremely low as compared to that of six innervated kidneys. Because renal denervation did not diminish pressor and vascular hyperresponsiveness in 3-day RAS rabbits, the signal that originates in the kidney following RAS and that results ultimately in pressor and vascular hyperresponsiveness is not mediated by renal nerves.     

Effect of elevated blood pressure, renin and aldosterone on renal sodium handling in two-kidney Goldblatt hypertensive rats

The effect of elevated blood pressure, renin and aldosterone on renal Na+ retention in two-kidney Goldblatt hypertensive rats were investigated. The technique involved retrograde perfusion from the renal veins via the kidneys, and then through the renal arteries and dorsal aorta. Sodium retention in the stenosed kidney of 7 and 30-60 days post-stenosis hypertensive rats was 82 and 70% higher than in normotensive sham-operated rats respectively. Sodium rention in the clipped kidney, 1 day post-stenosis, was insignificant. However, the contralateral kidney of the 1 day post-stenosis rats retained 27% more Na+. The 1 and 7 days post-stenosis rats had higher plasma aldosterone concentrations than controls, while the 30-60 days post-stenosis rats showed lower levels. The plasma renin activity of the 1 day post-stenosis rats showed 65% higher activity than the sham controls with no significant change in the 30-60 days post-stenosis. Therefore Na+ retention may be mediated by aldosterone in the 7 days post-stenosis rats. Natriuresis in the non-stenosed kidneys of both the 7 and 30-60 days post-stenosis rats may be modulated by an increase in filtration rate due to hypertrophy.     

Excretory function of denervated kidney after inhibition of prostaglandin synthesis and furosemide administration in conscious dogs

The experiments were carried out on unanaesthetized dogs with exteriorized ureters for separate urine collection from the left (denervated) and the right (intact) kidney. The osmolality and concentrations of sodium, potassium, calcium, magnesium, zinc, copper, chloride and creatinine were determined in the plasma as well as in the urine of the two kidneys. The function of the denervated and the innervated kidney was compared prior to and after indomethacin administration (5.0 mg/kg b.w.). The excretory function of both kidneys was also compared after furosemide treatment alone (0.5 mg/kg b.w.) as well as indomethacin pretreatment. Renal denervation increased urine flow rate, calcium and copper excretion. After administration, sodium excretion from the denervated kidney was higher than that from the intact one. Calcium excretion of the two kidneys did not differ significantly, while copper excretion from the denervated kidney was diminished, Furosemide administration after pretreatment with indomethacin did not lead to any difference between the denervated and intact kidney. The results show that renal nerves and prostaglandins participate jointly in the regulation of sodium, copper and calcium excretion. Renal prostaglandins do not change the response of the denervated kidney to furosemide as compared to the intact kidney.     

Interaction among atrial natriuretic factor (ANF), vasopressin, and renal nerves in terms of renal responses in rats.

The relationship between the renal nerves and vasopressin in terms of the natriuretic and diuretic responses to atrial natriuretic factor (ANF--0.25 microgram/kg/min for 15 min), was investigated in unilaterally denervated anesthetized rats before and after the administration of a vasopressin V2 specific antagonist (AVPX)--(40 micrograms/kg bolus followed by 0.4 microgram/kg/min infusion). Administration of the AVPX or ANF did not alter the arterial pressure. Acute renal denervation or AVPX administration independently produced significant increases in sodium and water excretion. ANF infusion by itself produced a greater increase in urine flow and sodium excretion from the denervated kidney compared to the intact kidney before the administration of AVPX. However, after the administration of AVPX renal responses to ANF from the intact kidneys were enhanced such that they were not significantly different from the denervated kidneys. These results suggest that the full physiological response to ANF may be masked by tonic renal nerve activity or antidiuretic actions of vasopressin. Furthermore, since combined renal denervation and AVPX administration does not produce any greater potentiation of the renal responses to ANF than either of these manipulations alone, it is suggested that they may act via a common mechanism, possibly altering activity in the renal nerves.     

Dopamine production by the isolated perfused rat kidney

We used isolated perfused rat kidneys to examine dopamine (DA) production and its relation to renal function. Both innervated and chronically surgically denervated kidneys perfused with a solution containing neither albumin nor tyrosine, excreted 0.2 +/- 0.1 ng DA X min-1 X g wet weight-1 during the 10-min collection period between 30 and 40 min after starting perfusion. When perfused with 6.7% albumin, without tyrosine, innervated kidneys excreted 1.0 +/- 0.06 ng DA X min-1 X g-1 and denervated kidneys excreted 1.0 +/- 0.07 DA X min-1 X g-1. When 0.03 mM tyrosine was included in the albumin perfusate, innervated kidneys excreted 1.2 +/- 0.1 ng DA X min-1 X g-1 (p less than 0.1). Under these conditions DA excretion continued for at least 100 min at which time it was 0.6 ng X min-1 X g-1 and 86 ng/g kidney weight had been excreted. Denervated kidneys perfused with albumin + tyrosine excreted 0.9 +/- 0.13 ng DA X min-1 X g-1. Renal stores of free DA, conjugated DA, and dihydroxyphenylalanine (DOPA) could have provided at the most 30 ng/g of DA. Carbidopa inhibited DA excretion completely. DA excretion did not correlate with renal vascular resistance, inulin clearance, or fractional sodium excretion. In summary, nonneural tissue in isolated perfused kidneys produced DA at the same rate as denervated kidneys in vivo. Less than one-third of the DA produced by isolated kidneys could have come from intrarenal stores of DOPA, free DA, and conjugated DA; the rest was synthesized from unknown precursors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of nNOS in regulation of renal function in hypertensive Ren-2 transgenic rats

The present study was performed to evaluate the role of neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) during the developmental phase of hypertension in transgenic rats harboring the mouse Ren-2 renin gene (TGR). The first aim of the present study was to examine nNOS mRNA expression in the renal cortex and to assess the renal functional responses to intrarenal nNOS inhibition by S-methyl-L-thiocitrulline (L-SMTC) in heterozygous TGR and in age-matched transgene-negative Hannover Sprague-Dawley rats (HanSD). The second aim was to evaluate the role of the renal sympathetic nerves in mediating the renal functional responses to intrarenal nNOS inhibition. Thus, we also evaluated the effects of intrarenal L-SMTC administration in acutely denervated TGR and HanSD. Expression of nNOS mRNA in the renal cortex was significantly increased in TGR compared with HanSD. Intrarenal administration of L-SMTC decreased the glomerular filtration rate (GFR), renal plasma flow (RPF) and sodium excretion and increased renal vascular resistance (RVR) in HanSD. In contrast, intrarenal inhibition of nNOS by L-SMTC did not alter GFR, RPF or RVR and elicited a marked increase in sodium excretion in TGR. This effect of intrarenal L-SMTC was not observed in acutely denervated TGR. These results suggest that during the developmental phase of hypertension TGR exhibit an impaired renal vascular responsiveness to nNOS derived NO or an impaired ability to release NO by nNOS despite enhanced expression of nNOS mRNA in the renal cortex. In addition, the data indicate that nNOS-derived NO increases tubular sodium reabsorption in TGR and that the renal nerves play an important modulatory role in this process.     

Role of the renal nerve in glucocorticoid hypertension

The present study was designed to investigate the involvement of the renal nerve in glucocorticoid hypertension and to assess the role of the renin-angiotensin system in dexamethasone-induced hypertension. The elevated blood pressure in dexamethasone treated rats showing a significant increase in plasma renin concentration (PRC) and activity (PRA) was attenuated dose-dependently by the angiotensin I converting enzyme (ACE) inhibition. Bilateral renal denervation caused a partial decrease in the elevated blood pressure, abolished the increased PRC and PRA, and reduced the dose-dependent decrease in blood pressure with ACE inhibition in dexamethasone treated rats. Although the reduction in body weight and increases in urine volume, urinary sodium excretion and hematocrit were clearly seen following dexamethasone administration, dexamethasone-treated renal denervated rats showed the same degree of change in any of the variables as dexamethasone-treated sham-operated rats. Thus, our results indicate that the stimulation of the renin-angiotensin system through the activation of the renal nerve may be partially responsible for the dexamethasone-induced high blood pressure and, therefore, bilateral renal denervation reduces, partially but significantly, the elevated blood pressure, suggesting that the attenuation of oversecretion of renin contributes to the lowering of the blood pressure.     

The role of renal nerves in the response to dipsogenic stimuli in the rat.

The effect of bilateral renal denervation on water intake and urine volume during specific thirst challenges was studied in rats. Renal denervation attenuated significantly the drinking response elicited by the administration of 30% polyethylene glycol (PG, extracellular challenge) but had no effect on the drinking response after an intracellular challenge (2.5 M NaCl) or after a 24-h water deprivation period. Furthermore, during a PG challenge total water intake was the same in two groups of rats, one with denervated kidneys and the other with beta-adrenergic neural activity in efferent renal nerves eliminated by blocking agents. Urine volumes were not affected by PG administration or water deprivation in denervated rats but were increased significantly after administration of 2.5 M NaCl. These results indicate that renal nerves play an important role in the physiological processes controlling extracellular thirst, and suggest that this role may be related to the neural control of release of renin.     

电刺激肾神经传入纤维对肾水钠钾排出的影响

本文探讨肾神经传入纤维对肾排泄功能的影响及其机制。在戊巴比妥钠麻醉猫中,切除双侧颈动脉窦神经、主动脉神经和迷走神经(SAD+VD),电刺激肾神经传入纤维使动脉血压明显升高,去神经肾的尿量,排钠量显著增多,排钾量和肾小球滤过率不变。神经完好肾的排钠量显著增加,尿量、排钾量和肾小球滤过率均无显著变化。在刺激肾神经传入纤维时,将动脉血压控制在对照期血压水平,两侧肾的尿量、排钠量、排钾量显著减少;神经完好肾的肾小球滤过率减少,而去神经肾的肾小球滤过率无显著改变。脊髓横断不能消除神经完好肾上述肾排泄功能的改变,但可消除去神经肾排泄功能的改变。这些结果表明,在SAD+VD猫中,控制动脉血压不变时,刺激肾神经传入纤维可使有神经肾和去神经肾排尿、排钠和排钾减少。在神经完好肾中这些反应可在脊髓水平完成。     

Supersensitivity to norepinephrine in chronically denervated kidneys: evidence for a postsynaptic effect

Denervation supersensitivity in chronically denervated kidneys increases renal responsiveness to increased plasma levels of norepinephrine. To determine whether this effect is caused by presynaptic (i.e., loss of uptake) or postsynaptic changes, we studied the effect of continuous infusion of norepinephrine (330 ng/min, i.v.) and methoxamine (4 micrograms/min, i.v.), an alpha 1-adrenergic agonist that is not taken up by nerve terminals, on renal function of innervated and denervated kidneys. Ganglionic blockade was used to eliminate reflex adjustments in the innervated kidney and mean arterial pressure was maintained at preganglionic blockade levels by an infusion of arginine vasopressin. With renal perfusion pressure controlled there was a significantly greater decrease in renal blood flow (-67 +/- 9 vs. -33 +/- 8%), glomerular filtration rate (-60 +/- 9 vs. -7 +/- 20%), urine flow (-61 +/- 7 vs. -24 +/- 11%), sodium excretion (-51 +/- 15 vs. -32 +/- 21%), and fractional excretion of sodium (-50 +/- 9 vs. -25 +/- 15%) from the denervated kidneys compared with the innervated kidneys during the infusion of norepinephrine. During the infusion of methoxamine there was a significantly greater decrease from the denervated compared with the innervated kidneys in renal blood flow (-54 +/- 10 vs. -30 +/- 14%), glomerular filtration rate (-51 +/- 11 vs. -19 +/- 17%), urine flow (-55 +/- 10 vs. -39 +/- 10%), sodium excretion (-70 +/- 9 vs. -59 +/- 11%), and fractional excretion of sodium (-53 +/- 10 vs. -41 +/- 10%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of renal innervation to hypertension in rat autosomal dominant polycystic kidney disease

The kidney has both afferent (sensory) and efferent (sympathetic) nerves that can influence renal function. Renal innervation has been shown to play a role in the pathogenesis of many forms of hypertension. Hypertension and flank pain are common clinical manifestations of autosomal dominant (AD) polycystic kidney disease (PKD). We hypothesize that renal innervation contributes to the hypertension and progression of cystic change in rodent PKD. In the present study, the contribution of renal innervation to hypertension and progression of renal histopathology and dysfunction was assessed in male Han:SPRD-Cy/+ rats with ADPKD. At 4 weeks of age, male offspring from crosses of heterozygotes (Cy/+) were randomized into either 1) bilateral surgical renal denervation, 2) surgical sham denervation control, or 3) nonoperated control groups. A midline laparotomy was performed to allow the renal denervation (i.e., physical stripping of the nerves and painting the artery with phenol/alcohol). Blood pressure (tail cuff method), renal function (BUN) and histology were assessed at 8 weeks of age. Bilateral renal denervation reduced the cystic kidney size, cyst volume density, systolic blood pressure, and improved renal function (BUN) as compared with nonoperated controls. Operated control cystic rats had kidney weights, cyst volume densities, systolic blood pressures, and plasma BUN levels that were intermediate between those in the denervated animals and the nonoperated controls. The denervated group had a reduced systolic blood pressure compared with the operated control animals, indicating that the renal innervations was a major contributor to the hypertension in this model of ADPKD. Renal denervation was efficacious in reducing some pathology, including hypertension, renal enlargement, and cystic pathology. However, sham operation also affected the cystic disease but to a lesser extent. We hypothesize that the amelioration of hypertension in Cy/+ rats was due to the effects of renal denervation on the renin angiotensin system.     

A denervated nonfiltering kidney preparation in the rat: a model for study of renin release

To examine the role of the renal vascular receptor in the control of renin secretion in the rat, a denervated, nonfiltering kidney model (DNFK) was developed. The left kidney was subjected to a 2-hr period of total renal ischemia followed by ureteral ligation and section Denervation was accomplished by stripping all visible nerves and painting the renal vessels with 5% phenol. Forty-eight hours later lissamine green dye was injected iv and failed to appear in either the cortical or medullary tubules, indicating that glomerular filtration had ceased. Histological study of these kidneys revealed diffuse tubular necrosis with extensive intratubular cast formation. Norepinephrine content of the DNFK was reduced 91% compared to the contralateral normal kidney (P less than 0.001). In another group of anesthetized rats with a single DNFK, 15 min of suprarenal aortic constriction (SAC) increased plasma renin activity (PRA) from 3.4 +/- 0.6 to 11.5 +/- 1.6 ng AI/ml/hr; in a time control series, PRA was unchanged. To exclude the influence of adrenal catecholamines in this response, bilateral adrenalectomy was performed in a separate group of animals with a DNFK. In this series, SAC also markedly increased PRA. The present data indicate that in the rat the macula densa, the renal nerves, and adrenal catecholamines were not essential for the hyperreninemia induced by a reduction in renal perfusion pressure.     

Systemic vasodilatation and renal sodium excretion: Effects of hydralazine and diazoxide

The effects on renal sodium excretion of two systemic vasodilators, hydralazine and diazoxide, were investigated in volume expanded, anesthetized rats with unilaterally denervated kidneys. Urinary sodium excretion and fractional excretion of filtered sodium increased following hydralazine but decreased following diazoxide. Changes in renal hemodynamics were dissimilar as well: renal plasma flow was increased following hydralazine, but unchanged with diazoxide. All changes in renal sodium excretion and renal hemodynamics following hydralazine were prevented by pretreatment with indomethacin. Renal denervation accentuated the increases in fractional sodium excretion and renal blood flow that occured following hydralazine.Hydralazine and diazoxide differ substantially in their effects on renal sodium excretion, apparently due to the stimulation of renal prostaglandins by the former agent. Although renal innervation attenuates the natriuretic effect of hydralazine, stimulation of the sympathetic nervous system does not account for differences in the renal effects of these two drugs.     

The renin-angiotensin system in rats made hypertensive by ligation of the kidney poles (38584).

The renin-angiotensin system was studied in experimental renal hypertension produced by ligation of the poles of the left kidney followed by contralateral nephrectomy. Plasma renin concentration of renin substrate was lower and that of angiotensin I converting enzyme was higher in hypertensive animals. The juxtaglomerular index decreased in the medial zone of the kidney, while heavily granulated areas appeared in the poles. Ligated kidneys of rats that remained normotensive showed juxtaglomerular indices intermediate between the control and the hypertensive rats. Differences in renal renin content between the groups correspond to those for the juxtaglomerular index, but were smaller. No differences between the experimental groups were observed in iso-renin content in the brain; however in all animals with ligated kidney poles, hypertensive or normotensive, there was a tendency for iso-renin in the adrenals, left ventricular myocardium, and especially aorta to be lower than in controls.