Antihypertensive and bilateral renal responses to diuretics in 2-kidney, 1-clip Goldblatt hypertensive rats

Experiments were conducted to assess the effect of furosemide or amiloride alone and a combination of both agents on each kidney in anesthetized 2-kidney, 1 clip Goldblatt hypertensive rats (n = 25). Intravenous infusion of furosemide alone (1.02 mg/kg.hr) significantly reduced the blood pressure by 14 +/- 5 mmHg. There were 6- to 10-fold increases in water, absolute sodium and fractional sodium excretions and a 2-fold increase in potassium excretion in the nonclipped kidney. A smaller but significant increase in the excretory function was also observed in the clipped kidney. There was no significant change in GFR of both kidneys. Indomethacin pretreatment (2 mg/kg) failed to significantly alter the vasodepressor and renal responses to furosemide in both hypertensive and normal rats. Removal of the renal artery clip from the hypertensive rats reduced the blood pressure by 12 +/- 3 mmHg and enhanced the function of the ipsilateral, unclipped kidney. Subsequent administration of furosemide further increased the excretory response. Administration of amiloride alone (2.4 mg/kg.hr) or with furosemide into hypertensive rats reduced the arterial pressure and increased excretion rates of urine flow and urinary sodium. Potassium excretion rate decreased bilaterally in amiloride treated rats but did not alter significantly in rats which received a combination of amiloride and furosemide. These results indicate that diuretics ameliorate the excretory function of both the stenotic kidney and the nonstenotic kidney and that the improvement of the kidney function is independent of prostaglandin. Furthermore, removal of the stenosis accentuates the beneficial effect of diuretics on the kidney.     

Nephroprotective effect of pigmented violacein isolated from Chromobacterium violaceum in wistar rats

The present study aimed to analyze the nephroprotective property of violacein obtained from the bacterium, Chromobacterium violaceum. The nephrotoxicity in the animal model was induced by gentamicin, potassium dichromate, mercuric chloride, and cadmium chloride-induced nephrotoxicity in the Wistar rats was analyzed by measuring the serum creatinine, uric acid, and urea level. The present investigation revealed the nephroprotective property on convoluted proximal tubule (S1 and S2 segments) and the straight proximal tubule (S3 segment). Also, violacein significantly improved the renal function by the renal protective property on S2 segment of proximal tubule from the nephrotoxicity stimulated by mercuric chloride, potassium dichromate, cadmium chloride and gentamicin in animal models. Animal model studies revealed that violacein at 20 and 40 mg/kg p.o improved the renal function and significantly reduced the increased amount of uric acid, creatinine, and blood urea compared to the control.     

Infusions of chemicals into the brain and the development of sustained elevations of blood pressure in the rat

Osmotic minipumps were used to infuse carbachol chloride (1.23 μg/hr), echothiophate iodide (0.5 μg/hr), histamine dihydrochloride (10 μg/hr), prostaglandin E₂ (1.0 μg/hr) and thyrotropin-releasing hormone (0.5 and 5.0 μg/hr) solutions into the cerebral ventricles of unanesthetized rats and blood pressure was measured by the tail-cuff method. Histamine dihydrochloride, prostaglandin E₂ and thyrotropin-releasing hormone produced an initial rise in blood pressure, but were not effective in producing sustained elevations in blood pressure. Carbachol infusions elevated blood pressure throughout the 7-day infusion period when results were compared to saline-infused animals. Infusions of echothiophate iodide, an anticholinesterase agent, produced an initial rise in blood pressure but these pressor effects were not sustained. In animals infused with echothiophate for 7 days, the pressor response to a challenge dose of echothiophate was diminished.     

Time-course of changes in blood glucose and ketone bodies, plasma lipids and liver fatty acid composition in streptozotocin-diabetic male rats.

Male rats were given streptozotocin (100 mg/kg) by intraperitoneal injection. Groups of control and streptozotocin-treated animals were sacrificed at daily intervals for 4 days after injection. Over this period, treated rats lost weight continuously while control animals progressively gained weight. Within 24 h of treatment blood glucose and plasma free fatty acids were raised to levels which were sustained for the remainder of the experiment. After 48 h blood ketone bodies, plasma cholesterol and triglycerides were maximally raised and liver glycogen and blood lactate similarly lowered. The percentage composition of major fatty acids in liver lipids was unchanged until 4 days after treatment when there were significant increases in the proportion of oleate and linoleate and reductions in stearate and arachidonate. The data confirm that streptozotocin induces a rapid and sustained diabetes. It is suggested that metabolic experiments, in streptozotocin-diabetic rats, may be performed 48 h after treatment.     

Interaction of amiloride and hydrochlorothiazide with atrial natriuretic factor in the medullary collecting duct

Medullary collecting duct function was studied using the in vivo microcatheterization technique in three groups of rats receiving amiloride, hydrochlorothiazide, or both diuretics. In each group of animals, atrial natriuretic factor (ANF99-126) was given in the second phase of the experiment. The combination of amiloride and hydrochlorothiazide resulted in a more marked natriuresis than either diuretic given as a single agent. Sodium reabsorption in the medullary collecting duct, as a fraction of the delivered load, was reduced from 64% (amiloride) and 69% (hydrochlorothiazide) to 29% (amiloride and hydrochlorothiazide). Atrial natriuretic factor reduced collecting duct sodium reabsorption when added to amiloride or hydrochlorothiazide to 23% and to 41%, respectively, but had no additional effect when given with amiloride and hydrochlorothiazide. Potassium excretion with amiloride and hydrochlorothiazide was intermediate between amiloride or hydrochlorothiazide given as single agents. With the diuretic combination, potassium transport showed no significant reabsorption or secretion along the medullary collecting duct, amiloride was associated with potassium reabsorption, and hydrochlorothiazide was associated with potassium secretion in the duct. The results confirm the importance of the medullary collecting duct as a site of diuretic action. The known additive effects of amiloride and hydrochlorothiazide on sodium excretion and the opposing effects of these agents on potassium excretion occur, to a major degree, in the medullary collecting duct. Furthermore, the additive effects of amiloride and ANF indicate that blocking of amiloride-sensitive sodium channels is not the only mechanism of action of ANF on duct salt transport in vivo.     

Effects of acute cold exposure on rectal temperature, blood glucose and plasma free fatty acids in alloxan-diabetic rats

These experiments were carried out to study the effects of acute cold exposure (0-2 degrees C/4 hr) on rectal temperature, blood glucose and plasma free fatty acids (FFA) in alloxan-diabetic rats. Male Wistar rats weighing 170-190 g were used and diabetes was induced by i.v. alloxan injection (40 mg/kg body wt). Cold exposure produced severe hypothermia in diabetic rats. After 4 hr of cold, blood glucose of diabetic rats was reduced from 296 +/- 16 to 86 +/- 12 mg/dl (P less than 0.01), and FFA increased slightly, but was not statistically different (P greater than 0.05) from the initial value. As expected, interscapular brown adipose tissue (IBAT) and retroperitoneal and epididymal white adipose tissues were significantly lower in diabetic than in control rats. Cold exposure reduced total IBAT lipids in control but not in diabetic animals. The results of this experiment suggest that diabetic rats were unable to maintain body temperature in the cold, probably because of a failure to generate an adequate amount of heat by nonshivering thermogenesis in brown adipose tissue.     

Reduction of the effects of diuretics or sodium chloride loading in the conscious rat by inhibitors of prostaglandin synthesis

In conscious rats pretreatment with indomethacin or flurbiprofen, two chemically unrelated inhibitors of prostaglandin synthesis, reduced urine volume and sodium excretion induced by four diuretics, acetazolamide, amiloride, bendrofluazide and frusemide, or oral sodium chloride loads. The maximum reduction in sodium excretion was limited to approximately 2 mmol/kg Na⁺ even when sodium excretion was greatly increased. In contrast these inhibitors did not appreciably affect potassium excretion. These results indicate that part of the natriuretic response in the rat to highly and moderately efficacious diuretics and to sodium chloride loading is modified by prostaglandins. We suggest that the lack of effects on potassium excretion indicate that the collecting tubule is the probable site of action.     

Alcohol-triggered signs of migraine: An animal model

We describe an animal model where characteristics of migraine can be triggered by alcohol administration. In rats chronically implanted with a cannula overlying the transverse sinus, we applied potassium chloride (KCl) (or saline) to the meninges to sensitize trigeminovascular afferents. We assessed effects of repeated KCl application on animal behavior using conditioned place avoidance paradigm. In KCl-treated rats we discovered that alcohol injections (0.2?mg/kg), but not saline, resulted in the development of extracephalic allodynia and signs of ongoing pain.     

热环境下复合电解质饮料的生理生化效应

本实验观察了复合电解质饮料对热环境下大白鼠与人体的生理生化效应。实验结果表明,复合电解质饮料具有维持人体在热环境下劳动时的水与电解质平衡,保留水份在体内,减少水份消耗,改善细胞能量代谢,提供能量,消除疲劳和提高耐热能力等作用。     

Yohimbine hydrochloride reversal of ketamine hydrochloride and xylazine hydrochloride immobilization of Bengal tigers and effects on hematology and serum chemistries

Six bengal tigers (Panthera tigris tigris) were immobilized five times at 2-wk intervals with ketamine hydrochloride (ketamine) and xylazine hydrochloride (xylazine) mixtures at different dose levels. Hematology and serum chemistry analyses on blood samples collected at each immobilization remained normal during the study. There were acute changes in hematocrit, chloride, potassium, glucose, and bilirubin as a function of xylazine dose level. The effect of yohimbine hydrochloride (yohimbine) on the depth and duration of immobilization was evaluated in a crossover design with every animal serving as its own control at each dose. Administration of yohimbine resulted in recovery of the animals within 4-8 min in contrast to greater than 60 min with no yohimbine treatment. There were no adverse effects noted with the yohimbine treatment and the tigers did not exhibit a relapse over the next 24 hr. Yohimbine at a dose of 5-15 mg per adult tiger provided effective reversal of 50-150 mg of xylazine per tiger.     

Response of hepatic carbohydrate and cyclic AMP metabolism to cadmium treatment in rats.

Daily intraperitoneal injection of cadmium chloride (0.25 or 1 mg/kg) for 21 or 45 days into rats significantly stimulated the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-diphosphatase, and glucose-6-phosphatase, increased the concentrations of glucose and urea in the blood, and decreased the levels of glycogen in the liver. Whereas chronic cadmium treatment failed to alter adenosine-3',5'-monophosphate phosphodiesterase (phosphodiesterase) activity, the endogenous levels of cyclic AMP (cAMP) and the activity of basal- and fluoride-stimulated forms of hepatic adenylate cyclase (AC) were markedly increased in cadmium-injected animals. Treatment with the higher dose (1.0 mg/kg) of cadmium chloride for 45 days produced greater metabolic alterations in hepatic tissue than those seen with the lower dose (0.25 mg/kg) given for a shorter period of time (21 days). Discontinuation of cadmium administration for 14 days in rats previously injected with cadmium chloride (1 mg/kg per day) for 21 days, failed to reverse the observed changes in hepatic cAMP or carbohydrate metabolism. A similar persistence of metabolic alterations was noted in rats treated with cadmium (1 mg/kg per day) for 45 days and subsequently maintained without additional treatment for 28 days. Administration of an acute dose of cadmium chloride (60 mg/kg) decreased hepatic phosphodiesterase activity and glycogen content 1 h after the injection. In addition, acute cadmium exposure increased blood glucose, serum urea, and hepatic cAMP levels, and produced an augmentation of basal- and fluoride-activated AC. However, the activities of various hepatic gluconeogenic enzymes remained unaffected in animals given an acute dose of cadmium chloride (60 mg/kg). Data provide evidence that suggests that the gluconeogenic potential of liver is markedly enhanced following chronic exposure to cadmium and that the cadmium-induced changes in carbohydrate metabolism may be associated with an enhanced synthesis of cAMP. In addition, the present study shows that the cadmium-induced metabolic alterations persist even after the cessation of cadmium treatment for a period of 28 days.     

Correction of mineral and protein metabolism by anabolic preparations and vitamin D2 in rats with dental caries

The effect of nerabol, namacyte and vitamin D2 introduction (separately or in combination) on the animal mineral and protein metabolism has been studied in the experiment on 210 white Wistar rats with reproduced caries. Biochemical and radioisotopic investigations have permitted determining the quantitative content of phosphorus, calcium, 14C-glycine in the saliva, blood serum, teeth, jaw bones and femur. The data obtained evidence for the pronounced caries-static effect of the tested preparations connected with their active influence on the mineral and protein metabolism of experimental animals as well as for the expediency to use the above drugs for complex prophylaxis and treatment of dental caries normalizing processes.     

Therapeutic Effects of Procainamide on Endotoxin-Induced Rhabdomyolysis in Rats

Overt systemic inflammatory response is a predisposing mechanism for infection-induced skeletal muscle damage and rhabdomyolysis. Aberrant DNA methylation plays a crucial role in the pathophysiology of excessive inflammatory response. The antiarrhythmic drug procainamide is a non-nucleoside inhibitor of DNA methyltransferase 1 (DNMT1) used to alleviate DNA hypermethylation. Therefore, we evaluated the effects of procainamide on the syndromes and complications of rhabdomyolysis rats induced by lipopolysaccharide (LPS). Rhabdomyolysis animal model was established by intravenous infusion of LPS (5 mg/kg) accompanied by procainamide therapy (50 mg/kg). During the experimental period, the changes of hemodynamics, muscle injury index, kidney function, blood gas, blood electrolytes, blood glucose, and plasma interleukin-6 (IL-6) levels were examined. Kidneys and lungs were exercised to analyze superoxide production, neutrophil infiltration, and DNMTs expression. The rats in this model showed similar clinical syndromes and complications of rhabdomyolysis including high levels of plasma creatine kinase, acute kidney injury, hyperkalemia, hypocalcemia, metabolic acidosis, hypotension, tachycardia, and hypoglycemia. The increases of lung DNMT1 expression and plasma IL-6 concentration were also observed in rhabdomyolysis animals induced by LPS. Treatment with procainamide not only inhibited the overexpression of DNMT1 but also diminished the overproduction of IL-6 in rhabdomyolysis rats. In addition, procainamide improved muscle damage, renal dysfunction, electrolytes disturbance, metabolic acidosis, hypotension, and hypoglycemia in the rats with rhabdomyolysis. Moreover, another DNMT inhibitor hydralazine mitigated hypoglycemia, muscle damage, and renal dysfunction in rhabdomyolysis rats. These findings reveal that therapeutic effects of procainamide could be based on the suppression of DNMT1 and pro-inflammatory cytokine in endotoxin-induced rhabdomyolysis.     

Effect of NSAIDS on serum electrolytes and osmolality

Rabbits and rats were injected two Nonsteroidal anti-inflammatory drugs (aspirin 300 mg/kg or indomethacin 3 mg/kg) intraperitoneally. One hour after injection blood was analyzed for serum electrolytes and osmolality. Administration of both aspirin and indomethacin in rabbits and rats caused increase in serum sodium, potassium, calcium, chloride, magnesium, phosphorus and osmolality. Results suggest the marked similarity in the action of aspirin and indomethacin on electrolytes and osmolality. It is concluded that the ingestion of aspirin and indomethacin can have a major effect on serum electrolytes and osmolality that may influence the interpretation of clinical data in patients taking these drugs.     

Reduced natriuresis after oral sodium load in cholestatic rats: role of compartment volumes and ANP

The purpose of this study was to assess the participation of the atrial natriuretic peptide (ANP)-cGMP system in electrolyte and volume handling of cholestatic rats submitted to an acute oral sodium load. Cholestasis was induced by ligation and section of the common bile duct (n = 51). Control rats were sham operated (n = 56). Three weeks after surgery, 24-hr urinary volume, sodium, potassium, cGMP and creatinine excretion were measured. Three days later, animals received 10 mmol/kg NaCl (1 M) by gavage, and urinary excretion was measured for 6 hr. In parallel groups of rats, plasma volume, electrolytes and ANP concentration, extracellular fluid volume (ECFV), and renal medullary ANP-induced cGMP production were determined in basal conditions or 1 hr after oral sodium overload. As compared with controls, cholestatic rats had a larger ECFV and higher plasma ANP (67.2 +/- 5.2 vs 39.7 +/- 3.5 pg/ml), but lower hematocrit and blood volume, and were hyponatremic. Cholestatic rats showed higher basal excretion of sodium, potassium, and volume than controls, but equal urinary cGMP. After the NaCl overload, cholestatic rats showed a reduced sodium excretion but equal urinary cGMP. One hr after sodium overload, both groups showed hypernatremia, but whereas in control rats ECFV and ANP increased (50.7 +/- 4.1 pg/ml), in cholestatic rats ECFV was unchanged, and plasma volume and ANP were reduced (37.5 +/- 5.8 pg/ml). ANP-induced cGMP production in renal medulla was similar in cholestatic and control nonloaded rats (14.2 +/- 5.2 vs 13.4 +/- 2.6 fmol/min/mg). One hr after the load, medullary cGMP production rose significantly in both groups, without difference between them (20.6 +/- 3.1 vs 22.7 +/- 1. 7 fmol/min/mg). We conclude that the blunted excretion of an acute oral sodium load in cholestatic rats is associated with lower plasma ANP due to differences in body fluid distribution and cannot be explained by renal refractoriness to ANP.     

归辛胶囊急性毒性实验研究

目的：进行归辛胶囊急性毒性实验,对小鼠和大鼠可能产生的毒性反应及严重程度,确定无毒反应剂量,为拟定人用安全剂量提供参考。方法：依据《中药、天然药物急性毒性研究技术指导原则》进行急性毒性实验。取小鼠、大鼠各40只,随机分为空白、归辛胶囊低、中、高剂量4个组,每组10只,分别对小鼠、大鼠灌胃给药,给药后连续地观察14天,于给药第1、7、14天称量动物体重,并观察动物饮食、外观、行为、分泌物、排泄物、死亡情况及中毒情况,测定半数致死量（LD50）;在药物毒性较低无法测出LD50时测定小鼠、大鼠的最大耐受量（MTD）。取小鼠、大鼠各40只,随机分为空白组和归辛胶囊高剂量组,每组20只,给药后连续观察14天测定最大耐受量（MTD）,观察指标同测定LD50结果：实验动物未出现死亡无法测出LD50,继而测定MTD,小鼠为24．0g／kg,大鼠为16．0g／kg,各组动物主要脏器均未发现明显病理学改变。结论：归辛胶囊推荐临床日用剂量为0．09g／kg,按此剂量用药具有安全性。     

Disturbances of morphological parameters in blood of rats orally exposed to aluminum chloride

The aim of this work was to assess changes of morphological parameters in the blood of rats after oral (po) administration of aluminum (Al), in relation to the time and the administered dose. The experiment was performed on female Wistar rats. The animals were administered aluminum chloride (100 mg Al/kg) daily for 21 d. Morphological assays: red blood cells (RBC), hemoglobin (HGB), hematocrit (HCT), iron serum concentration (Fe), MCH, MCHC, absolute corrected reticulocyte count (ACRC), white blood cells (WBC), and platelet count (PLT) were estimated on d 3, 7, 14, and 21, both in the control group and in intoxicated rats. After wk 1 of aluminum administration we observed a decrease of RBC, HCT, HGB and serum iron concentration in the blood of rats. The increase of the platelet count was observed earlier than changes in other parameters. Investigation has proved that the exposure of rats to aluminum administered orally results in normocytic anemia.     

Kaliuretic response to potassium loading in amiloride-treated dogs.

To assess whether an intact mechanism of sodium transport in the distal nephron is a prerequisite for the development of a kaliuresis in response to an acute potassium load (0.4 M KCl, 1 ml/min), the effects of a simultaneous infusion of KCl and amiloride (1 mg/kg/h) were evaluated in anesthetized dogs. A major reduction in potassium excretion mainly due to a sharp decrease in urine K+ concentration to one tenth of control levels was found after amiloride. The simultaneous infusion of KCl and amiloride resulted in a rapid and major increase in kaliuresis that was accounted for mostly by the rise in urine K+ concentration. The increased kaliuresis after the acute potassium infusion was of similar magnitude when expressed as percent value of control to that previously reported in dogs not receiving amiloride; the absolute rates of K+ excretion, however, were only 2.7 and 7.3% (before and after KCl infusion, respectively) of the values in dogs not receiving amiloride. Our observations suggest that potassium infusion in the intact dog increases kaliuresis primarily as a result of a more favorable chemical gradient of this cation between blood and/or distal tubular cells and urine. Yet, when a chemical gradient is the only driving force of potassium secretion, as was the case in our amiloride-treated dogs, the absolute rate of kaliuresis is very modest. The presence of an unimpaired electrical profile and sodium transport mechanisms in the distal nephron, although not critical for the development of kaliuresis in response to a K+ load, accounts for a severalfold rise in renal potassium excretion above basal levels.     

Beneficial effect of verapamil in ischemic acute renal failure in the rat

To investigate the possible protective effect of Ca2+ blockers in ischemic acute renal failure (ARF), verapamil, in a dose of 10 micrograms/kg body wt/min was administered for 100 min, starting 15 min before the total occlusion of the left renal artery after right nephrectomy in rats. Mean 24-hr creatinine clearance, blood urea, and serum creatinine levels, 24 hr after declamping, were used as a measure of kidney function. These values which were 135 +/- 1.9 microliter/min, 231 +/- 22 mg%, and 2.25 +/- 0.22 mg%, respectively, in the untreated rats, were found to be significantly different, i.e., 326.3 +/- 33.2 microliter/min, P less than 0.001, 112 +/- 25 mg%, P less than 0.001, and 1.26 +/- 0.28 mg%, P less than 0.01, respectively, in the verapamil-treated animals. Increased 24-hr total urine creatinine, sodium, osmolality, and a lower fractional excretion of sodium were also observed in the verapamil-treated rats with ARF. The combination of propranolol 1 mg/kg body wt/min and verapamil 10 micrograms/kg body wt/min for 100 min had no additive effect on renal function. In another group of ARF rats in which verapamil was started after declamping, no alleviating effect was observed. It is concluded that verapamil, an inhibitor of cellular membrane transport, when given prior to the renal ischemia, offers a partial but significant protection in this model of ischemic ARF.     

Effect of vagotomy on postcastration gonadotropin secretion in male rats

The postcastration increase in gonadotropins was studied in intact and vagotomized male rats. Rats underwent vagotomy or sham surgery immediately prior to castration. In the first experiment, rats were bled before castration and at 1, 2, 4, and 7 days after castration. Serum LH and FSH were significantly lower in vagotomized rats 1 day after castration. On days 2, 4, and 7 postcastration, serum gonadotropin levels were generally not different among experimental groups. In a second experiment, rats were decapitated at 12 or 24 hr after surgery and castration. Trunk blood was collected for assay of LH. Vagotomy had no effect on LH levels at 12 hr postcastration, but, at 24 hr postcastration, vagotomized rats had significantly lower serum LH than did sham-operated rats. These experiments indicate that vagotomy has a transient suppressive effect on gonadotropin release following castration. Such observations support the hypothesis that the vagus nerve may play a modulatory role in gonadotropin secretion.