RENAL RESPONSES TO ANGIOTENSIN II IN CONSCIOUS DOGS: EFFECTS OF ASPIRIN AND INDOMETHACIN

1. Angiotensin II was infused into the renal artery of unanaesthetized dogs at 0.4 and 2.0 ng/kg per min for 40 min each. 2. Indomethacin (3 mg/kg, and 1 mg/kg per h infusion i.v.) accentuated the angiotensin II-induced falls in glomerular filtration rate, renal blood flow and urine flow rate. Indomethacin did not alter the effects of angiotensin II on Na+ or K+ excretions. 3. Aspirin (35 mg/kg p.o. 2.5 h and 0.5 h prior to experiment) did not significantly change the renal effects of angiotensin II. 4. Both aspirin and indomethacin accentuated renal vasoconstriction during briefer (5 min) angiotensin II infusion. 5. Thus indomethacin and aspirin had markedly different effects on the actions of angiotensin II in the kidney. This suggests that at least one of these drugs has actions which affect angiotensin II-mediated vasoconstriction other than via cyclooxygenase inhibition.     

成人血清尿酸水平与肾功能异常的关系

目的 探索成人血尿酸（SUA）水平与肾功能异常的关系。方法 选取正常体检者12 138例为研究对象。通过问卷调查收集受试者一般资料,并检测血肌酐（Scr）、SUA和空腹血糖。依据估算肾小球滤过率（eGFR）将受试者分为肾功能异常组（1 607例）和肾功能正常组（10 531例）。在男性和女性分别以420 μmol/L和360 μmol/L为界分为高尿酸血症组和正常尿酸组;将正常尿酸组按SUA四分位数分为4组。在不同性别中分析肾功能异常的患者比例随SUA水平变化的趋势。在不同性别、年龄、文化程度、锻炼、高血压和糖尿病患病情况的亚组中采用Logistic回归分析SUA水平对肾功能的影响。结果 在男性和女性中,随着SUA水平升高,SUA四分位数各组和高尿酸血症患者占比在肾功能异常组中呈递增趋势（Z_男性=6.411,Z_女性=23.800,P<0.01）。Logistic回归结果显示与第一分位组相比,第二、三、四分位组和高尿酸血症组均为肾功能异常的危险因素（P<0.05）。在男性和女性中SUA与肾功能异常之间存在明显的剂量-反应关系（P _{for trend}<0.01）。这种关系在不同年龄、文化程度、锻炼情况、高血压和糖尿病患病情况亚组中都有统计学意义。结论 SUA水平升高与肾功能异常的风险增加有关,且存在剂量-反应关系。     

RENAL AUTOTRANSPLANTS IN SHEEP: INVESTIGATION OF RENAL FUNCTION AND RENOVASCULAR HYPERTENSION

1. A novel surgical preparation of sheep with a cervical renal autotransplant has been developed. 2. Glomerular filtration rate and effective renal plasma flow were 25.1 ± 1.0 ml/min and 208 ± 10 ml/min respectively (n= 26). 3. The responses to water load and deprivation, to AVP injection, to Na depletion and intravenous hypertonic saline load show the kidneys responded in an appropriate physiological manner. 4. Constriction of the carotid-renal artery to reduce mean renal arterial pressure to 23 ± 4 mmHg (n= 4) resulted in an increase in systemic mean arterial pressure from 70 ± 4 mmHg to 75 ± 4 mmHg within 5 min. Systemic blood pressure further increased to 110 ± 7 mmHg with 2 h of constriction, when renal arterial pressure had increased to 45 ± 2 mmHg.     

Acute interactions between endothelin and nitric oxide in the control of renal haemodynamics

1. Endogenous endothelin (ET) does contribute to control of renal vascular tone via nitric oxide (NO)-dependent vasodilation in the rat. 2. Endothelin mediates some of the renal vascular responses to acute nitric oxide synthase (NOS) inhibition, being particularly important when a rise in renal perfusion pressure occurs. 3. Tonically produced NO blunts the renal vasoconstrictor responses to acutely administered ET. 4. The similarity between the renal vascular responses to ET administration and NOS inhibition is not fortuitous but, in part, reflects important interactions between these vasoactive agents.     

Pharmacokinetics of trimazosin and its effects on blood pressure,renal function and proteinuria during short-term therapy of patients with impaired renal function and hypertension

Summary The kinetics and short-term (10 weeks) effects of trimazosin, an alpha₁-adrenoreceptor antagonist, on renal function and blood pressure in patients with moderate chronic renal insufficiency and hypertension, have been studied for the first time. Eight patients in whom the blood pressure was not normalized with a diuretic alone underwent pharmacokinetic studies and assessment of the renal function during a 10-week period of trimazosin therapy. Trimazosin significantly lowered blood pressure (recumbent and upright) without significantly altering renal function. Renal vascular resistance was decreased by 14%. Fractional sodium excretion, proteinuria and laboratory serum tests remained unchanged. Neither body weight nor pulse rate were affected. Moderate renal insufficiency did not modify the pharmacokinetics of the drug. Thus, trimazosin, as second-step antihypertensive agent, appeared to be safe and effective in patients with moderate renal insufficiency and hypertension, without exerting favourable or adverse renal effects during short-term therapy.     

Effect of cross-fostering on blood pressure and renal function in the New Zealand genetically hypertensive rat

1. The severity of hypertension displayed by adult spontaneously hypertensive rats (SHR) and Dahl (SS/Jr) rats can be reduced by 20-30 mmHg if the hypertensive pup is cross-fostered to a normotensive mother within the first 2 weeks of birth. In the SHR, at least, this blood pressure-lowering effect arises through programming of the neonatal kidney to excrete sodium more effectively. Thus, cross-fostering may only be effective in lowering pressure in salt-sensitive hypertensive strains. Accordingly, the aim of the present study was to determine whether cross-fostering is effective in lowering adult blood pressure in the salt-resistant New Zealand genetically hypertensive (GH) rat. 2. Genetically hypertensive and control normotensive (N) rat pups were reared by either their natural mothers or a foster mother of the opposite strain (NX and GHX). Blood pressure was tracked from the age of 6-18 weeks, at which time renal function was assessed using standard clearance techniques in anaesthetized rats. Renal function was also assessed in a separate group of young rats at 5-6 weeks of age. 3. Cross-fostered GHX rats had lower blood pressure than GH rats, but this difference was only apparent until 9 weeks. The NX rats had higher blood pressures than N rats, but again pressure converged at 10 weeks. Basal renal function did not differ between GH and GHX rats or between N and NX rats at either age. However, young GH rats had lower renal blood flow, glomerular filtration rate, urine output and sodium excretion than N rats. 4. These data show that cross-fostering is effective in lowering blood pressure in GH rats, albeit transiently. The kidneys do not appear to play a role, because renal function did not differ under the current experimental conditions between GH and GHX rats. However, the kidney may play a greater role in the onset of hypertension in the GH rat than previously thought.     

Measurement of renal function in patients with chronic kidney disease

Chronic kidney disease affects millions of people worldwide and is associated with an increased morbidity and mortality as a result of kidney failure and cardiovascular disease. Accurate assessment of kidney function is important in the clinical setting as a screening tool and for monitoring disease progression and guiding prognosis. In clinical research, the development of new methods to measure kidney function accurately is important in the search for new therapeutic targets and the discovery of novel biomarkers to aid early identification of kidney injury. This review considers different methods for measuring kidney function and their contribution to the improvement of detection, monitoring and treatment of chronic kidney disease.     

RENAL RESPONSES TO SLIGHT ELEVATIONS OF RENAL ARTERIAL PLASMA ANGIOTENSIN II CONCENTRATION IN DOGS

1. Angiotensin II was infused into the renal artery of intact kidneys of slightly volume expanded anaesthetized dogs at rates of 125, 250, 500, and 1000 pg/kg body weight per min, resulting in elevations of the calculated renal arterial plasma angiotensin II concentration of 16·9 (s.e.m. = 2·1), 35·0 (s.e.m. = 4·3), 73·3 (s.e.m. = 8·8), and 159·8 (s.e.m. = 20·4) pg/ml. 2. Angiotensin II caused significant dose-dependent decreases of renal blood flow and of renal plasma flow of -4·1% (s.e.m. = 1·5, P(0·05) at the lowest and of -19·6% (s.e.m. = 1·4, P(0·001) at the highest rate of infusion. Glomerular filtration rate remained essentially unchanged at the two lower infusion levels and decreased by -6·7% (s.e.m. = 2·2, P(0·05) and -8·3% (s.e.m. = 2·5, P(0·05) at the higher rates of infusion. Filtration fraction thus increased by +6·3% (s.e.m. = 2·4, P(0·05) at the lowest and by +14·2% (s.e.m. = 3·6, P(0·01) at the highest rate of infusion. 3. Urine volume decreased by -7·7% (s.e.m. = 0·8, P(0·001) at the lowest and by -35·2% (s.e.m. = 4·8, P(0·001) at the highest rate of infusion, while the study showed similar dose-dependent decreases for urinary sodium and potassium excretion and for the fraction of filtered sodium excreted.     

Urinary Excretion and Diuretic Action of Furosemide in Rats: Increased Response to the Urinary Excretion Rate of Furosemide in Rats with Acute Renal Failure

A urinary excretion–response curve representing the urinary excretion rate of furosemide versus the urinary excretion rate of (Na⁺ + K⁺) was used to analyze furosemide action in rats with uranyl nitrate-induced acute renal failure (ARF) with and without dopamine coadministration. Urinary excretion of furosemide, but not its serum concentration, was the determinant for the diuretic action of furosemide. Increased diuretic response was observed in ARF rats, although the total diuretic response and urinary recovery of furosemide within 2 hr decreased. Dopamine enhanced furosemide-induced diuresis in ARF rats in terms of the total urine output and urinary electrolyte excretion, although the urinary excretion–response curves were not different. This enhancement by dopamine was found to be caused by the augmented urinary excretion of furosemide and the increased response to this drug in ARF rats. These findings suggest the contribution of decreased concentrating ability along the nephron and/or increased sensitivity of cells at the site of action to this drug.     

Effect of orchiectomy on renal function in control and diabetic rats with chronic inhibition of nitric oxide

• 1 Male gender is associated with higher blood pressure (BP) and more rapid loss of renal function in a spectrum of clinical and experimental renal diseases, including diabetic nephropathy. Consequently, modulation of testosterone levels could exert beneficial effects in the diabetic kidney.
• 2 The aim of the present study was to determine whether testosterone deficiency (orchiectomy) could influence BP and renal function in streptozotocin‐diabetic rats, with or without accelerated endothelial dysfunction achieved by chronic inhibition of nitric oxide (NO) synthesis using N^G‐nitro‐l‐ arginine methyl ester (l ‐NAME; 40–100 mg / L in the drinking water for 2 weeks), as well as in age‐matched non‐diabetic rats subjected to the same interventions.
• 3 Orchiectomy did not affect l ‐NAME‐induced increases in BP in non‐diabetic or diabetic rats. In non‐diabetic rats, orchiectomy prevented l ‐NAME‐induced increases in proteinuria. These effects on proteinuria were not observed in diabetic rats. In non‐diabetic rats, orchiectomy had no effect on renal haemodynamics in animals receiving vehicle and did not affect l ‐NAME‐induced changes in renal haemodynamics, characterized by reductions in renal plasma flow (RPF) and higher filtration fractions (FF). In intact diabetic rats, l ‐NAME treatment resulted in lower RPF. This difference was not observed in diabetic rats subjected to orchiectomy, although l ‐NAME‐treated diabetic orchiectomized rats had lower RPF and higher FF compared with vehicle‐treated intact diabetic rats.
• 4 In conclusion, we report modest beneficial effects of orchiectomy on proteinuria in normal, but not in diabetic, rats with inhibition of NO production. This suggests that testosterone reduction does not attenuate the deleterious impact of the diabetic metabolic milieu in the kidney.

     

硝普钠对充血性心力衰竭患者肾功能的影响

目的评价硝普钠对充血性心力衰竭（CHF）患者肾功能的影响。方法检测128例CHF患者（其中62例合并有不同程度的肾功能不全）静脉应用硝普钠或硝酸甘油前后血浆尿素氮（BUN）、肌酐（Cr）、肾小球滤过率（GFR）的变化情况,比较每组用药前后和两组间用药前后肾功能检测指标。结果CHF患者静脉应用硝普钠或硝酸甘油前后BUN,Cr,GFR的变化无统计学意义。结论对CHF患者短期、小剂量静脉滴注硝普钠,并严密监测肾功能安全可行。     

Dissolution testing of acetylsalicylic acid by a channel flow method—correlation to USP basket and intrinsic dissolution methods

A new modification of the channel flow dissolution method is introduced together with the theoretical basis to extract the solubility and mass transfer parameters from the dissolution experiments. Correlation of drug dissolution profiles in the channel flow apparatus was evaluated with respect to USP basket and intrinsic dissolution methods at pH 1.2 or 6.8. Acetylsalicylic acid (ASA) was studied as a pure drug substance and as three simple tablet compositions with microcrystalline cellulose (MCC) and/or lactose as excipients. The channel flow measurements of 100% ASA tablets correlated well with the results of intrinsic dissolution tests. In the channel flow method as well as in the USP basket method the release of ASA was fastest from the tablet compositions containing lactose, while the slowest dissolution rate was observed with the composition containing MCC as the only excipient. As presumed, the dissolution rate of the weak acid was decreased as the pH of the medium was lowered, which was clearly confirmed also by the three dissolution methods. MCC forms matrix tablets and in the USP basket method the dissolution profiles followed square root of time kinetics indicating that diffusion was the rate-controlling step of ASA dissolution. Also the channel flow results indicated that the dissolution of ASA was controlled by mass transfer. The swelling behaviour of the tablets is different in the channel flow method as compared to the basket method: only one tablet surface is exposed to the dissolution medium in the channel flow system. The contact between the tablet surface and the dissolution medium is more similar between the channel flow and intrinsic dissolution methods.     

VASCULAR ACTIONS OF ENDOTHELIN IN THE RABBIT KIDNEY

1. The effect of two doses of endothelin, 10 and 50 ng/kg per min, i.v., on glomerular filtration rate (GFR), tubular stop flow pressure and pre- and post-glomerular vascular resistance have been studied in anaesthetized rabbits. 2. Blood pressure did not change significantly in response to 10 ng/kg per min endothelin or vehicle infusion, but rose steadily during infusion of 50 ng/kg per min endothelin, increasing 11.8 +/- 2.7 mmHg by 90 min of infusion. 3. Glomerular filtration fraction (3H-inulin extraction ratio) rose and remained elevated throughout the endothelin infusion at 50 ng/kg per min. GFR did not change significantly until 70-90 min of the infusion (50 ng/kg per min) when it decreased by about 35%. No significant changes were seen at 10 ng/kg per min endothelin. 4. Sodium excretion rate rose in response to the lower dose, due to an increase in fractional sodium excretion. No changes in sodium excretion were seen at the higher dose of endothelin. 5. Glomerular capillary pressure rose significantly in response to endothelin infusion (50 ng/kg per min). 6. Renal blood flow fell progressively in response to endothelin (50 ng/kg per min), to about one-third of the pre-infusion value. 7. Renal vascular resistance increased progressively with both doses of endothelin, by about 35% at 10 ng/kg per min and about 400% at 50 ng/kg per min after 70-90 min. Preglomerular resistance increased from 1.0 +/- 0.1 to 5.0 +/- 1.9 mmHg/mL per min in response to endothelin 50 ng/kg per min. Postglomerular resistance rose from 1.0 +/- 0.1 to 5.6 +/- 2.17 mmHg/mL per min. 8. Thus endothelin infusion caused progressive renal vasoconstriction with similar magnitude increases in both pre- and postglomerular vessels. The vasoconstriction of the kidney caused by endothelin occurred at a dose which did not effect systemic blood pressure.     

OPIOID MECHANISMS CONTROLLING RENAL FUNCTION

1. Over the past 50 years considerable evidence has been reported suggesting that endogenous opioids participate in the control of renal function. 2. Exogenous administration of opioids produces profound changes in the renal excretion of water and sodium. 3. Opioids produce changes in urine output and urine sodium excretion by multiple integrated neural and hormonal mechanisms within the periphery, central nervous system and kidneys. 4. Although opioid antagonist administration does not consistently reveal an action of endogenous opioid systems on renal function, this may result from the quiescent nature of the endogenous opioid system under basal conditions. 5. Manipulations that activate endogenous opioid systems have begun to reveal important, previously unrecognized mechanisms that control kidney function and can enhance renal tubular sodium reabsorption in normal and potentially pathological states.     

Comparison of the antihypertensive and renal effects of tertatolol and nadolol in hypertensive patients with mild renal impairment

Summary The antihypertensive and renal haemodynamic effects of 5 mg/day tertatolol (T), a new nonselective and long-acting beta-adrenoceptor blocker, and 80 mg/day nadolol (N) in hypertensive patients with mild renal impairment have been compared in a randomized double-blind trial.Before and after 30 days of active treatment, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by use of a simultaneous i.v. bolus of ^99mTc-DTPA and ¹³¹I-hippuran. Both T and N significantly decreased blood pressure and heart rate, and induced an insignificant increase in GFR and ERPF.There were no differences between the effect of the treatments on blood pressure and heart rate.Despite the persistent fall in BP and HR, renal function was maintained during both T or N treatment, suggesting that both drugs may act by a direct intrarenal vasodilator mechanism.     

Acute changes in renal function induced by bisoprolol,a new cardioselective beta-blocking agent

Summary The acute effects of bisoprolol 10 mg i.v., a new beta₁-selective adrenoceptor antagonist, on heart rate, mean blood pressure (mBP), glomerular filtration rate (GFR), para-aminohippuric acid clearance (C_PAH), sodium clearance, urine volume and plasma renin activity (PRA), were studied in 6 patients with essential hypertension. Heart rate decreased by 23%, mBP remained unchanged, and GFR decreased by 14% and C_PAH by 23%. PRA was depressed on average by 25%. Urine volume and sodium clearance also declined by 9 and 13%, respectively, but the changes were not statistically significant. The fall in heart rate was significantly correlated with that in GFR and C_PAH. Changes in GFR were correlated significantly with those in C_PAH. The acute changes in renal function induced by bisoprolol are considered to be due to a reduction in cardiac output and increased systemic vascular resistance.     

Systemic and renal haemodynamic effects of angiotensin converting enzyme inhibition by zabicipril in young and in old normal men

Summary Zabicipril is a recently introduced angiotensin converting enzyme (ACE) inhibitor, which has been observed in experimental animals to increase diuresis, natriuresis, glomerular filtration rate (GFR) and renal plasma flow (RPF). We have investigated the acute effects of zabicipril on systemic and renal haemodynamics in two groups of 8 sodium-replete normal men, aged 23 to 30 y and 65 to 74 y. Zabicipril 0.5 mg, 1 mg or 2.5 mg and a placebo were administered orally, at one week intervals, in a random order and in a double blind fashion. Haemodynamic measurements were performed at base line and every hour for 4 hours after intake of drug or placebo. Cardiac output (Q) was measured by Doppler echography, and RPF and GFR by the constant infusion technique using I¹²³ iodohippurate and Cr⁵¹ EDTA, respectively.In the young men zabicipril did not affect Q, heart rate (HR), systemic arterial pressure (AP) or GFR, but it did increase RPF at the 4th hour after the highest dose (from 540 to 653 ml · min^–1 · m^–2). In the old men zabicipril had similar actions, but the effect of the highest dose on RPF (from 355 to 415 ml · min^–1 · m^–2) was less marked than in the young men. In the young and old men the inhibition of ACE peaked at about of 90% or more from the 2th to the 4th hour after the highest dose of zabicipril.We conclude that, in normal men, zabicipril increases the renal fraction of cardiac output in the absence of a concomitant change in systemic haemodynamics. This specific effect of zabicipril on the kidney may be less important with advancing age.     

Systemic and renal effects of an ETA receptor subtype-specific antagonist in healthy subjects

1. Endothelins (ETs) might play a pathophysiological role in a variety of vascular diseases. The aim of the present study was to characterize the effects of BQ-123, a specific ET_A receptor antagonist on systemic and renal haemodynamics in healthy subjects. This was done at baseline and during infusion of exogenous ET-1.
2. The study was performed in a balanced, randomized, placebo-controlled, double blind 4 way cross-over design in 10 healthy male subjects. Subjects received co-infusions of ET-1 (2.5 ng kg⁻¹ min⁻¹ for 120 min) or placebo and BQ-123 (15 μg min⁻¹ for 60 min and subsequently 60 μg min⁻¹ for 60 min) or placebo. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate (PAH) and the inulin plasma clearance method, respectively.
3. BQ-123 alone had no renal or systemic haemodynamic effect. ET-1 significantly reduced RPF (−24%, P<0.001) and GFR (−12%, P=0.034). These effects were abolished by co-infusion of either dose of BQ-123 (RPF: P=0.0012; GFR: P=0.020).
4. BQ-123 reversed the renal haemodynamic effects induced by exogenous ET-1 in vivo. This indicates that vasoconstriction in the kidney provoked by ET-1 is predominantly mediated by the ET_A receptor subtype.

     

Life-history traits of standard and autochthonous cladocerans: II. Acute and chronic effects of acetylsalicylic acid metabolites

Metabolic products are often more toxic than their pharmacological parent compounds. Therefore, the acute and chronic effects of the main metabolites--salicylic acid (SAL), gentisic acid (GEN), and o-hydroxyhippuric acid (HDP)--of acetylsalicylic acid (ASA), the active ingredient in Aspirin and many other pharmaceuticals, were assessed using standard (Daphnia magna) and autochthonous (Daphnia longispina) cladocerans. The sequence of decreasing levels of acute and chronic toxicity of ASA metabolites to daphnids was GEN > SAL > HDP. HDP did not present acute toxicity, but chronic exposures enabled the production of abnormal neonates and, in particular, egg abortion. Thus, reproduction was the end point most susceptible to HDP. On the other hand, SAL and GEN induced changes in the normal patterns of reproduction and growth of both species. In general, D. longispina was more sensitive than was D. magna, although the population growth of the autochthonous species was superior under SAL exposures than that of the standard test species. Although the concentrations that were determined to have a toxic effect were above the levels detected in aquatic environmental samples, exposure to low levels of pharmacologically active substances for a duration longer than the test period may induce changes in nontarget organisms.     

Treatment of mercuric chloride poisoning with dimercaptosuccinic acid and diuretics: preliminary studies

The distribution and excretion of mercury were studied in mice given a single injection of HgCl2 with or without chelation treatment. DMS (2,3-dimercaptosuccinic acid) given intravenously (0.5 mmol SH/kg) to mice 24 h after the mercury injection reduced the kidney Hg level significantly, while NAPA (N-acetyl-DL-penicillamine) and BAL (2,3-dimercaptopropanol) did not. The effectivity of DMS to remove Hg from kidneys was comparable to that of BAL-sulph (2,3-dimercaptopropane-1-sulfonate), irrespective of whether these chelating agents were given orally or intravenously. Immediate chelation treatment with DMS or mercaptodextran reduced the renal Hg level to about 50% of control levels, as measured 3 d after the treatment. Combination of DMS with immediate intraperitoneal treatment with spironolactone was even more effective in reducing the renal levels, and acted both by increasing the fecal and urinary excretion. The DMS treatment, as well as DMS + spironolactone in combination, could protect against kidney damage following injection of 30 mumol HgCl2/kg. Such treatment was essentially nontoxic.