Inhibition of nitric oxide synthase enhances superoxide activity in canine kidney

To evaluate the role of a potential interaction between superoxide anion (O(2)(-)) and nitric oxide (NO) in regulating kidney function, we examined the renal responses to intra-arterial infusion of a superoxide dismutase mimetic, tempol (0.5 mg.kg(-1).min(-1)), in anesthetized dogs treated with or without NO synthase inhibitor, N(omega)-nitro-l-arginine (NLA; 50 microg.kg(-1).min(-1)). In one group of dogs (n = 10), tempol infusion alone for 30 min before NLA infusion did not cause any significant changes in renal blood flow (RBF; 5.2 +/- 0.4 to 5.0 +/- 0.4 ml.min(-1).g(-1)), glomerular filtration rate (GFR; 0.79 +/- 0.04 to 0.77 +/- 0.04 ml.min(-1).g(-1)), urine flow (V; 13.6 +/- 2.1 to 13.9 +/- 2.5 microl.min(-1).g(-1)), or sodium excretion (U(Na)V; 2.4 +/- 0.3 to 2.2 +/- 0.3 micromol.min(-1).g(-1)). Interestingly, when tempol was infused in another group of dogs (n = 12) pretreated with NLA, it caused increases in V (4.4 +/- 0.4 to 9.7 +/- 1.4 microl.min(-1).g(-1)) and in U(Na)V (0.7 +/- 0.1 to 1.3 +/- 0.2 micromol.min(-1).g(-1)) without affecting RBF or GFR. Although NO inhibition caused usual qualitative responses in both groups of dogs, the antidiuretic (47 +/- 5 vs. 26 +/- 4%) and antinatriuretic (67 +/- 4 vs. 45 +/- 11%) responses to NLA were seen much less in dogs pretreated with tempol. NLA infusion alone increased urinary excretion of 8-isoprostane (13.9 +/- 2.7 to 22.8 +/- 3.6 pg.min(-1).g(-1); n = 7), which returned to the control levels (11.6 +/- 3.4 pg.min(-1).g(-1)) during coadministration of tempol. These data suggest that NO synthase inhibition causes enhancement of endogenous O(2)(-) levels and support the hypothesis that NO plays a protective role against the actions of O(2)(-) in the kidney.     

Effects of calcitonin gene-related peptide on renal blood flow in the rat

The effects of alpha-rat calcitonin gene-related peptide (alpha-rCGRP) on systemic and renal hemodynamics and on renal electrolyte excretion were examined in normal anesthetized rats. In one group of rats (n = 7), infusions of alpha-rCGRP at doses of 10, 50, 100, and 500 ng/kg/min for 15 min each produced dose-related and significant decreases in mean arterial pressure from a control of 130 +/- 3 mm Hg to a maximal depressor response of 91 +/- 2 mm Hg. During the first three doses of alpha-rCGRP, renal blood flow progressively and significantly increased from a control of 5.0 +/- 0.3 ml/min to a peak level of 6.3 +/- 0.3 ml/min achieved during the 100 ng/kg/min infusion. With the highest infusion rate of 500 ng/kg/min, renal blood flow fell below the control level to 4.5 +/- 0.2 ml/min (P less than 0.05). The responses in renal blood flow and mean arterial pressure were associated with reductions in renal vascular resistance. After cessation of alpha-rCGRP infusions, arterial pressure, renal blood flow, and renal vascular resistance gradually returned toward the baseline values. In another group of rats (n = 9), infusion of alpha-rCGRP for 30 min at 100 ng/kg/min produced a significant reduction in urinary sodium excretion from 0.28 +/- 0.06 to 0.14 +/- 0.5 muEq/min (P less than 0.05). Urine flow and urinary potassium excretion also appeared to decrease, but the changes were not significantly different (P greater than 0.05) from their respective baselines. These results demonstrate that alpha-rCGRP is a potent and reversible hypotensive and renal vasodilatory agent in the anesthetized rat. The data also suggest that alpha-rCGRP may have significant effects on the excretory function of the kidney.     

Atrial natriuretic factor and renal sodium excretion during ventilation with PEEP in hypervolemic dogs.

Controlled mandatory ventilation with positive end-expiratory pressure (PEEP) reduces renal sodium excretion. To examine whether atrial natriuretic factor (ANF) is involved in the renal response to alterations in end-expiratory pressure in hypervolemic dogs, experiments were performed on anesthetized dogs with increased blood volume. Changing from PEEP to zero end-expiratory pressure (ZEEP) increased sodium excretion by 145 +/- 61 from 310 +/- 61 mumol/min and increased plasma immunoreactive (ir) ANF by 104 +/- 27 from 136 +/- 21 pg/ml. Changing from ZEEP to PEEP reduced sodium excretion by 136 +/- 36 mumol/min and reduced plasma irANF by 98 +/- 22 pg/ml. To examine a possible causal relationship, ANF (6 ng.min-1.kg body wt-1) was infused intravenously during PEEP to raise plasma irANF to the same level as during ZEEP. Sodium excretion increased by 80 +/- 36 from 290 +/- 78 mumol/min as plasma irANF increased by 96 +/- 28 from 148 +/- 28 pg/ml. We conclude that alterations in end-expiratory pressure lead to great changes in plasma irANF and sodium excretion in dogs with increased blood volume. Comparison of the effects of altering end-expiratory pressure and infusing ANF indicates that a substantial part of the changes in sodium excretion during variations in end-expiratory pressure can be attributed to changes in plasma irANF.     

Increased H(2)O(2) counteracts the vasodilator and natriuretic effects of superoxide dismutation by tempol in renal medulla

A membrane-permeable SOD mimetic, 4-hydroxytetramethyl-piperidine-1-oxyl (tempol), has been used as an antioxidant to prevent hypertension. We recently found that this SOD mimetic could not prevent development of hypertension induced by inhibition of renal medullary SOD with diethyldithiocarbamic acid. The present study tested a hypothesis that increased H2O2 counteracts the effects of tempol on renal medullary blood flow (MBF) and Na+ excretion (UNaV), thereby restraining the antihypertensive effect of this SOD mimetic. By in vivo microdialysis and Amplex red H2O2 microassay, it was found that interstitial H2O2 levels in the renal cortex and medulla in anesthetized rats averaged 55.91 +/- 3.66 and 102.18 +/- 5.16 nM, respectively. Renal medullary interstitial infusion of tempol (30 micromol x min-1x kg-1) significantly increased medullary H2O2 levels by 46%, and coinfusion of catalase (10 mg x min-1x kg-1) completely abolished this increase. Functionally, removal of H2O2 by catalase enhanced the tempol-induced increase in MBF, urine flow, and UNaV by 28, 41, and 30%, respectively. Direct delivery of H2O2 by renal medullary interstitial infusion (7.5-30 nmol x min-1x kg-1) significantly decreased renal MBF, urine flow, and UNaV, and catalase reversed the effects of H2O2. We conclude that tempol produces a renal medullary vasodilator effect and results in diuresis and natriuresis. However, this SOD mimetic increases the formation of H2O2, which constricts medullary vessels and, thereby, counteracts its vasodilator actions. This counteracting effect of H2O2 may limit the use of tempol as an antihypertensive agent under exaggerated oxidative stress in the kidney.     

Reversal of indomethacin-induced decreases in renal function by an isosterically-modified prostaglandin analog

A recently discovered isosterically-modified prostaglandin analog, 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl ] propyl) benzoic acid, was studied in conscious Na-deficient dogs to determine if this compound could reverse the deleterious renal effects induced by inhibition of renal cyclooxygenase. Indomethacin (2 mg/kg i.v.) reduced renal function significantly in all dogs studied: GFR decreased from 38 +/- 3 to 26 +/- 1 ml/min (P less than 0.01) and ERPF from 124 +/- 15 to 79 +/- 8 ml/min (P less than 0.01). On separate occasions, the six dogs used in this study were treated with a saline placebo intravenously or with the PG analog (0.1 mg/kg i.v.) 60 min after receiving indomethacin. After placebo treatments renal function remained suppressed for the duration of observation (2 hours). After treatment with PG analog, GFR was restored to pre-indomethacin levels within 1 hour (36 +/- 3 ml/min) and remained at this level or higher for the duration of the experiment. ERPF was restored to pre-indomethacin levels within 30 min of PG analog injection (140 +/- 7 ml/min) and subsequently rose ml/min) for the duration of the experiment. Urinary electrolyte excretion was suppressed by indomethacin and despite the large increase in ERPF, Na excretion was not augmented by PG analog. This study demonstrates that a synthetic, isosterically-modified prostaglandin analog can effectively reverse the hemodynamic effects of non-steroidal antiinflammatory drug treatment on renal function while not affecting renal Na excretion.     

Hormonal regulation of renal sodium and water excretion during normotensive sodium loading in conscious dogs

Saline was infused intravenously for 90 min to normal, sodium-replete conscious dogs at three different rates (6, 20, and 30 micromol x kg(-1) x min(-1)) as hypertonic solutions (HyperLoad-6, HyperLoad-20, and HyperLoad-30, respectively) or as isotonic solutions (IsoLoad-6, IsoLoad-20, and IsoLoad-30, respectively). Mean arterial blood pressure did not change with any infusion of 6 or 20 micromol x kg(-1) x min(-1). During HyperLoad-6, plasma vasopressin increased by 30%, although the increase in plasma osmolality (1.0 mosmol/kg) was insignificant. During HyperLoad-20, plasma ANG II decreased from 14+/-2 to 7+/-2 pg/ml and sodium excretion increased markedly (2.3+/-0.8 to 19+/-8 micromol/min), whereas glomerular filtration rate (GFR) remained constant. IsoLoad-20 decreased plasma ANG II similarly (13+/-3 to 7+/-1 pg/ml) concomitant with an increase in GFR and a smaller increase in sodium excretion (1.9+/-1.0 to 11+/-6 micromol/min). HyperLoad-30 and IsoLoad-30 increased mean arterial blood pressure by 6-7 mm Hg and decreased plasma ANG II to approximately 6 pg/ml, whereas sodium excretion increased to approximately 60 micromol/min. The data demonstrate that, during slow sodium loading, the rate of excretion of sodium may increase 10-fold without changes in mean arterial blood pressure and GFR and suggest that the increase may be mediated by a decrease in plasma ANG II. Furthermore, the vasopressin system may respond to changes in plasma osmolality undetectable by conventional osmometry.     

Interaction between prostaglandin E2 and leukotriene D4 on the excretion of electrolytes by the dog kidney in vivo

Recent experiments indicate that prostaglandin E2 potentiates the vasodilatory properties of leukotrienes in the skin microcirculation. The present experiments were undertaken to study the effect of leukotriene D4 and prostaglandin E2 on renal hemodynamics and urinary electrolytes in the dog. Experiments were performed in three groups of anesthetized Mongrel dogs: the first group was studied under hydropenia, whereas the two remaining groups were studied during water diuresis with (Group 3) or without indomethacin (Group 2). LTD4 (100 ng/min) and PGE2 (3 ug/min) were infused in the left renal artery to minimize systemic effects of these compounds. LTD4 alone failed to influence urinary sodium excretion in all 3 groups. In Group 1, urinary sodium increased from 77 +/- 6 to 393 +/- 74 uEq/min during PGE2, and further increased to 511 +/- 52 uEq/min during LTD4 + PGE2. No change occurred in the contralateral right kidney. In this group, glomerular filtration as well as renal plasma flow were not statistically influenced. In Group 2, the same phenomenon was observed for urinary sodium. The combined infusion of LTD4 + PGE2 increased urinary sodium without significant changes in glomerular filtration and renal plasma flow. Finally, in Group 3, indomethacin was shown to reduce the natriuretic effects of LTD4 and PGE2: during PGE2 alone, urinary sodium increased from 90 +/- 14 to 260 +/- 66 uEq/min, and only rose from 80 +/- 10 to 175 +/- 19 uEq/min during the combined infusion of LTD4 and PGE2. In groups 2 and 3, free water clearance was utilized as an index of sodium chloride reabsorption in the thick ascending limb: this parameter increased from 2.35 +/- 0.25 to 4.70 +/- 0.30 ml/min, while urinary volume was increasing from 3.55 +/- 0.25 to 10.05 +/- 0.65 ml/min, during LTD4 + PGE2. Indomethacin, administered in Group 3, (3 mg/kg/hr) again abolished the effect of combined PGE2 + LTD4. These results indicate a potentiating effect of leukotriene D4 on the PGE2-induced natriuresis in the anesthetized dog. These phenomena occurred in the absence of significant changes in renal hemodynamics, therefore suggesting a direct tubular effect of these arachidonic acid metabolites. Finally, the water diuresis experiments suggest a proximal site of action of PGE2 and LTD4.     

Cardiovascular and renal effects of calcitonin gene-related peptide in hypertensive dogs

The systemic cardiovascular and renal effects of synthetic beta-human calcitonin gene-related peptide (beta-hCGRP) were examined in conscious normotensive and one-kidney one-clip (1K-1C) hypertensive dogs. beta-hCGRP was infused intravenously at 10 and 50 ng/kg/min for 75-min periods each. Mean arterial pressure did not change significantly (p greater than 0.05) in either group during low dose infusion of beta-hCGRP, but infusion of beta-hCGRP at 50 ng/kg/min produced a fall in mean arterial pressure from 140 +/- 4 to 116 +/- 6 mmHg (p less than 0.05) in the hypertensive dogs (n = 4) and from 100 +/- 4 to 78 +/- 3 mmHg (p less than 0.05) in the normotensive dogs (n = 4). Heart rates increased significantly during infusion of beta-hCGRP in both groups. Also, renal sodium and potassium excretion decreased (p less than 0.05) in the two groups at both the low and high doses of beta-hCGRP. Creatinine clearance was unchanged in normal dogs and decreased (p less than 0.05) in 1K-1C hypertensive dogs at the high rate of beta-hCGRP infusion. The clearance of p-aminohippurate increased approximately 20% (p less than 0.05) in both groups with the low dose infusion of beta-hCGRP but further increases were elicited only in the normotensive dogs in response to the elevation in the beta-hCGRP infusion rate. Plasma renin and aldosterone levels increased (p less than 0.05) above control levels during the maximum hypotensive response to beta-hCGRP infusion in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute angiotensin II increases plasma F2-isoprostanes in salt-replete human hypertensives

Angiotensin (Ang) II induces oxidative stress in vitro and in animal models of hypertension. We tested the hypothesis that Ang II increases oxidative stress in human hypertension, as assessed by plasma F2-isoprostane concentrations. Plasma F2-isoprostanes, hemodynamic and endocrine parameters were measured at baseline and following a 55 min infusion of 3 ng/kg/min Ang II in 13 normotensive and 13 hypertensive volunteers ingesting a high- (200 mmol/d) or low- (10 mmol/d) sodium diet. Mean arterial pressure (MAP) and body mass index were higher in hypertensive subjects. Ang II infusion increased MAP (p<.001) and plasma aldosterone concentrations (p<.001) and decreased plasma renin activity (p<.001) and renal plasma flow (p<.001) to a similar extent in both groups. Plasma F2-isoprostane concentrations were similar at baseline. There was no effect of Ang II on F2-isoprostane concentrations during low-salt intake in either group (normotensive 51.7 +/- 7.1 to 53.7 +/- 6.5 pg/ml and hypertensive 52.2 +/- 8.2 to 56.2 +/- 10.0 pg/ml; mean +/- SE). During high-salt intake, Ang II increased F2-isoprostane concentrations in the hypertensive group (52.3 +/- 7.2 to 63.2 +/- 10.4 pg/ml, p=0.010) but not in the normotensive group (54.2 +/- 4.4 to 58.9 +/- 6.6 pg/ml, p=0.83). Acute Ang II infusion increases oxidative stress in vivo in hypertensive humans. The renin-angiotensin system may contribute to oxidative stress in human cardiovascular disease.     

Fluid volume and osmoregulation in humans after a week of head-down bed rest

Body fluid homeostasis was investigated during chronic bed rest (BR) and compared with that of acute supine conditions. The hypothesis was tested that 6 degrees head-down BR leads to hypovolemia, which activates antinatriuretic mechanisms so that the renal responses to standardized saline loading are attenuated. Isotonic (20 ml/kg body wt) and hypertonic (2.5%, 7.2 ml/kg body wt) infusions were performed in eight subjects over 20 min following 7 and 10 days, respectively, of BR during constant sodium intake (200 meq/day). BR decreased body weight (83.0 +/- 4.8 to 81.8 +/- 4.4 kg) and increased plasma osmolality (285.9 +/- 0.6 to 288.5 +/- 0.9 mosmol/kgH(2)O, P < 0.05). Plasma ANG II doubled (4.2 +/- 1.2 to 8.8 +/- 1.8 pg/ml), whereas other endocrine variables decreased: plasma atrial natriuretic peptide (42 +/- 3 to 24 +/- 3 pg/ml), urinary urodilatin excretion rate (4.5 +/- 0.3 to 3.2 +/- 0.1 pg/min), and plasma vasopressin (1.7 +/- 0.3 to 0.8 +/- 0.2 pg/ml, P < 0.05). During BR, the natriuretic response to the isotonic saline infusion was augmented (39 +/- 8 vs. 18 +/- 6 meq sodium/350 min), whereas the response to hypertonic saline was unaltered (32 +/- 8 vs. 29 +/- 5 meq/350 min, P < 0.05). In conclusion, BR elicits antinatriuretic endocrine signals, but it does not attenuate the renal natriuretic response to saline stimuli in men; on the contrary, the response to isotonic saline is augmented.     

Effects of captopril and enalapril on sodium excretion and blood pressure in sodium-deficient dogs

Inhibition of angiotensin I-converting enzyme (ACE) (kininase II) provides a powerful new method for evaluating the role of the renin-angiotensin-aldosterone and kallikrein-kinin systems in the control of aldosterone secretion, renal function, and arterial blood pressure. This study compares the effects of long-term administration of a sulfhydryl inhibitor, captopril, with a nonsulfhydryl inhibitor, enalapril (1-[N-[1-(ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-L-proline), in conscious sodium-deficient dogs. Plasma aldosterone concentration (PAC), plasma renin activity (PRA), urinary sodium excretion (UNaV), arterial pressure (AP), blood kinins (BK), urinary kinins (UK), and urinary kallikrein activity (UKA) were determined during long-term inhibition of ACE in sodium-deficient dogs. In response to captopril administration (20 mg/(kg . day], PAC decreased from 38.9 +/- 6.7 to 14.3 +/- 2.3 ng/dl, PRA increased from 3.58 +/- 0.53 to 13.7 +/- 1.6 ng/(ml . h), UNaV increased from 0.65 +/- 0.27 to 6.4 +/- 1.2 meq/day, AP decreased from 102 +/- 3 to 65 +/- 2 mm Hg, BK increased from 0.17 +/- 0.02 to 0.41 +/- 0.04 ng/ml, UK increased from 7.2 +/- 1.5 to 31.4 +/- 3.2 micrograms/day, and UKA decreased from 23.6 +/- 3.1 to 5.3 +/- 1.2 EU/day. Quantitatively similar changes in AP, UNaV, and PAC were observed in sodium-deficient dogs in response to long-term enalapril administration (4 mg/(kg X day]. In sodium-deficient dogs maintained on captopril or enalapril for several days, angiotensin II (AngII) infusion (3 ng/(kg X min] restored PAC, UNaV, and AP to levels observed in untreated sodium-deficient dogs. These data indicate that the long-term hypotensive and natriuretic actions of inhibitors of ACE are mediated by inhibition of AngII formation and that the renin-angiotensin system plays an essential role in regulating aldosterone secretion, renal function, and AP during sodium deficiency.     

Analysis of tert-butyl hydroperoxide induced constrictions of perfused vascular beds in vitro

tert-Butyl hydroperoxide (t-BOOH), an inducer of oxidative stress in vitro, elicits constrictor responses of the isolated, rat kidney and mesenteric arteries perfused (5 ml/min) with physiological salt solutions (PSS) at 37 degrees C gassed with carbogen. We hypothesized that generation of superoxide anions (O(2)(-)) accounts for these responses. We assessed responses to t-BOOH in preparations with/without endothelium, and in the absence/presence of antioxidant compounds, catalase and tempol, scavengers of hydroxyl (OH(-)) radical and O(2)(-), respectively. t-BOOH (0.01-50 micromol) induced (expressed as % of 50 micromol KCl vasoconstriction) were abolished by endothelium denudation, perfusion with Ca(2+)-free PSS and by nifedipine, (1 nM). Infusion of t-BOOH (0.1 microM) did not significantly (P > 0.05) affect phenylepherine E(max) in the mesenteric arteries, however it reduced phenylepherine E(max) responses in the kidney from 94.9 +/- 3.9 % to 64.7 +/- 4.7 %. Nitroblue tetrazolium, as well as alpha-phenyl N-tert-butyl nitrone, at 100 microM, but not catalase (500 IU) significantly attenuated t-BOOH (10 micromol) vasoconstrictor responses. Tempol (100 microM), a membrane permeable antioxidant, also significantly reduced t-BOOH (10 micromol) responses from 17.0 +/- 1.9 % (control) to 9.6 +/- 0.5 % (+tempol) in the mesenteric arteries and from 40.4 +/- 4.2 % (control) to 20.7 +/- 1.5 % (+tempol) in the kidney. Our data suggest that t-BOOH elicits vasoconstriction via two distinct mechanisms: (i) increased influx of extracellular Ca(2+), and (ii) generation of free radicals including O(2)(-) anions.     

Acute effects of angiotensin II on renal haemodynamics and excretion in conscious dogs

The effects of a 60-min intravenous infusion of angiotensin II (A II; 4 or 20 ng A II/min/kg body weight) on renal blood flow (RBF; electromagnetic flow transducer, control value 19-25 ml/min/kg), glomerular filtration rate (GFR; control value 4.2-5.0 ml/min/kg), mean arterial blood pressure, sodium excretion, water excretion, and plasma A II and plasma aldosterone concentrations were examined in 6 chronically instrumented female conscious beagle dogs kept on three different dietary sodium intakes (SI): SI 0.5 or SI 2.5 mmol Na/kg/day or SI 4.5 mmol Na/kg/day plus an oral saline load prior to the experiment SI 4.5(+) dogs. Four nanograms A II decreased RBF and GFR in SI 4.5(+) dogs without changing the filtration fraction (FF%); in SI 0.5 dogs the RBF decreased, and the FF% increased. Twenty nanograms A II decreased RBF and increased FF% in all dietary protocols, less in SI 4.5(+) dogs. The mean arterial blood pressure increased in all dietary protocols by 10-15 mm Hg (4 ng A II) and 32-37 mm Hg (20 ng A II). Sodium and water excretions decreased by 32 and 46%, respectively, in SI 4.5(+) dogs at both doses of A II. The plasma aldosterone concentration increased in all but one protocol: 4 ng A II, SI 4.5(+) dogs. It is concluded that when A II plasma concentrations are most likely borderline to pathophysiological conditions (up to an average of 370 pg/ml), the GFR is less decreased than the RBF. This phenomenon also can be observed at lower plasma A II concentrations (average 200 pg/ml), when the renin-angiotensin system had been previously moderately activated.     

Portal venous infusions of L-glutamine in anaesthetized dogs do not influence renal function.

It has been reported that the intraportal infusion of glutamine in Munich-Wistar rats will cause depression of renal perfusion and the urinary excretion of salt and water. We have attempted to reproduce these findings in anaesthetized dogs. L-Glutamine was infused at doses between 120 and 150 mumol/min into the portal vein and femoral vein of anaesthetized dogs. No effect was observed on portal venous pressure, blood pressure, or kidney function. Similar data were obtained with D-glutamine. Liver biopsy revealed no abnormalities. When 1.5-3 micrograms histamine (free base) was infused into the portal system, portal venous pressure rose from 15.2 +/- 0.33 to 24.8 +/- 0.40 cmH2O (p < 0.05) (1 cmH2O = 98.1 Pa). Glutamine infusions do not appear to initiate hepatorenal reflexes in dogs as they have been reported to do in rats.     

Volume expansion during NOS substrate donation with L-arginine: regulatory offsetting of renal response?

The responses to infusion of nitric oxide synthase substrate (L-arginine 3 mg.kg(-1).min(-1)) and to slow volume expansion (saline 35 ml/kg for 90 min) alone and in combination were investigated in separate experiments. L-Arginine left blood pressure and plasma ANG II unaffected but decreased heart rate (6 +/- 2 beats/min) and urine osmolality, increased glomerular filtration rate (GFR) transiently, and caused sustained increases in sodium excretion (fourfold) and urine flow (0.2 +/- 0.0 to 0.7 +/- 0.1 ml/min). Volume expansion increased arterial blood pressure (102 +/- 3 to 114 +/- 3 mmHg), elevated GFR persistently by 24%, and enhanced sodium excretion to a peak of 251 +/- 31 micromol/min, together with marked increases in urine flow, osmolar and free water clearances, whereas plasma ANG II decreased (8.1 +/- 1.7 to 1.6 +/- 0.3 pg/ml). Combined volume expansion and L-arginine infusion tended to increase arterial blood pressure and increased GFR by 31%, whereas peak sodium excretion was enhanced to 335 +/- 23 micromol/min at plasma ANG II levels of 3.0 +/- 1.1 pg/ml; urine flow and osmolar clearance were increased at constant free water clearance. In conclusion, L-arginine 1) increases sodium excretion, 2) decreases basal urine osmolality, 3) exaggerates the natriuretic response to volume expansion by an average of 50% without persistent changes in GFR, and 4) abolishes the increase in free water clearance normally occurring during volume expansion. Thus L-arginine is a natriuretic substance compatible with a role of nitric oxide in sodium homeostasis, possibly by offsetting/shifting the renal response to sodium excess.     

Equimolar doses of atrial and brain natriuretic peptides and urodilatin have differential renal actions in overt experimental heart failure

A hallmark of overt congestive heart failure (CHF) is attenuated cGMP production by endogenous atrial natriuretic peptide (ANP) with renal resistance to ANP. ANP and brain natriuretic peptides (BNP) are of myocardial origin, whereas urodilatin (Uro) is thought to be derived from kidney. All three peptides are agonists to the natriuretic peptide-A receptor. Our objective was to compare the cardiorenal and humoral actions of ANP, BNP, and Uro in experimental overt CHF. We determined cardiorenal and humoral actions of 90 min of intravenous equimolar infusion of ANP, BNP, and Uro (2 and 10 pmol.kg-1.min-1) in three separate groups of anesthetized dogs with rapid ventricular pacing-induced overt CHF (240 beats/min for 10 days). BNP resulted in increases in urinary sodium excretion (U(Na)V) (2.2+/-0.7 to 164+/-76 microeq/min, P<0.05) and glomerular filtration rate (GFR) (27+/-4 to 52+/-11 ml/min, P<0.05) that were greater than those with Uro (P<0.05), whereas ANP did not result in increases in U(Na)V or GFR. Increases in plasma cGMP (25+/-2 to 38+/-2 pmol/ml, P<0.05) and urinary cGMP excretion with BNP (1,618+/-151 to 6,124+/-995 pmol/min, P<0.05) were similar to those with Uro; however, there was no change with ANP. Cardiac filling pressures were reduced in all three groups. These studies also support the conclusion that in experimental overt CHF, renal resistance to natriuretic peptides in increasing rank order is BNP相似文献   

Prostaglandin E2 induced changes in renal blood flow, renal interstitial hydrostatic pressure and sodium excretion in the rat

Prostaglandin E2, when infused into the renal artery of the dog, is a vasodilator and increases both renal interstitial hydrostatic pressure and sodium excretion. Similar studies in the rat, however, have been inconclusive. The present study examined the effect of prostaglandin E2 infusion into the renal interstitium, by means of a chronically implanted matrix, on renal blood flow, renal interstitial hydrostatic pressure and sodium excretion in the rat. Prostaglandin E2 was continuously infused directly into the kidney interstitium to mimic endogenous prostaglandin E2 production by renal cells. The maximum change in each of these parameters occurred when 10(-5) M PGE2 was infused. Renal blood flow increased from 4.70 +/- 0.91 to 5.45 +/- 0.35 ml/min (p less than 0.05) while renal interstitial hydrostatic pressure decreased from 3.9 +/- 0.4 to 2.6 +/- 0.5 mmHg (p less than 0.05) and fractional excretion of sodium decreased from 1.02 +/- 0.20 to 0.61 +/- 0.12% (p less than 0.05). Thus, the present study demonstrates that renal interstitial infusion of prostaglandin E2 increases total renal blood flow but decreases both renal interstitial hydrostatic pressure and urinary sodium excretion in the rat.     

Effect of chemical sympathectomy on renal hydroelectrolytic handling in dogs with chronic caval constriction

The effect of renal selective chemical sympathectomy by intrarenal infusion of 6-hydroxydopamine (6-OHDA, 5 mg/kg body weight) on the renal excretion of water and electrolytes was studied in 7 dogs in whom a syndrome of sodium and water retention and ascites formation was induced by partial constriction of thoracic inferior vena cava. Propranolol (1 mg) and phentolamine (3 mg) were also injected to obviate acute systemic hemodynamic changes. Sympathectomy was performed once in 4 dogs and three times in 3 dogs. Sympathectomy induced an abrupt and transient increase in urinary flow (from 170 +/- 30 to 890 +/- 60 ml/24 h) and sodium excretion (from 4.5 +/- 1.5 to 178 +/- 21 mEq/24 h). This was accompanied by an important fall in plasma renin activity (from 2.2 +/- 0.2 to 0.5 +/- 0.1 ng angiotensin I/ml/h) and aldosterone, and disappearance of ascites. It is concluded that chemical sympathectomy, by increasing renal sodium and water excretion, mobilizes the ascites induced by chronic caval constriction, a fact that highlights the role of the renal sympathetic system in the pathogenesis of sodium and water retention by the kidney.     

Cardiorenal reflexes do not attenuate the renal effects of infused atriopeptin in conscious dogs.

Low-dose infusions of atriopeptin produce only a modest diuresis and natriuresis. However, these infusions also decrease atrial pressures, a change that has been postulated to elicit an antidiuretic and antinatriuretic reflex from cardiac receptors and thereby to attenuate the direct renal effects of atriopeptin. To determine whether the renal effects of intravenously administered atriopeptin might be attenuated by a cardiorenal reflex, we infused alpha-human atrial natriuretic peptide (alpha-hANP) into cardiac-denervated and sham-operated (normal) conscious dogs. Following a control period, alpha-hANP was infused into each dog at 12.5, 25, or 50 ng.kg-1.min-1 for 1 hr. Infusion of alpha-hANP at 50 ng.kg-1.min-1 produced similar decreases in left atrial pressure in both normal and cardiac-denervated dogs (peak changes, -1.6 +/- 0.8 vs -2.4 +/- 0.9 mm Hg, respectively). Increases in urine flow (peak changes, 0.13 +/- 0.05 vs 0.20 +/- 0.06 ml/min) and sodium excretion (peak changes, 56 +/- 22 vs 70 +/- 11 microEq/min) also were not different between groups. The lower doses of alpha-hANP also elicited renal and hemodynamic responses in the cardiac-denervated dogs that did not differ significantly from those in the normal dogs. These data indicate that the diuresis and natriuresis elicited by intravenously administered alpha-hANP are not attenuated by a cardiorenal reflex in conscious dogs.     

Tempol improves renal hemodynamics and pressure natriuresis in hyperthyroid rats

Hyperthyroidism in rats is associated with increased oxidative stress. These animals also show abnormal renal hemodynamics and an attenuated pressure-diuresis-natriuresis (PDN) response. We analyzed the role of oxidative stress as a mediator of these alterations by examining acute effects of tempol, a superoxide dismutase mimetic. The effects of increasing bolus doses of tempol (25-150 micromol/kg) on mean arterial pressure (MAP), renal vascular resistance (RVR), and cortical (CBF) and medullary (MBF) blood flow were studied in control and thyroxine (T4)-treated rats. In another experiment, tempol was infused at 150 micromol.kg(-1).h(-1) to analyze its effects on the glomerular filtration rate (GFR) and on PDN response in these animals. Tempol dose dependently decreased MAP and RVR and increased CBF and MBF in control and T4-treated rats, but the T4 group showed a greater responsiveness to tempol in all of these variables. The highest dose of tempol decreased RVR by 13.5 +/- 2.1 and 5.5 +/- 1.2 mmHg.ml(-1).min(-1) in hyperthyroid (P < 0.01) and control rats, respectively. GFR was not changed by tempol in controls but was significantly increased in the hyperthyroid group. Tempol did not change the absolute or fractional PDN responses of controls but significantly improved those of hyperthyroid rats, although without attaining normal values. Tempol increased the slopes of the relationship between renal perfusion pressure and natriuresis (T4+tempol: 0.17 +/- 0.05; T4: 0.09 +/- 0.03 microeq.min(-1).g(-1).mmHg(-1); P < 0.05) and reduced 8-isoprostane excretion in hyperthyroid rats. These results show that antioxidant treatment with tempol improves renal hemodynamic variables and PDN response in hyperthyroid rats, indicating the participation of an increased oxidative stress in these mechanisms.