Augmentation of renal response by magnesium lithospermate B

Magnesium lithospermate B and adenine were given simultaneously to rats p.o. in order to investigate their renal effects. In rats given magnesium lithospermate B at a dose of 5 mg/kg body weight/day for 12 or 24 days, glomerular filtration rate, renal plasma flow and renal blood flow were increased significantly. A significant increase in renal function parameters was also found in rats given 10 mg of magnesium lithospermate B. Urinary excretion of prostaglandin E2 was increased by administration of magnesium lithospermate B, while those of 6-keto-prostaglandin F1 alpha and thromboxane B2 were unaffected at a dose of 5 mg or 10 mg/kg body weight/day for 12 or 24 days. The activity of kallikrein in urine increased markedly and significantly in rats given 5 or 10 mg of magnesium lithospermate B for 12 or 24 days. From these results, it seems that magnesium lithospermate B increases renal function by improving the renal circulatory state through activation of kallikrein and promotion of prostaglandin E2 production.     

抑肽酶剂量对体外循环炎性反应的作用及影响

目的：观察不同剂量抑肽酶对体外循环（ＣＰＢ）心脏手术炎性反应的作用及差异。方法：３２例拉膜置换病人,随机双盲分为３组：对照组、抑肽酶小剂量组、抑肽酶大剂量组,分别于ＣＰＢ前、ＣＰＢ结束、停机后２h取桡动脉血,测定中性粒细胞ＣＤ１１b表达及细胞因子ＴＮＦ－α、ＩＬ－６血浆清凉,:凶肽酶大剂量组中性粒细胞ＣＤ１１b的表达,细胞因子ＴＮＦ－α血浆水平各时间点无明变化,且ＩＬ－６释放减少,小剂量抑肽酶只在停机后２h部分下调ＣＤ１１b表达及降低ＴＮＦ－α血浆水平,两组相比,小剂量抑肽酶作用明显减弱,结论：抑肽酶的抗赕作用存在量效关系,大剂量抑肽酶的效能好于小剂量抑肽酶。     

Sodium excretion in response to vasopressin and selective vasopressin receptor antagonists

The mechanisms by which arginine vasopressin (AVP) exerts its antidiuretic and pressor effects, via activation of V2 and V1a receptors, respectively, are relatively well understood, but the possible associated effects on sodium handling are a matter of controversy. In this study, normal conscious Wistar rats were acutely administered various doses of AVP, dDAVP (V2 agonist), furosemide, or the following selective non-peptide receptor antagonists SR121463A (V2 antagonist) or SR49059 (V1a antagonist). Urine flow and sodium excretion rates in the next 6 h were compared with basal values obtained on the previous day, after vehicle treatment, using each rat as its own control. The rate of sodium excretion decreased with V2 agonism and increased with V2 antagonism in a dose-dependent manner. However,for comparable increases in urine flow rate, the V2 antagonist induced a natriuresis 7-fold smaller than did furosemide. Vasopressin reduced sodium excretion at 1 mug/kg but increased it at doses >5 umg/kg,an effect that was abolished by the V1a antagonist. Combined V2 and V1a effects of endogenous vasopressin can be predicted to vary largely according to the respective levels of vasopressin in plasma,renal medulla (acting on interstitial cells), and urine (acting on V1a luminal receptors). In the usual range of regulation, antidiuretic effects of vasopressin may be associated with variable sodium retention. Although V2 antagonists are predominantly aquaretic, their possible effects on sodium excretion should not be neglected. In view of their proposed use in several human disorders, the respective influence of selective (V2) or mixed (V1a/V2) receptor antagonists on sodium handling in humans needs reevaluation.     

Augmentation of the immune response of the murine liver by levamisole.

Murine hepatic nonparenchymal cells (NPC) were studied following in vivo treatment with levamisole. This agent was found to increase the cytolytic action of these cells against YAC-1 and P815 target cells. An increase in the cytostatic activity against liver-derived murine colon adenocarcinoma 38 tumor cells was also observed. Treatment with levamisole also augmented the proliferation of the hepatic NPC. Supernatants generated by these cells contained an agent capable of stimulating the proliferation of bone marrow cells from the same mice. The effect of levamisole on different subsets of NPC derived from the liver in this model is discussed.     

Role of vasopressin in the haemodynamic response to laparoscopic cholecystectomy

We studied 10 patients undergoing laparoscopic cholecystectomy (group 1) and five control patients (group 2). We measured heart rate, arterial pressure, right atrial pressure (RAP), cardiac index (CI), systemic vascular resistance index (SVRI), intrathoracic pressure (ITP), plasma osmolality, adrenaline, noradrenaline and arginine vasopressin (aVP) concentrations, and serum renin activity (SRA), and calculated the atrial transmural pressure gradient (ATPG). We recorded significant decreases in mean arterial pressure (MAP), SVRI and CI in both groups (P < 0.05) after induction of anaesthesia. MAP and SVRI increased (P < 0.01) while CI decreased further in group 1 patients during the pneumoperitoneum. In group 1 plasma aVP concentration increased after insufflation of the pneumoperitoneum to a level sufficient to cause the recorded haemodynamic changes. ATPG decreased in group 1 patients during the pneumoperitoneum and this is a recognized trigger for aVP release.      

Arginine vasopressin response to anaesthesia produced by halothane,enflurane and isoflurane

Some of the effects of inhalational anaesthetics may be mediated by (3-endorphins acting on opioid receptors. Stimulation of such receptors has been shown both to promote and to inhibit the release of arginine vasopressin (AVP). Ten rabbits were studied to determine the response of plasma AVP to a predetermined time/concentration “dose” of halothane, enflurane or isoflurane. Abolition of corneal reflex was used as a standard end-point. Plasma samples were obtained from awake animals and after exposure to the anaesthetics, the sequence being randomly assigned. No significant changes in plasma AVP concentrations were observed when predetermined time/concentration “doses” of the agents were administered to the rabbits. Anaesthesia produced by halothane, enflurane or isoflurane, therefore, is not necessarily accompanied by changes in plasma AVP.     

Changes in intracellular sodium during the hydroosmotic response to vasopressin.

During vasopressin (VP)-induced water movement, toad urinary bladder epithelial cells undergo unique morphological changes. The osmolality within these responding cells remains relatively stable despite the large transcellular transport of water. We hypothesized that the hydroosmotic response to VP may be associated with a net increase in sodium either as an aid in maintaining the intracellular osmolality or as part of a Na-Ca exchange process. Changes in intracellular sodium (Nai) were monitored over time in individual hemibladders using 23Na NMR. Hemibladders were mounted as bags on glass pipets and filled with deionized water. During NMR studies, the serosal bath consisted of aerated 2.4 mM HCO3 amphibian Ringer's (pH 8.1) made up with 15% D2O containing the shift reagent, dysprosium tripolyphosphate (1 mM). This reagent allowed for visualization of Nai by shifting the extracellular Na signal; it did not affect basal or VP stimulated water flow, short-circuit current, or high energy phosphate metabolism as seen by 31P NMR. Changes in Nai were determined by integrating the area under the unshifted Na peak at each measurement and expressing differences as a ratio relative to baseline. The initial Nai signal from unstimulated hemibladders remained stable in these tissues over at least 180 minutes. Within 30 minutes of VP (20 mU/ml) exposure, however, the Nai peak increased 2.47 times above pretreatment baseline (N = 16, P less than 0.001). The Nai signal returned toward baseline values with removal of VP from the serosal bath but only after approximately 90 minutes. When change in cell shape and water movement were prevented by having isotonic sorbitol in the mucosal bath, VP produced no change in the Nai signal (N = 10).(ABSTRACT TRUNCATED AT 250 WORDS)     

Augmentation of cell-mediated cytotoxicity against renal carcinoma cells by recombinant interleukin 2

The effects of recombinant interleukin 2 (IL-2) on natural killer (NK) cell activity against established renal carcinoma cell lines CaKi 1, KU-2, and freshly prepared renal carcinoma cells were studied. Augmentation of NK cell activity by IL-2 was dose- and time-dependent. The results indicate that the optimal dose of IL-2 was 100 to 500 U/mL, and that cytotoxicity increased significantly even at a low concentration such as 4 U/mL. IL-2 induced significantly higher levels of cytotoxicity against renal carcinoma cells than did gamma-interferon. The influence of IL-2 on lymphocyte subpopulations was then examined using flow cytometry with monoclonal antibodies OKT3, OKT4, OKT8, Leu 7, and Leu 11. The results showed that IL-2 increased the number of cells positive to Leu 11, the so-called active NK cells. We concluded that IL-2 has an important role in the treatment of renal carcinoma.     

Sustained response to vasopressin in isolated rat cortical collecting tubule

The effect of arginine vasopressin (ADH) on water permeability and transepithelial voltage was examined in cortical collecting tubules from a specific pathogen-free line of male Sprague-Dawley rats (75-125 g body weight). Tubules were bathed in a medium resembling serum ultrafiltrate (310 mOsm/kg H2O) at 38 degrees C. Osmotic water permeability (Pf, micron/sec) was determined by the volume flow occurring with a hypo-osmotic perfusate (210-220 mOsm/kg H2O) and diffusional water permeability (Pd, micron/sec) was calculated from the lumen-to-bath flux of tritiated water using an isosmotic perfusate. In the absence of ADH, both Pf and Pd were low, 17 +/- 6 and 9.0 +/- 0.6 (SEM), respectively. ADH added to the bath at concentrations above 0.5 microunits/ml increased Pf, with a maximal response at 40 microunits/ml or greater. With 100 microunits/ml ADH, Pf and Pd were, respectively, 994 +/- 117 and 37.0 +/- 2.4. Without ADH, the transepithelial voltage was variable (range, -5.4 to +2.5 mV; mean, -1.9 +/- 0.4); however, with 100 microU/ml ADH, it hyperpolarized (lumen-negative) by 4.2 +/- 0.8 mV. In contrast to findings in the rabbit, both the hyperpolarization and the increased water permeability persisted for at least 3 hr. The higher water permeabilities are consistent with the shorter length of the cortical collecting tubule in the rat, and may reflect the importance of attaining osmotic equilibration within the cortex during maximal antidiuresis.     

The renal response to preeclampsia

Proteinuria and decreased renal function are classic hallmarks of preeclampsia. The kidney, with its reliance on glomerular blood flow and glomerular barrier integrity, provides a unique window to view the preeclamptic disease process. This review briefly details the characteristic renal structural changes seen in preeclampsia and then focuses on the disordered renal hemodynamics and other determinants of ultrafiltration. Both renal blood flow and glomerular filtration rate (GFR) decrease in preeclampsia, although absolute values may remain above the nonpregnant range. A decrease in the ultrafiltration coefficient (K f ), in the order of 50%, either alone or in combination with reduced renal blood flow, is presented as the most likely mechanism for the decrease in GFR. Proteinuria develops, at least in part, secondary to impaired glomerular barrier integrity with a loss of size selectivity revealed by fractional dextran clearance studies and it is proposed, although yet to be proven, that this is accompanied by a loss of glomerular barrier charge selectivity.     

The effect of aprotinin on renal function in orthotopic liver transplantation

BACKGROUND: In the European Multicenter Study on the Use of Aprotinin in Liver Transplantation (EMSALT), a randomized, double-blind, placebo-controlled, prospective study, we demonstrated that aprotinin significantly reduces intraoperative blood loss during orthotopic liver transplantation (OLT). Aprotinin is metabolized in the kidney and potentially nephrotoxic at high concentrations. Renal insufficiency is a common and serious complication after OLT. It is unknown whether aprotinin increases the risk of renal failure after OLT. METHODS: We analyzed intraoperative urine output, need for postoperative dialysis, perioperative serum creatinine levels, and creatinine clearance in 93 patients enrolled in EMSALT, receiving a high dose of aprotinin, a regular dose, or placebo. RESULTS: Peak increase in serum creatinine exceeding 0.5 mg/dl during one of the postoperative days occurred in 11 (35%) patients in the placebo group, in 11 (34%) patients in the high-dose group, but only in 1 (3%) patient in the regular-dose group (P=0.007). Furthermore, a perioperative decrease in creatinine clearance was seen in the placebo group (-23.9+/-10.1 ml/min) but not in both high-dose (-1.6+/-13.3 ml/min) and regular-dose (9.7+/-10.3 ml/min) groups (P<0.02 comparing regular-dose and placebo group). CONCLUSIONS: Despite its potential nephrotoxicity, the use of aprotinin for reducing blood loss during OLT does not lead to a higher incidence of postoperative renal insufficiency. In combination with the observed reduction in blood loss, these findings support the prophylactic use of regular-dose aprotinin during OLT.     

The impact of renal dysfunction on aprotinin pharmacokinetics during cardiopulmonary bypass.

Aprotinin is a serine protease inhibitor that undergoes metabolism in the kidney. Because elimination is almost entirely renal, the clearance of aprotinin may be reduced in patients with renal insufficiency. Unfortunately, there are no data regarding aprotinin pharmacokinetics in cardiac surgical patients with renal insufficiency or end-stage renal disease (ESRD) undergoing cardiopulmonary bypass (CPB). We, therefore, determined the clearance (ApCl) and elimination half-life (T1/2) of aprotinin in 26 cardiac surgical patients with normal and abnormal renal function (creatinine clearance [CrCl] 0-122 mL/min) undergoing CPB. Subjects were given a 2 million kallikrein inhibiting unit (KIU) initial dose of aprotinin, followed by a 0.25 million KIU/h infusion. No aprotinin was added to the pump prime. Plasma aprotinin concentrations were sampled at 30 min after completion of the loading dose, 30 and 60 min after the onset of CPB, at the end of CPB, and at 8, 24, and 32 h after completion of the loading dose. ApCl was directly related and the elimination T1/2 inversely related to CrCl (r = 0.75 and 0.42, respectively). In patients with a CrCl >50 mL/min, the T1/2 and ApCl were 7.8 h and 53 mL/min, respectively, compared with 19.9 h and 25 mL/min (P < 0.05, P < 0.002, respectively) for patients with ESRD. In conclusion, ApCl is reduced, and T1/2 is prolonged in patients with renal insufficiency or ESRD undergoing CPB. Dosing modifications may be necessary for patients with abnormal renal function undergoing cardiac surgery. IMPLICATIONS: Because aprotinin is metabolized and eliminated in the kidney, its clearance may be reduced in patients with renal insufficiency. Our data suggest that aprotinin clearance is reduced, and aprotinin half-lives are prolonged in patients with renal insufficiency undergoing CPB. Dosing modification may therefore be indicated when aprotinin is administered to these patients for cardiac surgery.     

Augmentation of the systemic host anti-tumor response through laser excision.

This study examines whether primary laser excision results in augmentation of the systemic host anti-tumor response to tumor rechallenge. Single R3230AC mammary tumor implants, (0.5 x 0.5 x 1.0 mm), were grown in 112 female Fisher 344 rats. The animals were randomized. Group S tumors were excised by scalpel. Group E was excised with a Surgistat electrocautery (Valley Labs, Boulder, CO). Group CS was excised with a Sharplan 1100 CO2 laser (Sharplan, Allendale, NJ) at 25 watts (W) continuous wave (CW) (0.2 mm spot size) and the wound was "sterilized" with a 5-mm spot size by gently heating the tissue without blanching. Group K was excised with a KTP/532 laser (Laserscope, San Jose, CA) at 17 W CW using a 400 microns fiber. Group Y was excised with a Sharplan 2100 Nd:YAG laser set at 15W CW using a 0.2 mm clear sapphire tip. A second tumor implant, (0.5 x 0.5 x 1.0 mm), was placed at a remote site 14 days postoperatively. An unoperated control group was implanted. Secondary tumor volumes were measured for 36 days and the mean tumor volumes (MTV) were statistically compared. The MTV in groups CS, K, Y, and E was less than control (P less than 0.01). The MTV in groups CS, K, Y, and E was less than group S, although this was not statistically different. Lasers and cautery appear to increase the host response against subsequent tumor challenge. This study corroborates earlier studies of other modalities. Further studies to determine whether this host sensitization is an immune response and to elucidate the mechanisms of this effect are warranted.     

Lithium induced polyuria and renal vasopressin receptor density

BACKGROUND.: Lithium, a drug frequently used for treatment of affective disorders,is known to cause a vasopressin resistant state, leading topolyuria and polydipsia. It has been suggested that lithiuminteracts with the renal V₂-vasopressin receptor. Detailed studieson the influence of lithium on the AVP receptor, however, haveso far been difficult due to the lack of a suitable radioligandwith high specific activity and high affinity. METHODS.: Using ¹²⁵I-[8-(p-(OH)-phenylpropionyl)]-LVP, we studied theeffects of lithium on V₂-vasopressin receptors in male Sprague-Dawleyrats and LLC-PK₁ cells. Rats, having free access to water, wereorally treated with 10 mg lithium/100 mg b.w./day or placebofor 10 days. Scatchard analysis was performed using membranesprepared from homogenized renal papillae. RESULTS.: Lithium caused significant polyuria and an impaired renal concentrationcapacity after water deprivation. Binding studies showed noeffect of lithium on binding affinity K_D (0.98±0.21 nmol/lvs. 0.86±0.15 nmol/l (Li) (n.s.). Receptor density, however,significantly decreased from 130±12.3 nmol/kg proteinin controls (n=8) to 101.7±13.4 nmol/kg protein (n=8),(P<0·05). Plasma osmolality and AVP were not significantlyaltered by lithium treatment. Vasopressin receptor density onLLC-PK₁-cells, a pig renal cell line, was not changed by preincubationwith lithium (312±22 nmol/kg vs. 329±25 nmol/kg(Li) (n=6, n.s.). CONCLUSIONS.: The decrease of AVP-receptor density in vivo might be relatedto vasopressin resistance, either primary, or secondary to otherfactors, e.g. actual water transport.