Fluxes and distribution of calcium in rat liver cells: kinetic analysis and identification of pools

1. Fluxes and distribution of Ca were studied in the perfused rat liver. Kinetic analysis of (45)Ca exchange revealed three compartments with time constants of 4, 14 and 223 min, pool sizes of 250, 385 and 670 mumole.kg(-1) wet wt. respectively, and one non-exchangeable compartment of 400 mumole.kg(-1).2. (45)Ca uptake by in situ mitochondria followed, as a function of cell loading time, a mono-exponential function with a time constant of 16 min. This suggests that the second compartment may be identified as the intracellular pool of Ca. The calculated cell transmembrane flux of Ca was 28 mumole.kg(-1) min(-1) or 0.17 p-mole.cm(-2).sec(-1).3. The maximum (45)Ca uptake by in situ mitochondria was 2.3 n-mole.mg(-1) of protein which represents, on the basis of 50 mg of mitochondrial protein per g of fresh liver, 115 mumole.kg(-1) or 30% of the cytoplasmic pool. A pool of 10.8 n-mole.mg(-1) protein (or 540 mumole.kg(-1)) of non-exchangeable Ca (at steady state) was probably in the form of Ca phosphate precipitated in the mitochondrial matrix.4. Extracellular Ca pools were studied using competitor of Ca binding (La) or Ca chelators (EGTA). La displaced specifically a homogeneous pool of Ca (tau = 5.1 min) which represented a fraction (55 mumole.kg(-1)) of the rapidly exchangeable Ca (first compartment) without perturbing other external pools. On the other hand, EGTA displaced completely that compartment, and about 85% of the Ca of the third compartment. These results suggest that the first and the major fraction of the third compartments are extracellular. They account for 63% of total exchangeable Ca.5. A model of distribution and exchange of Ca in hepatocytes is proposed.     

Plasma Protein Dynamics: Albumin and IgG Capillary Permeability,Extravascular Movement and Regional Blood Flow in Unanesthetized Rabbits

The turnover rate constants for extravascular albumin and immunoglobulin-G (IgG) and the turnover rates and extravascular spaces for the proteins and regional blood flow were determined in different tissues in unanesthetized rabbits. The turnover rate constant in percent per minute for extravascular albumin was 1.9 in the kidney cortex and 1.4 in the kidney medulla, about 0.8-1.4 in the lung, small intestine, choroid plexus and heart muscle and about 0.2-0.6 in the skeletal muscle, stomach wall and gall bladder. The turnover rate constants for IgG were similar or lower. The plasma equivalent extravascular albumin space was 145 μl/g in the kidney medulla, about 100 μ1/g in the gall bladder, heart muscle, choroid plexus and small intestine, 30–70 μl/g in the kidney cortex, lung, stomach wall and triceps muscle. The extravascular IgG spaces were similar or smaller. In the liver, spleen and adrenals where extravascular spaces could not be determined, the ratios total IgG space/total albumin space were about 1.3-1.5. Extraction of albumin defined as turnover rate of extravascular albumin/regional plasma flow could not be determined in the liver, spleen and adrenals. It was zero in the brain cortex, about 0.001 % in the lung and around 0.01-0.05 % in most other tissues. The results suggest that in the walls of the capillaries of the kidney cortex, stomach wall, skeletal muscle and gall bladder there was convection of the proteins with pinocytosis and/or through large pores, diffusion playing little role. The albumin and the IgG passed through the tissues and were drained essentially by bulk flow. In the heart muscle, choroid plexus, lung and small intestine there seemed to be some diffusion of albumin through the capillary wall in addition to convection. Accumulation of IgG in the liver, spleen and adrenals was probably caused by adsorption to cells belonging to the RES.     

Organ pattern of age-related changes in the aminoacyl-tRNA synthetase activities of the mouse

The specific activities of 17 aminoacyl-tRNA synthetases from liver, lung, heart, spleen, kidney, small intestine and skeletal muscle of young (2 months) and aged (39 months) female Han:NMRI mice were determined under standard conditions of sample preparation and assay. The average reduction of total activity during ageing is 70% for liver, 50% for lung and spleen, nearly 40% for heart and kidney and nearly 20% for intestine and skeletal muscle. Detailed comparison reveals no general, but an organ-specific pattern.

Aminoacyl-tRNA synthetases were, furthermore, found to be ribosome-associated in higher proportions in liver tissue from aged mice.     

Intestinal resorption with 3H labeled enzyme mixture (wobenzyme)

0.2 g of an enzyme mixture (Wobenzym) labelled with 3H-acetic anhydride, were given orally to guinea pigs, which were arranged in 4 groups of 5 animals. The animals of each group were sacrificed at intervals of 30 minutes, 2, 4 and 24 hours after application. Radioactivity of the small and large intestine, plasma, urine, liver, heart, kidney, and skeletal muscle were determined. It could be shown that the labelled mixture of enzymes was absorbed from the intestine and was demonstrable in significant amounts in plasma, urine, heart, kidney, liver and skeletal muscle.     

The effect of purinergic P2 receptor blockade on skeletal muscle exercise hyperemia in miniature swine

Purpose

ATP could play an important role in skeletal muscle blood flow regulation by inducing vasodilation via purinergic P2 receptors. This study investigated the role of P2 receptors in exercise hyperemia in miniature swine.

Methods

We measured regional blood flow with radiolabeled-microsphere technique and systemic hemodynamics before and after arterial infusion of the P2 receptor antagonist reactive blue 2 during treadmill exercise (5.2 km/h, ~60 % VO₂max) and arterial ATP infusion in female Yucatan miniature swine (~29 kg).

Results

Mean blood flow during exercise from the 16 sampled skeletal muscle tissues was 138 ± 18 mL/min/100 g (mean ± SEM), and it was reduced in 11 (~25 %) of the 16 sampled skeletal muscles after RB2 was infused. RB2 also lowered diaphragm blood flow and kidney blood flow, whereas lung tissue blood flow was increased (all P < 0.05). Infusion of RB2 increased arterial lactate concentration during exercise from 1.6 ± 0.5 to 3.4 ± 0.6 mmol/L and heart rate from 216 ± 12 to 230 ± 9 beats/min, whereas blood pressure was unaltered. Arterial ATP infusion caused a ~twofold increase in blood flow in 15 of the 16 sampled muscle tissues and this effect was abolished after RB2 infusion.

Conclusions

These results indicate that P2 receptors play a role in regulating skeletal muscle blood flow during exercise in miniature swine.     

Selective tissue accumulation of manganese and its effect on regional blood flow and haemodynamics after intravenous infusion of its chloride salt in the rat

Manganese chloride (MnCl2), with or without the addition of trace amounts of 54Mn2+, was administered as a 7-min i.v. infusion in rats. Tissue accumulation of 54Mn2+ was determined 0-15 min after the infusion, and cardiac output, regional blood flows and vascular resistances were measured 5 and 60 min after the infusion by the microsphere technique. The plasma half-life of 54Mn2+ was found to be 4.7 min. Mn2+ accumulated in several organs, the highest relative concentrations being seen in the liver, duodenum, jejunum, kidney and heart, and intermediate concentrations in the ileum, colon, stomach and spleen. There was no uptake in the lung, skeletal muscle or brain. During the infusion of 180 mumol/kg b.w. of Mn2+, the arterial blood pressure fell from a mean of 123 +/- 5 mm Hg to a minimum of 85 +/- 7 mm Hg, and thereafter returned to normal. Five minutes after termination of the infusion, there was a decrease in cardiac output and minute work but not in total peripheral resistance, a finding interpreted as a negative inotropic effect of Mn2+. At this time blood flow was decreased in the stomach, ileum, colon, spleen and skin, and increased in duodenum, jejunum and liver. The blood flows were normalized 60 min after termination of the infusion in all organs except the liver and heart. The effects are probably due to the calcium-antagonistic properties of Mn2+ and the tissue accumulation is most probably a result of intracellular accumulation through calcium channels. The relation between tissue accumulation and tissue selectivity of blood-flow alterations is unexplained.     

Glucose uptake and binding of digoxin to skeletal muscle

Physical exercise induces increased uptake of both digoxin and glucose in exercising skeletal muscle. Glucose uptake could be a regulatory factor for the digoxin binding to skeletal muscle, since in dogs, insulin and glucose infusion have been reported to increase the uptake of digoxin in muscle. In the present study on eight healthy digitalized subjects (0.5 mg digoxin daily) the uptake of glucose in skeletal muscle was achieved by infusion of 6 mg/kg body weight/min glucose, 0.004 IE/kg body weight/min insulin and 300 micrograms/h somatostatin. Serum and skeletal muscle digoxin levels were analysed before and during the infusion. We found no changes in the digoxin levels in serum and skeletal muscle in spite of an increased uptake of glucose in the muscle. Thus, glucose uptake in skeletal muscle is probably not an important regulatory factor for the change in muscle digoxin binding induced by exercise.     

Deposition of immune complexes containing cationized antibodies in myocardial small blood vessels of mice

Small myocardial blood vessels constitute a site for preferential deposition of preformed cationic immune complexes. This preferential deposition was demonstrated with a limited dose (100 micrograms) of cationized rabbit antibodies to human serum albumin, injected into C57B1/6J mice either alone or in the form of preformed immune complexes. Heart, kidney, liver, intestine, and skeletal muscle were examined for immune deposits by immunofluorescence microscopy. Highly cationized antibodies injected alone showed deposition in glomeruli and in the liver along the sinusoids but not in other tissues. Immune complexes containing native rabbit antibodies deposited only in liver in a Kupffer cell pattern. Moderate and highly cationized antibodies in immune complexes deposited in myocardial small blood vessels, liver, and glomeruli, but not in intestine or skeletal muscle. These complexes deposited via electrostatic interactions since unrelated polycationic molecules, protamine sulfate or cationized rabbit serum albumin, injected 1 min prior to cationic antibodies in immune complexes blocked deposition in myocardial small vessels, glomeruli, and liver. Administration of protamine or cationized rabbit serum albumin 1 min after deposition of cationized immune complexes resulted in displacement of the immune deposits in heart, kidney, and liver, but not when the injection was given 1 hr later. The presented data indicate that with passage of time the immune deposits rearrange and forces other than charge-charge interactions retain them in myocardial vessels.     

正常大鼠不同脏器微血管通透性的定量研究

大鼠颈动脉注射１％ＦｌＮａ荧光显微镜下活体观察肠系膜微血管血流状态及ＦｌＮａ的渗出情况。同时，在不同时点经股动脉采血，测定血浆内ＦｌＮａ浓度随时间的变化，用组织匀浆测定不同脏器中ＦｌＮａ浓度随时间的变化规律，并辅以冰冻切片进行观察。活体观察发现。ＦｌＮａ注入体内后，经微血管通融向周围组织渗出，最后汇集了淋巴管。血浆及组织匀浆ＦｌＮａ浓度的测定表明，不同脏器组织ＦｌＮａ浓度随时间的衰减过程各不相同，     

中华眼镜蛇毒组份Ⅲ的药代动力学及组织分布研究

目的:观察中华眼镜蛇(Najanajaatra)蛇毒组份Ⅲ在兔体内的药代动力学过程和在小鼠体内的分布状况。方法:用氯胺-T法对眼镜蛇毒组份Ⅲ进行碘化标记,用放射性核素示踪动力法检测血液中的药物浓度,以放射性参与量(脏器与血液放射比)的比值作为组份Ⅲ在组织中分布的依据。结果:兔静脉注射眼镜蛇毒组份Ⅲ75、150和300μg／kg3个剂量后,快分布相半衰期T_1/2α为39.6-42.5min,慢分布相半衰期T_1/2β为16.8-17.3h,消除相半衰期T_1/2γ为21.7-22.1h。小鼠尾静脉注射[¹²⁵Ⅰ]-组份Ⅲ后,2h及4h放射性参与量大于1的器官为肝脏、肾脏、肺脏、心脏和肌肉,其中以肾脏分布最高,且4h放射性参与量高于2h。结论:兔静脉注射组份Ⅲ3个剂量后,血药-时间曲线经3P87药动学程序拟合符合三房室模型特征,3个时相的半衰期各剂量组之间无显著差异,曲线下面积(AUC)与剂量成正比,表明药物在兔体内的分布和消除为一级线性动力学过程。小鼠静注组份Ⅲ后2h,以肾脏分布最高,肝脏与肺脏的放射性参与量也较高,尿中含量很高。     

Tight junction permeability and liver plasma membrane fluidity in lithocholate-induced cholestasis.

The present study correlated the reversibility of bile flow (BF) impairment with biochemical and morphological changes in the liver after injection of a cholestatic dose (12 mumole/100 g body weight) of lithocholic acid (LCA). BF declined maximally at 60 min but recovered totally at 210 min after LCA treatment. During the cholestatic period, there was an increase in tight junction permeability as measured by the bile to plasma (B/P) ratio of inulin and using lanthanum as a tracer. Cholesterol content and the cholesterol/phospholipid ratio in liver plasma membranes (LPM) were augmented while the fluidity of bile canalicular membranes (BCM) was decreased at 30 and 60 min after LCA injection. These changes in cholesterol content and membrane fluidity seemed to be correlated with LCA incorporation in LPM; their reversal at 120 min preceded the recovery of BF (210 min). Some biochemical disorders were evident after LCA injection, but they did not correlate with the variation in BF. These data suggest that increased tight junction permeability and decreased BCM fluidity are important pathogenic steps in LCA-induced cholestasis.     

Circulatory Effects Evoked by ‘Physiological’ Increases of Arterial Osmolality

The effects of moderate arterial hyperosmolality (+ 20 mOsm/kg H₂O), produced by short term intravenous hypertonic infusion, on vascular resistance in skin, skeletal muscle, intestine, and kidney were analysed in the anesthetized cat. Vascular resistance decreased in all four regions in response to the hypertonicity both before and after regional sympathectomy and the effects were not significantly altered by β-adrcno-ceptor blockade. Arterial blood pressure rose during the hypertonic infusion despite the decreased vascular resistance and an unchanged heart rate, indicating an increased stroke volume and cardiac output. Similar increases of arterial osmolality are known to occur in heavy exercise and in hemorrhage. The present results may therefore suggest that blood borne hyperosmolality is a factor which can contribute to the overall cardiovascular adjustments in these situations.     

Deformierung und Zerstörung von Erythrocyten durch Noradrenalin in normalen und hämorrhagischen Hunden

Zusammenfassung Normalen Hunden wurde in Nembutal^®-Narkose Noradrenalin (NA) i. v. infundiert. Bei einer Infusionsrate von ca. 2 /min · kg veränderten die Erythrocyten ihre bikonkave Form. Sie wurden stechapfelörmig. 10 min nach Ende der Infusion waren alle Zellen wieder normal bikonkav. Die NA-Wirkung unterblieb bei hämorrhagischen Hunden (Blutdruck 40 mm Hg) und bei Steigerung der Infusionsrate auf 8 NA. Es wird diskutiert, ob NA die Fließeigenschaften der Erythrocyten durch Formveränderungen beeinflussen kann.

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Summary Anesthetized dogs received infusions of nor-adrenaline (0.5–8 /kg · min). During infusion the shape of the erythrocytes was observed in its own plasma in a coverglass preparation. 10 min after start of a 2 infusion up to 90% of the erythrocytes became more or less creanated. 10 min after stopping the infusion all erythrocytes showed normal biconcave shapes. Infusion of 8 /kg · min did not influence the shape. No changes were observed in dogs subjected to severe hemorrhage. During the hypotensive periode (40 mm Hg) neither the shape nor the concentration of free fatty acids responded to infusion of 0.5–2 NA/min · kg. It is discussed whether NA might disturb the microcirculation in capillaries by changing the flow properties of shape transformed erythrocytes.

     

Pharmacokinetics, stability, and blood partition of 7-anilino-5,8-isoquinolinedione, a new isoquinonlinedione derivative

Pharmacokinetics of IQO4, a new isoquinolinedione derivative, after 30-min intravenous administration of the drug, 5 mg/kg, to rats, the stability, and the blood partition between plasma and blood cells of IQO4 were evaluated. After intravenous administration, IQO4 was eliminated fast with the mean total body clearance of 105 ml/min/kg. IQO4 was almost completely metabolized in rats; 5.18% of intravenous dose of IQO4 was excreted in 24-hr urine and IQO4 was under detection limit in whole gastrointestinal tract as 24 hr. IQO4 has a good affinity to liver, small intestine, heart, lung, and kidney as reflected to greater-than-unity tissue-to-plasma ratios. IQO4 was unstable in rat whole blood, plasma, and liver homogenates when incubated in a water-bath shaker for 24 hr kept at 37 degrees C and at a rate of 50 oscillations per min. The disappearance rate constants of IQO4 were 0.0611, 0.O436, and 0.174 hr(-1) for rat whole blood, plasma, and liver homogenates, respectively. However, IQO4 was stable for up to 3-hr incubation in human gastric juices. The plasma-to-blood cell concentration ratios of IQO4 were independent of initial blood concentrations of IQO4, 0.5, 2, and 10 microg/ml, when the rabbit whole blood was incubated for up to 120 min; the ratios were in the range of 1.56-3.60. Since IQO4 was unstable in blood, considerable in vitro 'blood storage effect' in the plasma concentration of IQO4 was observed.     

Genotoxicity of paracetamol in mice and rats

The genotoxicity of paracetamol, including covalent bindingto DNA, induction of DNA single-strand breaks (SSBs), and inhibitionof replicative and repair synthesis of DNA, has been investigatedin rodents in vivo. In the covalent binding studies male ICRmice were fasted and pretreated with diethyl maleate to depletehepatic glutathione (GSH) and 300 mg/kg of [G-³H]paracetamolwas administered intraperitoneally (i.p.). Animals were killedat 2, 6, 24, 72 and 168 h after paracetamol and hepatic or renalDNA and protein were isolated and the extent of covalent bindingdetermined. Maximal binding to liver DNA, 8.4 ± 3.1 pmol/mgof DNA, was observed at 2 h and declined rapidly to 2.6 pmol/mgat 24 h. Measurable binding (1.4 pmol/mg of DNA) was detectedat 7 days. Protein binding in the liver in these animals peakedbetween 2 and 6 h (887 pmol/mg of protein at 2 h) and declinedmonoexponentially to 52 pmol/mg at 7 days. Although based ona limited body of data, covalent binding was also detected inDNA isolated from the kidney. DNA damage measured as SSBs byalkaline elution was induced in nuclear DNA isolated from theliver but not from the kidney, 2 h after i.p. injection of paracetamolat 600 mg/kg in male B6 mice. Only marginal DNA damage was notedat 300 mg/kg. The alkaline elution profile from damaged livernuclei was markedly biphasic, suggesting that breaks were inducedin DNA from a subpopulation of liver cells. The non-hepatotoxicparacetamol regioisomer, acetyl-m-aminophenol (600 mg/kg), whichbinds covalently to proteins, did not cause DNA SSBs. Pretreatmentof animals with diethyl maleate enhanced the paracetamol-inducedDNA SSBs, while phenobarbital and N-acetylcysteine had no markedeffects. In male Wistar rats, which are more resistant to paracetamoltoxicity, no increase in the level of DNA SSBs was seen in liveror kidney 4 h after exposure to 600 mg/kg paracetamol. Paracetamol(150 mg/kg and higher) inhibited DNA synthesis in B6 mice, asevidenced by a marked decrease in the incorporation of [³H]thymidine([³H]TdR) between 15 and 75 min in the liver, spleen, intestine,bone marrow and kidney. The decrease in DNA synthesis was transient,and between 90 and 150 min the rate of radiolabel incorporatedwas at the control level or increased in all the organs, exceptthe kidney. Paracetamol, at 300 mg/kg, increased the level ofDNA SSBs detected in the liver, spleen and kidney of both B6mice and Wistar rats 2 h after administration of 4-nitroquinolineN-oxide (NQO). Covalent binding of paracetamol metabolites toliver and renal DNA in diethyl maleate-pretreated mice and inductionof DNA SSBs in mouse liver were observed at hepatotoxic dosesof paracetamol and probably involve reactive metabolite(s) ofparacetamol. These effects could be early events in the developmentof liver necrosis. The inhibition of (³H)TdR incorporation andthe enhancement of NQO-induced DNA SSBs, on the other hand,occur at lower doses and in organs with low capacities for metabolizingparacetamol to reactive metabolite(s). These effects are mostprobably due to inhibition of ribonucleotide reductase by paracetamol,as previously demonstrated in vitro.     

Circulatory effects evoded by 'physiological' increases of arterial osmolality.

The effects of moderate arterial hyperosmolality (+20 mOsm/kg H2O), produced by short term intravenous hypertonic infusion, on vascular resistance in skin, skeletal muscle, intestine, and kidney were analyzed in the anesthetized cat. Vascular resistance decreased in all four regions in response to the hypertonicity both before and after regional sympathectomy and the effects were not significantly altered by beta-adreno-ceptor blockade. Arterial blood pressure rose during the hypertonic infusion despite the decreased vascular resistance and an unchanged heart rate, indicating an increased stroke volume and cardiac output. Similar increases of arterial osmolality are known to occur in heavy exercise and in hemorrhage. The present results may therefore suggest that blood borne hyperosmolality is a factor which can contribute to the overall cardiovascular adjustments in these situations.     

Glutathione homeostasis and turnover in the totally hepatectomized rat: evidence for a high glutathione export capacity of extrahepatic tissues.

Glutathione (GSH) homeostasis and turnover were investigated in totally hepatectomized (HX) rats. A technique is described to remove the liver totally, with preservation of the hepatic portal and vena caval vasculature. Euglycemia could be maintained with hourly infusions of 50 mg 100 g-1 b.m. of glucose after bolus i.v. injection of glucose at the same dose. The efficiency of the animal model was demonstrated by examination of paraclinical blood parameters: progressive increases in total plasma bilirubin and alkaline phosphatase activity were noted after HX; the other parameters tested were predominantly in the normal range during the observation period of 6 hours. Histological examination revealed an acute but reversible impairment of intestine and kidneys. These results indicate that the surgical procedure and postoperative care were able to secure sufficient physiological conditions for the experiments over a longer period. 3 to 6 hours after HX we observed a decreased but stable plasma GSH level in anhepatic rats (about 50% of the control value). The GSH levels of brain and kidney were not changed. With increasing time period after HX the heart and lung GSH levels were depressed. A small depression of muscle GSH concentration was observed 4 and 6 hours after HX. A progressive increase in the concentration of oxidized glutathione was seen in brain and kidney. Our observations could be indicative for a high GSH export capacity of extrahepatic tissues contributing about 50% of the total GSH influx into circulation. Probably, the skeletal musculature is an important GSH origin for plasma.     

Transcapillary Fluid Movements in Sympathectomized Intestine and Skin during Hemorrhagic Hypotension

Net transcapillary fluid exchange in skin tissue (paw) and small intestine was observed during a 90 min period of hemorrhagic hypotension at 50 mm Hg in the cat. Reflex fluid transfer was prevented by regional sympathectomy and α-adrenergic blockade. Early in hemorrhage, fluid absorption from the extravascular space occurred in both tissues, apparently caused by osmosis. The process was thus co-ordinated in time with a positive arterio-venous osmolar difference, in turn caused by a marked arterial hyperosmolality. Experimental arterial hyperosmolality of similar magnitude, created by i.v. infusion of hypertonic glucose in non-bled animals, led to transcapillary fluid absorption in both intestine and skin and at rates similar to those in bleeding. Regional hypotsionen per se caused no fluid absorption. Later in hemorrhage (> 30 min), plasma fluid moved into the extravascular space both in skin and intestine, apparently due to a gradual increase of capillary hydrostatic pressure. It is concluded that the arterial hyperosmolality during bleeding can cause transcapillary fluid absorption in intestinal and skin tissues, as previously shown for skeletal muscle (Järhult 1973). The hemodynamic significance of this process for plasma volume regulation in hemorrhage is, however, much greater in skeletal muscle than in intestine and skin, mainly due to the much larger total mass of the muscle tissue.     

Distribution of the thrombomodulin antigen in the rabbit vasculature

The purpose of this study was to determine the distribution of the thrombomodulin (TM) antigen in the rabbit vasculature in vivo. Acetone-fixed, frozen sections of various tissues (brain, heart, aorta, lung, liver, spleen, kidney, small intestine, large intestine, skeletal muscle, bone, and skin) were stained by indirect immunofluorescence with goat affinity-purified antibodies to TM. Both large and small vessels (including capillaries) had demonstrable TM antigen localized to the endothelium while vascular smooth muscle and connective tissue cells were negative. The parenchyma of the organs examined were also negative. Based on antibody dilutions and brightness of staining, there is an indication that lung, followed by heart and intestinal vessels, has the highest concentration of antigen; kidney glomerular capillary loops have the least. These results also indicate that TM is an excellent cell type-specific marker of endothelial cells as the endothelium of all vessels and vascular beds was positive.     

β-Caryophyllene,a natural sesquiterpene,modulates carbohydrate metabolism in streptozotocin-induced diabetic rats

The study was designed to evaluate the antihyperglycemic effects of β-caryophyllene (BCP), a natural sesquiterpene from spices on streptozotocin (STZ) induced diabetic rats. Diabetes mellitus was induced by a single intraperitoneal injection of STZ (40 mg/kg b.w.) in adult male Wistar rats. Diabetic rats exhibited an increase in glucose and HbA_1c with a significant fall in insulin and hemoglobin levels. Aberrations in carbohydrate metabolic enzymes were noticed in liver, kidney and skeletal muscle of diabetic rats. A fall in liver and skeletal muscle glycogen with alterations in glycogen synthase and phosphorylase activities was also observed. Oral administration of BCP in dose dependent manner and glibenclamide (600 μg/kg b.w.), a standard oral hypoglycemic drug to diabetic rats for 45 days significantly decreased glucose with increased plasma insulin levels and ameliorated the altered activities of carbohydrate metabolic enzymes to near normal. The insulinotropic effect of BCP was supported by immunohistochemical studies. BCP at a dose of 200 mg/kg b.w. exerted significant antidiabetic effects than other two doses (100 and 400 mg/kg b.w.). We conclude that administration of BCP has beneficial effects in glucose homeostasis in diabetic rats.