Absence of a losartan interaction with renal lithium excretion in the rat.

1. The interaction of losartan, a non-peptide specific AT1 receptor antagonist with the renal handling of lithium was analysed in conscious normotensive Wistar rats and compared with the known increase in renal tubular lithium reabsorption induced by the non-steroidal anti-inflammatory drug, indomethacin. 2. The rats were treated for five days with losartan (10 mg kg-1 day-1, orally), indomethacin (2.5 mg kg-1 day-1, intramuscularly) or their solvents. Lithium chloride (16.7 mg kg-1, i.p.) was given as a single dose on the fifth day; renal functions were then measured. 3. Indomethacin, in the absence of any effect on creatinine clearance, increased renal fractional lithium reabsorption and led to an increase in plasma lithium levels. 4. Losartan did not modify renal lithium handling and its plasma level. No change was observed in renal lithium clearance, the quantity of filtered lithium or the fractional reabsorption of the metal. As expected, losartan had no effect on systolic blood pressure in normotensive rats. 5. In conclusion, our results indicate that losartan, when given orally in the rat at a dose of 10 mg kg-1 day-1 over five days, does not modify renal lithium handling. They suggest that blockade of the angiotensin II receptors does not interfere with renal lithium reabsorption, which occurs mainly at a proximal tubular site.     

Effects of icatibant on the ramipril-induced decrease in renal lithium clearance in the rat

The interaction between an inhibitor of angiotensin I converting enzyme (ramipril) and renal lithium handling was analysed in conscious, normotensive Wistar rats in the absence or the presence of a specific bradykinin B2 receptor antagonist, icatibant. The rats were treated for 5 days with ramipril (1 mg/kg/day p.o.) or its vehicle, alone or together with icatibant (0.1 mg/kg/day, s.c. infusion). Lithium chloride (8.3 mg/kg i.p.) was given as a single dose on day 5. Systolic blood pressure and heart rate were measured by tail plethysmography on day 3 (3, 9 and 15 h after ramipril administration) and renal function on day 4 (0-6 and 6-24 h urine sampling) and day 5 (0-6 h urine sampling). In another group of rats, 24 h sodium excretion was assessed during the first 4 days of ramipril treatment. Ramipril decreased renal lithium clearance (90+/-8 vs. 142+/-10 microl/min/100 g, P<0.001, n=24) and increased the fractional lithium reabsorption (74.3+/-1.9 vs. 66.7+/-1.7%, P<0.05) and plasma lithium concentration (0.108+/-0.006 vs. 0.085+/-0.004 mM, P<0.01). Alteration of renal lithium handling by ramipril was associated with a decrease in systolic blood pressure (-15% 3 h after ramipril administration) and sodium excretion (0-6 h after ramipril). The 24-h sodium excretion, however, tended to increase. Icatibant had no effect per se on renal function but attenuated the ramipril-induced decrease in renal lithium clearance (118+/-16 vs. 90+/-8 microl/min/100 g, n=12 and 24 respectively, P<0.05 one-tailed test) and systolic blood pressure. These results suggest that endogenous bradykinin contributes to the ramipril-associated alteration in renal lithium handling. Bradykinin B2 receptor-mediated vasodilation seems to be involved.     

A specific B2-bradykinin receptor antagonist HOE 140 abolishes the antihypertrophic effect of ramipril.

To evaluate the role of bradykinin in the antihypertrophic effect of the angiotensin-converting enzyme (ACE) inhibitor, ramipril, we investigated the influence of HOE 140, a specific B2-receptor antagonist, on the effects of ramipril on left ventricular hypertrophy (LVH) in rats with aortic banding. Ramipril at a dose of 1 mg kg-1 day-1 for 6 weeks prevented the increase in blood pressure and development of LVH after aortic banding; plasma ACE activity was significantly inhibited. A lower dose of ramipril (10 micrograms kg-1 day-1 for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity, but prevented LVH after aortic banding. The antihypertrophic effects of the higher and the lower dose ramipril, as well as the antihypertensive action of the higher dose of ramipril were abolished by the coadministration of HOE 140 (500 micrograms kg-1 day-1). The present data show for the first time that the beneficial effects of an ACE-inhibitor on LVH in rats with hypertension caused by aortic banding can be prevented by a specific B2-receptor antagonist.     

Nonlinear disposition of lithium in rats and saturation of its tubular reabsorption by the sodium‐phosphate cotransporter as a cause

We previously reported the contribution of sodium‐phosphate cotransporter to the tubular reabsorption of lithium in rats. In the present study, the dose dependency of the renal handling of lithium was examined in rats. When lithium chloride at 1.25 mg/kg, 2.5 mg/kg and 25 mg/kg was intravenously injected as a bolus, the areas under the plasma concentration‐time curve of lithium until 60 minutes were calculated to be 6.23 mEq·min/l, 8.77 mEq·min/l and 64.6 mEq·min/l, respectively. The renal clearance of lithium and its fractional excretion increased with increments in the dose administered. The renal clearance of lithium strongly correlated with the urinary excretion rate of phosphate in the 1.25 mg/kg group (r = 0.840) and 2.5 mg/kg group (r = 0.773), whereas this correlation was weak in the 25 mg/kg group (r = 0.306). The infusion of foscarnet, a typical inhibitor of sodium‐phosphate cotransporter, decreased the fractional reabsorption of lithium in rats administered lithium chloride at 2.5 mg/kg, but did not affect it in rats administered 25 mg/kg. These results demonstrate the nonlinearity of the renal excretion of lithium in rats, with the saturation of lithium reabsorption by the sodium‐phosphate cotransporter potentially being involved.     

Kappa-opioid-receptor agonists modulate the renal excretion of water and electrolytes in anaesthetized rats.

1. Subcutaneous injection of the kappa-opioid agonists U50,488 (10 mg kg-1) and tifluadom (3.5 mg kg-1) into Inactin-anaesthetized, saline-infused rats was associated with a diuresis, antinatriuresis and antikaliuresis which lasted for up to 2 h. A high (5 mg kg-1), but not low (0.1 mg kg-1), dose of naloxone blocked the renal effects of U50,488. 2. U50,488 administration in anaesthetized, vasopressin-deficient Brattleboro DI rats was associated with an attenuated diuresis, though the antinatriuretic response remained intact. 3. The diuretic action of U50,488 was associated with an increase in glomerular filtration rate while fractional fluid reabsorption remained steady. In contrast, fractional sodium and potassium reabsorption were increased. 4. These data suggest that kappa-opioid agonists alter renal handling of both water and electrolytes. This appears to be mediated by two separate mechanisms: increased fluid loss largely reflects altered glomerular events while the fall in electrolyte excretion results from altered tubular handling.     

The diuretic action of 8-cyclopentyl-1,3-dipropylxanthine, a selective A1 adenosine receptor antagonist.

1. The diuretic effect of the selective A1 adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), was investigated in anaesthetized rats. 2. CPX (0.1 mg kg-1, i.v.) produced significant increases in urine flow, and the excretion rate and fractional excretion of both sodium and chloride. By contrast, CPX administration did not result in any significant change in the excretion of potassium. 3. The diuretic effect of CPX was accompanied by a transient increase in inulin clearance although p-amino-hippurate clearance was unaffected, indicating the CPX induced a temporary elevation of glomerular filtration rate but no change in renal blood flow. 4. The fractional excretion of lithium (a marker of delivery of fluid out of the proximal tubule) was also significantly increased by CPX. However, other measures of tubular function derived from lithium clearance indicated that there were no changes in the handling of sodium or water in the distal regions of the nephron. 5. CPX did not significantly alter the relationship between either free water reabsorption or free water clearance and the distal delivery of sodium, which suggests that CPX does not affect the renal concentration/dilution mechanism. 6. The results of this study show that the diuresis and increased excretion of sodium and chloride induced by CPX (0.1 mg kg-1) in the rat, occurs with only transient elevation in glomerular filtration rate and no change in renal blood flow. The primary reason for the diuresis appears to be inhibition of sodium reabsorption in the proximal tubule.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of captopril on renal hemodynamics and segmental tubular reabsorption of sodium in humans

Acute angiotensin-converting enzyme inhibitors (ACEIs) have been found to induce natriuresis in humans as well as in experimental animals. However, the tubular sites involved have not been precisely evaluated in humans. Using both free-water and lithium clearance, the latter as a marker of proximal tubular reabsorption, we measured segmental tubular movement of sodium before and after acute captopril administration in eight healthy normotensive volunteers on normal sodium diet. Captopril decreased slightly but significantly glomerular filtration rate (GFR), filtration fraction, and mean arterial pressure (MAP), whereas renal plasma flow (RPF) was unchanged. Captopril acutely increased excretion rate and fractional excretion of sodium. When assessed by lithium clearance, both absolute and fractional proximal reabsorption of sodium and fractional distal reabsorption of sodium were found to be decreased by captopril. When assessed by free-water clearance, both fractional proximal and distal reabsorption of sodium were found to be decreased by captopril but only the decrease in fractional proximal reabsorption was significant. These results indicate that captopril-induced natriuretic effect is due to decreased sodium reabsorption in both proximal and distal sites of the nephron. Shifts in segmental tubular sodium reabsorption obtained from either free-water or lithium clearance are directionally similar but quantitatively different. Results obtained from lithium clearance indicate that the rate of fluid delivery to the diluting segment is at least twice as great as that estimated from free-water calculations. Lithium clearance techniques therefore appear to be more sensitive in detecting subtle changes in segmental tubular reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stereospecificity of the effects of ozolinone on renal hemodynamics and on segmental tubular sodium reabsorption in conscious rats

The study was performed to elucidate the effects of the two stereoisomers of ozolinone (d,l) on renal hemodynamics and proximal tubular Na reabsorption. Clearance experiments were performed in conscious water-loaded female Wistar rats. The clearances of [3H]inulin, [14C]tetraethylammonium and lithium were used as estimates for glomerular filtration rate, renal plasma flow and delivery of fluid from the proximal tubules, respectively. When the baseline parameters had stabilized, d- or l-ozolinone was injected i.v. in doses of 4, 20 and 100 mg/kg. 1-Ozolinone caused a transient and dose-dependent diuretic-natriuretic response with no evidence of a ceiling. At peak natriuresis, 2.5-5 min after 100 mg/kg of 1-ozolinone, the fractional Na excretion was increased from 0.5 to 25%; this was associated with an increased fractional excretion of lithium from 27 to 60%, and small transient decreases of renal hemodynamic parameters. d-Ozolinone had no significant effects except for a small natriuresis after 100 mg/kg. It is concluded that in water-loaded conscious rats 1-ozolinone is a powerful diuretic which, in contrast to d-ozolinone, increases the delivery of fluid from the proximal tubule as judged from changes in lithium clearance.     

Analgesic and anti-inflammatory activities in rats of alpha-(3,5-di-t-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), and its intestinal damage

alpha-(3,5-Di-t-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), an anti-inflammatory drug, possesses analgesic activity in rat models. In the acetic acid-induced writhing test, the oral ED50 values for KME-4, indomethacin, naproxen and ibuprofen were 5.2, 3.8, 7.0 and 18.6 mg kg-1, respectively, and the relative order of potency of these drugs correlated with their inhibitory effect on acetic acid-induced vascular permeability in rats. KME-4 also had analgesic activity in the tests of Randall-Selitto and adjuvant arthritic flexion, but the dose required was greater than that needed in the writhing test. KME-4 (10 mg kg-1 day-1 orally) has a preventive effect against adjuvant-induced arthritis in rats, and its efficacy was more potent than indomethacin (2 mg kg-1 day-1) as judged from various parameters determined. When administered orally to rats once daily for 12 days, KME-4 caused perforating ulceration of the small intestine but this action was less potent than the effect of indomethacin, naproxen and ibuprofen.     

Changes of lithium elimination in acute polyuric renal failure caused by cisplatin and mercuric chloride

Changes in lithium elimination were studied under the condition of experimentally induced polyuric acute renal failure by cisplatin (6 mg/kg body wt) or HgCl2 (3 mg/kg body wt). The histologically proven lesions of tubuli were associated with the decrease of plasma clearance of lithium (C(Li)) and polyfructosan-S (CP(FS). The decrease of these clearance values was not proportional and the ratio C(Li)/CP(FS) (indicating renal fractional excretion of Li+) increased significantly (p less than 0.01). The increase of C(Li)/CP(FS) was related to the increase of renal fractional sodium excretion (FENa) (p less than 0.01). The results suggest that the impairment of tubular cells by cisplatin or HgCl2 caused the decrease of tubular reabsorption of Li+ and Na+. From the pharmacokinetic point of view, these experiments suggest that changes in tubular transport of drugs should be taken into account in their dosing adjustment in patients with acute polyuric tubular lesion.     

Cyclosporin A treatment enhances angiotensin converting enzyme activity in lung and serum of rats

Nephrotoxicity and arterial hypertension are the most common side effects of treatment with cyclosporin A (CSA). Its effects on angiotensin converting enzyme (ACE) activity in the renal cortex, lung and serum of nephrotoxic rats have been investigated. Wistar rats were treated with CSA (20 mg kg-1 day-1 i.p.) or vehicle (olive oil containing 10% ethanol) for 14 days. On day 15, the rats were killed and ACE activity determined by radiometric assay using [3H]hippuryl-glycyl-glycine as substrate. CSA treatment resulted in a decrease in creatinine clearance, urine flow and body weight and a significant increase in serum and lung ACE activities (436 +/- 9 vs 391 +/- 7 nmol mL-1 min-1, P less than 0.001; 184 +/- 8 vs 142 +/- 10 nmol mg-1 min-1 P less than 0.01, respectively). In contrast, renal cortex ACE activity was reduced in the CSA-treated rats (0.35 +/- 0.02 vs 0.51 +/- 0.02 nmol mg-1 min-1, P less than 0.01). ACE activities in the renal cortex and serum were not affected by treatment with gentamicin (80 mg kg-1 day-1) for 11 days. In rats treated simultaneously with CSA and captopril (50 mg kg-1 day-1) ACE activity in the serum, lung and renal cortex was inhibited by 95, 93 and 92%, respectively. These changes in ACE activity were associated with a decreased systolic blood pressure in the rats receiving CSA and captopril. Therefore, ACE activity in the serum and lung of CSA-treated rats was increased, while its activity in the renal cortex was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nonlinearities in amoxycillin pharmacokinetics. I. Disposition studies in the rat.

Several features of amoxycillin pharmacokinetics in man are not well known in spite of the extensive clinical use of the antibiotic. In this paper it is demonstrated that amoxycillin disposition kinetics in rats is clearly nonlinear, and that this may be due mainly to its elimination mechanisms. At different intravenous bolus dose levels, and in steady-state perfusion studies, the most striking feature is an increased renal clearance as dose increases (from 3.5 to 7.0 mg kg-1 for intravenous bolus, and from 4.6 to 20.0 micrograms min-1 for intravenous perfusions). This phenomenon has been attributed to a saturation of the active renal tubular reabsorption of the antibiotic. When the intravenous dose is substantially increased (28.0 mg kg-1 bolus), plasma clearance tends to stabilize, probably because saturation of the active tubular secretion of amoxycillin takes place at these doses. Extrarenal clearance seems to remain linear throughout the entire dose range. On the basis of these observations and a review of selected bibliography, an interpretation of the kinetic disposition behaviour of amoxycillin in man is attempted.     

RENAL HANDLING OF ENDOGENOUS LITHIUM IN EXPERIMENTAL DIABETES MELLITUS IN THE RAT

1. The usefulness of determining the renal handling of endogenous lithium as a marker of proximal tubular sodium reabsorption was assessed in streptozotocin induced diabetes mellitus in the Sprague-Dawley rat. 2. The clearance and fractional excretion of lithium were determined before and following the development of diabetes mellitus, and compared with measurements of proximal tubular reabsorption made directly using micropuncture techniques. Endogenous lithium was measured in order to avoid the toxic tubular effects of exogenously administered lithium salts. 3. Although a trend existed for a reduction in the fractional excretion of lithium in diabetic animals (1.8 +/- 0.3 vs 2.4 +/- 0.5%; P greater than 0.20), this did not reach statistical significance and did not accurately reflect the change in directly measured tubular Na reabsorption. 4. The decrease in proximal tubular Na reabsorption demonstrated in diabetic animals treated with phlorizin was not significantly reflected in the fractional lithium excretion, although again a corresponding trend was evident (1.9 +/- 0.8 vs 0.6 +/- 0.2%; P greater than 0.10. 5. In summary, the significant alterations in tubular Na handling in diabetes mellitus, previously demonstrated directly using micropuncture techniques, are not reflected in the renal handling of endogenous lithium. This indirect method is inadequate to assess proximal tubular Na transport in experimental diabetes mellitus.     

Effects of cyclosporin A, gentamicin and furosemide on rat renal function: a lithium clearance study

1. This study applied clearance methods of inulin, lithium, potassium, sodium and para-aminohippuric acid (PAH) for investigation of the effects of cyclosporin A (CyA), furosemide and gentamicin on rat (n = 92) renal function. The drugs were dosed for 2 weeks; CyA 12.5 mg/kg per day, gentamicin 32 mg/kg per day and furosemide 5 mg/kg per day. 2. The questions asked were: could these methods differentiate the effects of drugs with different sites of action, and would gentamicin or furosemide exaggerate the nephrotoxicity of CyA? 3. Furosemide increased sodium clearance (CNa) 74% and fractional sodium clearance (FENa) 105%, while fractional sodium reabsorption in the distal nephron (FDNR) was reduced, compared with placebo-treated controls. 4. Gentamicin reduced CPAH 29% and Cin 37%, while FENa increased 335%. Proximal fractional reabsorption (PFR) and absolute proximal reabsorption (APR) decreased. 5. CyA depressed CPAH 32% and lithium clearance (CLi) 56%, and increased PFR. 6. The effects of CyA and furosemide in reducing renal function were not additive. 7. CyA plus gentamicin reduced CPAH to 35% of the value in untreated controls, equal to 52% of the CPAH of CyA-treated rats; Cin was reduced to 46% of the Cin of CyA-treated rats. 8. Rats given CyA, furosemide and gentamicin had decreased Cin, CPAH and CLi compared with rats given either CyA plus furosemide or gentamicin plus furosemide. 9. Thus, in this investigation of drugs known to have different sites of actions, the differences in renal and tubular function were discernible with the lithium clearance method. 10. The nephrotoxicities of CyA and of gentamicin were additive, while furosemide did not aggravate CyA nephrotoxicity.     

Effects of acute and short-time antibiotic treatment on renal lithium elimination and serum lithium levels in the rat

Male Wistar rats received a single stomach load (10 ml/kg) of a 150 mmol LiCl solution, either alone or together with tetracycline (33.5 mg/10 ml), ampicillin (33.5 mg/10 ml), or metronidazole (15 mg/10 ml). Urine was collected 1-5 hours after administration and blood samples were drawn after 1, 6, and 24 hours. All antibiotics caused a reduction in urinary lithium excretion but did not affect renal lithium clearance. Serum lithium levels were reduced by tetracycline and metronidazole 6 hours after administration but increased after 24 hours. Additional experiments including frequent mapping of serum lithium levels confirmed these findings. Tetracycline, also reduced renal sodium clearance and increased distal sodium reabsorption. Short-term daily treatment during one week with tetracycline or metronidazole showed that these initial changes were only transient, since after treatment for one week no differences could be observed between antibiotic-treated rats and control rats. The results indicate that antibiotics may cause a delay but no decrease of the gastrointestinal absorption of lithium and that they do not affect renal lithium clearance. Signs of lithium intoxication during combined use of lithium and antibiotics are therefore probably not caused by a renal interaction mechanism affecting the renal lithium clearance.     

Effects of furosemide on renal haemodynamics and proximal tubular sodium reabsorption in conscious rats.

1. The effects of furosemide given as constant i.v. infusion (7.5 mg kg-1 h-1) or bolus injections (0.5, 7.5 and 120 mg kg-1) on renal haemodynamics and proximal tubular Na reabsorption were studied in conscious water diuretic rats. The clearance of Li (CLi) was used as marker for Na delivery from the proximal tubules, and clearance of [14C]-tetraethylammonium (CTEA) and [3H]-inulin (CIn) as markers for renal plasma flow (RPF) and glomerular filtration rate (GFR), respectively. 2. Furosemide caused a transient increase of RPF and GFR followed by a secondary decrease below baseline levels; the latter could in part be counteracted by volume replacement. The filtration fraction (FF = GFR/RPF) was not significantly changed by furosemide. Fractional proximal Na excretion (CLi/CIn) was significantly increased by all doses of furosemide independent of changes in RPF, GFR and FF. 3. The peak diuretic/natriuretic effect of furosemide was markedly potentiated by volume replacement, probably due to prevention of antinatriuretic mechanisms triggered by volume depletion. 4. It is concluded that following i.v. furosemide administration there is a biphasic change in renal haemodynamics in conscious, restrained rats, and that the inhibition of proximal Na reabsorption, as manifested by changes in fractional Li excretion, is not likely to be due to changes in total renal haemodynamics.     

Influence of nicardipine on renal hemodynamics and segmental tubular reabsorption of sodium in humans

Calcium antagonists induced natriuresis in humans as well as in experimental animals. However, the tubular sites involved have not been precisely evaluated in humans. Using both free-water and lithium clearance, the latter as a marker of absolute sodium distal delivery, we measured segmental tubular movement of sodium before and after acute intravenous (i.v.) nicardipine administration 2.5 mg as a single dose in eight healthy normotensive volunteers on normal sodium diet. Nicardipine decreased slightly but significantly the mean arterial pressure (MAP) (from 98.9 +/- 8.8 to 91.8 +/- 9.2 mm Hg; p less than 0.01) and the renal vascular resistance (from 6,142 +/- 1,082 to 5,578 +/- 893 dynes.s/cm5 . 1.73 m2; p less than 0.05), whereas the glomerular filtration rate (GFR), the renal plasma flow (RPF), and the filtration fraction (FF) were unchanged. Nicardipine acutely increased the absolute and the fractional excretion of sodium (from 282 +/- 60 to 427 +/- 152 mumol/min.1.73 m2; p less than 0.01 and from 0.015 +/- 0.004 to 0.023 +/- 0.013; p less than 0.01, respectively). When assessed by either lithium clearance or free-water clearance, both proximal and distal fractional reabsorption of sodium were decreased by nicardipine. These results indicate that the nicardipine-induced natriuretic effect is due to decreased sodium reabsorption in both proximal and distal sites of the nephron. Shifts in segmental tubular sodium reabsorption obtained from either free-water or lithium clearance were directionally similar but quantitatively different.     

Digoxin-specific Fab fragments impair renal function in the rabbit.

A 2 mg kg-1 intravenous bolus dose of digoxin-specific Fab fragments produced a 28% reduction in creatinine clearance in rabbits after 24 h. Urine output was reduced, while plasma and urinary creatinine concentrations were unaffected and increased, respectively. By 5 days the creatinine clearance had returned to normal. The fractional excretion of Na+ was nearly halved, indicating that the tubular reabsorption of Na+ increased to compensate for the reduced glomerular filtration rate, suggesting that tubular (as opposed to glomerular) function was not impaired.     

Renal effects of alpha-adrenoceptor blockade during furosemide diuresis in conscious rats.

Clearance experiments were performed in conscious rats in order to investigate whether intravenous infusion of the non-selective alpha-adrenoceptor antagonist phentolamine could block compensatory sodium reabsorption during furosemide-induced volume contraction. By measuring inulin clearance, urinary excretion rates of sodium and water, and lithium clearance, the effects on proximal and distal nephron segments were dissociated. The renal effect of intravenous infusion of 0.3 mg/kg/hr phentolamine (n = 6) was compared with time control animals (n = 9). Furosemide was administered as constant intravenous infusion (7.5 mg/kg/hr) with simultaneous phentolamine infusion at four dose levels: 0 (n = 9), 0.3 (n = 6), 1.0 (n = 7) and 3.0 mg/kg/hr (n = 6). Phentolamine infusion reduced norepinephrine-induced increase in blood pressure at all three dose levels (n = 5). Phentolamine infusion induced transient antidiuresis and a prolonged antinatriuretic response. Compared with rats given furosemide only, phentolamine attenuated dose-dependently the diuretic and natriuretic peak response to furosemide. This effect was associated with dose-dependent reductions in mean arterial pressure. The reduced natriuretic response was due to a reduced fractional sodium excretion in the distal nephron segment (at all doses of phentolamine) and a reduction of the glomerular filtration rate (1.0 and 3.0 mg/kg/hr phentolamine). The fractional lithium excretion (FELi) increased to 65 +/- 3% at 0.3 mg/kg/hr phentolamine during the natriuretic peak response of furosemide, while it only increased to 52 +/- 3% during furosemide alone. At steady-state conditions (120-180 min. after start of furosemide infusion) after infusion with furosemide plus 0.3 mg/kg/hr phentolamine the animals were still volume-depleted, but the compensatory tubular Na reabsorption in the proximal tubules was inhibited (FELi = 48 +/- 2% versus 39 +/- 1% in rats given furosemide alone). During furosemide infusion plasma epinephrine increased 700% and plasma norepinephrine increased 50%. These results are compatible with increased systemic sympathetic nervous activity and a contributory role of proximal tubular alpha-adrenoceptors in mediating compensatory sodium reabsorption during acute furosemide-induced volume contraction.     

阿托伐他汀对高血压大鼠肾脏血管紧张素转换酶2表达的影响

目的:观察阿托伐他汀对两肾一夹(2K1C)高血压大鼠肾脏血管紧张素转换酶2(ACE2)表达的影响,探讨阿托伐他汀降血压作用可能的新的作用机制。方法:40只雄性Wistar大鼠随机分为5组(每组8只):假手术组、高血压组、缬沙坦组(20 mg·kg-1·d-1)、阿托伐他汀组(10 mg·kg-1·d-1)和阿托伐他汀组(30 mg·kg-1·d-1)。鼠尾容积法测定术前、术后1周及药物干预后4、8周的SBP变化。8周后,免疫组化法检测肾脏ACE2蛋白表达,放射免疫分析法测定心肌组织血管紧张素Ⅱ(AngⅡ)水平,RT-PCR法检测肾脏组织ACE2 mRNA表达。结果:高剂量阿托伐他汀组SBP较高血压组降低显著(P<0.01);高剂量阿托伐他汀组较高血压组降低心肌组织AngⅡ浓度显著(P<0.01);RT-PCR显示缬沙坦组和低、高剂量阿托伐他汀组肾脏组织ACE2 mRNA的表达较高血压组不同程度增高(P<0.05)。结论:2K1C高血压大鼠肾脏组织ACE2蛋白、ACE2 mRNA表达降低。阿托伐他汀在降低高血压大鼠SBP的同时,降低心肌组织AngⅡ浓度,增加肾脏组织ACE2蛋白、ACE2 mRNA表达。