Centrally acting leptin induces a resuscitating effect in haemorrhagic shock in rats

Centrally acting leptin induces the activation of the sympathetic nervous system with a pressor effect in normotensive rats. The purpose of the study was to examine central leptin-evoked action in critical haemorrhagic hypotension. In anaesthetized male Wistar rats subjected for irreversible haemorrhagic shock with mean arterial pressure (MAP) 20-25 mmHg haemodynamic parameters and plasma concentrations of adrenaline and noradrenaline were measured. Leptin given intracerebroventricularly (20 μg) evoked long-lasting rises in MAP and heart rate (HR), with a subsequent increase in renal, mesenteric and hindquarters blood flows and a 100% survival at 2 h. MAP and peripheral blood flow changes were inhibited by a pre-treatment with α(1)- and α(2)-adrenoceptor antagonists prazosin (0.5 mg/kg) and yohimbine (1 mg/kg), while β-adrenoceptor antagonist propranolol (1 mg/kg) blocked leptin-induced HR changes, without influence on MAP, peripheral blood flows and survival. Twenty min after leptin treatment, there were higher plasma concentrations of noradrenaline, but not adrenaline, in comparison with the saline-treated control group. In conclusion, centrally acting leptin induces a long-lasting pressor effect with an improvement in the survival rate in haemorrhage-shocked rats. The effect may be associated with the activation of the sympathetic nervous system.     

Effects of adrenaline on the dynamics of carbohydrate metabolism in rats treated chronically with adrenaline.

Following a subcutaneous injection of adrenaline (300 mug/kg), blood-glucose levels were lower in rats treated chronically with adrenaline (300 mug/kg twice a day for 28 days) than in control rats during at least 2.5 h after the injection. To explain this difference of response, the turnover rate of glucose was measured in control and adrenaline-treated rats during adrenaline infusion (0.75 mug/kg- minus 1 min- minus 1), with [U- minus 14C]glucose as tracer. It was found that the rate of appearance of glucose was greater in the control than in the adrenaline-treated group after a 120-min infusion of adrenaline. The rate of disappearance of glucose in the treated rats increased during the first 60 min of infusion and stayed at this elevated level for a subsequent 2 h, whereas in the control rats, it remained unchanged at the beginning of adrenaline infusion and significantly increased only during the second and third hours of infusion. In addition, the metabolic- clearance rate of glucose was not modified by adrenaline in the treated group, but in the control group, the initial clearance rate was significantly less than in the treated group, and decreased during the first hour of adrenaline infusion even though blood glucose reached values of 244 mg/100 ml. ,rom these data, it is suggested that rats adapt to a chronic exogenous supply of adrenaline by a reduced increase in glucose production in response to adrenaline infusion and a better glucose utilization, which possibly indicates a decrease in the inhibitory effect of adrenaline on insulin secretion.     

The effect of 5-fluorouracil on experimental acute pancreatitis

The present study was undertaken to elucidate the effects of different doses of 5-fluorouracil on experimental acute pancreatitis. Twelve mongrel dogs were used. Acute pancreatitis was induced by intraductal injection of sunflower-oil. Two groups of animals were treated with intravenous 5-fluorouracil: 1 mg/kg body weight for the first group of 5 animals, and 5 mg/kg body weight for the second one of 7 animals in subsequent three postoperative days. All the animals in the first group died within 24 to 36 hours due to acute haemorrhagic pancreatitis. All the animals in the second one survived longer than 36 hours. A statistically significant increase of serum amylase and lipase levels was found in pancreatitis with significant decrease of them during treatment. Three to 8 weeks later signs of chronic pancreatitis could be detected in surviving dogs.     

Effect of adrenaline on insulin secretion in rats treated chronically with adrenaline.

To determine whether rats could adapt to a chronic exogenous supply of adrenaline by a decrease in the well-known inhibitory effect of adrenaline on insulin secretion, plasma glucose and insulin levels were measured in unanesthetized control and adrenaline-treated rats (300 mug/kg twice a day for 28 days) during an adrenaline infusion (0.75 mug kg-1 min-1), after an acute glucose load (0.5 g/kg), and during the simultaneous administration of both agents. Chronic treatment with adrenaline did not modify the initial glucose levels but it greatly diminished the basal insulin values (21.57+/-2.48 vs. 44.69+/-3.3muU/ml, p less than 0.01). In the control rats, despite the elevated glucose concentrations, a significant drop in plasma insulin levels was observed within the first 15 min of adrenaline infusion, followed by a period of recovery. In the adrenaline-treated group, in which plasma glucose levels were lower than in control animals, plasma insulin levels did not drop as in control rats, but a significant increase was found after 30 min of infusion. During the intravenous glucose tolerance test, the plasma glucose and insulin responses showed similar patterns; however, during the concomitant adrenaline infusion, the treated rats showed a better glucose tolerance than their controls. These results indicate that rats chronically treated with adrenaline adapt to the diabetogenic effect of an infusion of adrenaline by have a lower inhibition of insulin release, although the lower basal insulin levels may indicate a greater sensitivity to endogenous insulin.     

Shock Caused by Continuous Infusion of Metaraminol Bitartrate (Aramine)

Increasing doses of metaraminol bitartrate (Aramine) in a continuous intravenous infusion were used to support the blood pressure in four patients. Under such treatment a state of shock developed, characterized by intense peripheral vasoconstriction, hypotension and anuria. In spite of an adequate fluid intake all patients showed severe hemoconcentration, and a critically low plasma volume could be demonstrated in two. While metaraminol (Aramine) was ineffective, noradrenaline still caused a moderate blood pressure response. Treatment with plasma expanders (Intradex) and small doses of noradrenaline (Levophed) resulted in transient improvement in one patient and complete recovery from shock in three. The peripheral vasoconstriction persisted up to 12 hours and renal function improved on the second day after the withdrawal of metaraminol. The etiology of this shock syndrome is believed to be similar to that of experimental shock produced with adrenaline and noradrenaline.     

Platelet aggregation and thromboxane A2 release in primary biliary cirrhosis and effect of D-penicillamine treatment

Platelet function was assessed in 28 patients with primary biliary cirrhosis (PBC), of whom 10 were receiving D-penicillamine. Patients not on D-penicillamine treatment had platelet aggregation similar to that in the healthy control group; the group treated with D-penicillamine showed significantly enhanced platelet aggregation in response to threshold doses of adrenaline and collagen but not ADP. Median thromboxane B2 production was also higher in D-penicillamine treated patients than in controls or untreated patients; this difference did not reach statistical significance. The addition of D-penicillamine in vitro to platelet rich plasma from normal subjects was shown to enhance adrenaline- and collagen-induced platelet aggregation. Abnormalities of platelet function in PBC patients did not correlate with serum cholesterol concentration or with liver function tests but were related to the stage of disease. The present study emphasises the need to consider the aetiology, disease stage and type of treatment when assessing platelet function and prostanoid release in liver disease.     

Biochemical Evidence of Anxiety in Dental Patients

Urinary metabolites before dental treatment were compared in a group of patients with dental phobia and in a matched control group. Plasma adrenaline, noradrenaline, and free fatty acids were estimated before treatment, immediately after sedation with diazapam 0·2 mg/kg body weight in the phobic patients, during induction of oral anaesthesia, and during and after surgery. Patients with dental phobia had significantly higher levels of adrenaline, which were only temporarily lowered by sedation, and which during treatment remained consistently higher than those of control patients.     

重症肌无力患者免疫球蛋白治疗的最佳剂量探讨

目的:探讨重症肌无力患者采用免疫球蛋白治疗的最佳剂量。方法:选择2007年8月到2014年11月在我院收治的174例重症肌无力患者,随机分为ACS组、小剂量IgG组和大剂量IgG组,分别每日静脉滴注15 mg肾上腺素、250 mg免疫球蛋白和500 mg免疫球蛋白进行治疗,对比三组的临床疗效、住院时间和呼吸机辅助时间。结果:经过治疗后,小剂量IgG组与ACS组总有效率无显著性差异(P0.05);大剂量IgG组总有效率明显高于小剂量IgG组和ACS组,具有显著性差异(P0.05);大剂量IgG组患者的住院时间和呼吸机辅助时间均明显少于ACS组和小剂量IgG组,具有显著性差异(P0.05)。结论:500 mg免疫球蛋白静脉滴注临治疗重症肌无力,临床疗效显著,能明显缩短患者的住院时间和呼吸机辅助时间,值得在临床上推广。     

Age-related differences in the cardiovascular responses to haemorrhagic shock in rats.

The cardiovascular responses to haemorrhagic shock were studied in male Sprague-Dawley rats of different age groups, ranging from 6-15 weeks (body weight 250-460 g). Haemorrhagic shock was induced by bleeding (2% body weight), under urethane anaesthesia, from the cannulated femoral artery at a rate of 1 ml/min. It was found that the younger rats had significantly smaller values of left ventricular pressure and dLVP/dtmax following haemorrhage and a greater mortality rate. Older animals exhibited significantly greater falls in blood pressure and pulse rate during the bleeding procedure, and slower recovery in these parameters after the bleeding was stopped. However, these rats had a significantly higher left ventricular pressure and dLVP/dtmax following haemorrhage, and a markedly lower mortality rate. The findings demonstrate the existence of age-related cardiovascular responses to haemorrhagic shock in rats.     

The importance of bisoprolol in prevention of heart left ventricular hypertrophy in patients with long term L-thyroxin suppressive therapy, after the operation of differentiated thyroid carcinoma

INTRODUCTION: Patients with differentiated thyroid carcinoma have to undergo radical surgical treatment, which includes total thyreoidectomy, radioiodine therapy and a life-time suppressive therapy with L-thyroxine. The aim of this study was a prospective evaluation of left ventricular hypertrophy during L suppressive-thyroxine treatment in patients treated for differentiated thyroid carcinoma. MATERIAL AND METHODS: The examined group comprised 50 patients with differentiated thyroid carcinoma, treated by total thyroidectomy and 131I therapy. Echocardiographic measurements were needed for estimation of left ventricular mass and its index, according to recommendations of American Echocardiography Society. RESULTS: During two-years long suppressive therapy we observed a significant rise in left ventricular mass. In woman group left ventricular mass was increased from 168+/-39 g to 204+/-45 g (p<0.001) and in men from 205+/-60 to 320+/-21 g. Likewise, left ventricular mass index was increased in women group from 96+/-18 g/m(2) to 116+/-25 g/m(2) (p<0.001) and in men group from 107+/-37 g/m(2) to 158+/-28 g/m(2). Simultaneous treatment with bisoprolol caused a regression of left myocardial hypertrophy. Already after 6 months of simultaneous treatment with L-thyroxin and bisoprolol, for left ventricular mass was reduced to normal: in woman 165+/-35 g, and in men to 178+/-38 g. Analogous results were obtained left ventricular mass index. After 6 months it was reduced to 94+/-12 g/m(2) in woman and in men to 132+/-32 g/m(2). CONCLUSIONS: 1. In differentiated thyroid cancer patients, treated postoperatively with L-thyroxine suppressive therapy, left ventricular hypertrophy is observed already during the first year of suppressive therapy and progresses during the next year of treatment. 2 Addition of a beta-adrenergic antagonist to suppressive doses of L-thyroxine causes a regression of left ventricular hypertrophy, thus, beta-adrenergic antagonists should be administered in this group of patients.     

Mesenteric microvessel reactivity in rats in mesenteric shock

Reactivity of rat mesenterial microvessels was studied during mesenterial shock. The development of the shock was discovered to involve two phases in the changes of microvascular reactivity. The sensitivity of microvessels to adrenaline was increased at the beginning of the shock whereupon it started descending. This phenomenon evidences that vasodilatation occurring at the late stages of the shock development is determined not only by a reduction in the concentration of endogenous adrenaline and noradrenaline but also by a decrease in the sensitivity of microvessels to these agents. The data obtained make it possible to explain the mechanism of steady vasodilatation in response to injection of exogenous adrenaline and noradrenaline, which is seen at the late stages of mesenterial shock.     

Reactivity of the cerebrocortical vasculature and energy metabolism to direct cortical stimulation in haemorrhagic shock.

Direct electrical stimulation of the cerebral cortex was used to determine the changes of cortical carbohydrate and oxidative metabolism and of vascular reactivity during haemorrhagic shock. The results were as follows. 1. Electrical stimulation of the brain cortex applied in the control period led to a marked vasodilation and NAD reduction that was preceded in part of the experiments by a transient NADH oxidation. It is suggested that the increase in cortical NADH fluorescence observed during direct stimulation is due to the fact that the rate of cytoplasmic NADH production exceeded the rate of mitochondrial NADH oxidation and of the rate of H+-transport from the cytoplasm into the mitochondria. 2. The cerebrocortical vascular and NAD/NADH redox state responses induced by electrical stimulation changed in the early hypovolaemic phase of shock. At this time, electrical stimulation of the brain cortex led to NADH oxidation in the majority of the experiments or in some experiments, the stimulation did not bring about changes in the redox state of the cortex. The total loss of the reactivity to direct stimulation of the cerebrocortical vessels and of energy metabolism preceded the occurrence of cortical ischaemia during the hypovolaemic phase of shock. 3. Since after reinfusion of the shed blood, redox state and vasculature remained unresponsive to stimulation even in those experiments in which the cortical ischaemia improved, it is concluded that the carbohydrate and oxidative metabolism of the brain cortex were already irreversibly damaged in the early phase of hypovolaemic shock.     

Intracellular oxygen tension and energy metabolism in the cat brain cortex during haemorrhagic shock.

The changes in intracellular oxygen tension and energy metabolism of the cat brain cortex were studied by surface fluororeflectometry during haemorrhagic shock. The results may be summarized as follows. (a) Intracellular oxygen tension, i.e. the maximum cortical NAD reduction obtained during nitrogen gas inhalation decreased gradually during the hypovolaemic phase of shock and finally, the brain cortex became ischaemic. (b) Partial uncoupling of the cerebrocortical mitochondrial respiration and oxidative phosphorylation appeared in the very early period of bleeding, as indicated by the overshot of the cortical NAD/NADH redox state towards oxidation subsequent to the cessation of nitrogen gas inhalation. Partial uncoupling of mitochondrial respiration and oxidative phosphorylation became more pronounced during the later phases of bleeding, finally, the mitochondrial electron transport stopped. In line with these changes the frequency and the amplitude of ECoG decreased gradually and markedly during the hypovolaemic phase of shock. (c) Microcirculation and energy metabolism of the cat brain cortex were severely and irreversibly damaged during the hypovolaemic phase of shock. This was clearly shown by the fact that in the majority of experiments the nitrogen anoxia after reinfusion failed to bring about changes in the cortical NAD/NADH redox state and the ECoG changes occurred during bleeding did not improve after reinfusion. It is concluded that the early disturbances of cerebrocortical energy metabolism play an important role in the development of neural and vascular lesions of the brain that occur during haemorrhagic shock.     

Immunological aspects in the L-asparaginase treatment of children with lymphoproliferative diseases]

A group of 20 children, including 14 with acute lymphoblastic leukemia and 6 with lymphosarcoma, was studied. 24 cures of l-asparaginase therapy were carried out. The increase of serum immunoglobulin (IgG, IgA, IgM) levels was found in children treated with smaller (from 300 to 500 I.U./kg b. w.) doses of asparaginase. In the group treated with higher doses (from 501 to 760 I.U./kg b. w.) the maximal increase of immunoglobulins was observed in the second half of the cure with l-asparaginase, followed by a decrease of the immunoglobulins levels at the end of treatment. The presence of anti-asparaginase antibodies in two children with anaphylactic shocks after l-asparaginase has been shown. In these two children and 6 others the lymphocyte count significantly dropped down on the day of shock before l-asparaginase injection.     

Anaphylaxis and plasma catecholamines

The concentrations of plasma catecholamines, cyclic AMP glucose, lactate and glycerol were measured in a high IgE-producing strain of Hooded-Lister rats. Immobilization caused an increase in the levels of plasma catecholamines, especially adrenalin. In rats immunized against egg albumin the rise was higher than in non-sensitized controls, possibly indicating a relationship between sympatho-adrenal activity and serum IgE levels. Anaphylaxis caused by egg albumin induced a rapid and huge increase of plasma catecholamines especially adrenaline. The increase of plasma catecholamines was more rapid and pronounced in awake than in anesthetized rats. The plasma levels of adrenaline following anaphylaxis were larger than those obtained following administration of 5 μg adrenaline i.v. Plasma cyclic AMP, glucose and lactate levels were markedly enhanced already before the injection of antigen. On the other hand, glycerol levels were initially low but increased in parallel to the rise in plasma catecholamines. Administration of dextran to Sprague-Dawley rats induced an anaphylactoid reaction and high plasma levels of adrenaline and noradrenaline. The results indicate a massive sympatho-adrenal activation in anaphylactic and anaphylactoid shock and the use of exogenous adrenaline may cause little additional activation of adrenoceptors.     

Randomised comparison between adrenaline injection alone and adrenaline injection plus heat probe treatment for actively bleeding ulcers.

OBJECTIVE: To compare endoscopic adrenaline injection alone and adrenaline injection plus heat probe for the treatment of actively bleeding peptic ulcers. DESIGN: Randomised prospective study of patients admitted with actively bleeding peptic ulcers. SETTING: One university hospital. SUBJECTS: 276 patients with actively bleeding ulcers detected by endoscopy within 24 hours of admission: 136 patients were randomised to endoscopic adrenaline injection alone and 140 to adrenaline injection plus heat probe treatment. MAIN OUTCOME MEASURES: Initial endoscopic haemostasis; clinical rebleeding; requirement for operation; requirement for blood transfusion; hospital stay, ulcer healing at four weeks; and mortality in hospital. RESULTS: Initial haemostasis was achieved in 131/134 patients (98%) who received adrenaline injection alone and 135/136 patients (99%) who received additional heat probe treatment (P = 0.33). Outcome as measured by clinical rebleeding (12 v 5), requirement for emergency operation (14 v 8), blood transfusion (2 v 3 units), hospital stay (4 v 4 days), ulcer healing at four weeks (79.1% v 74%), and in hospital mortality (7 v 8) were not significantly different in the two groups. In the subgroup of patients with spurting haemorrhage 8/27 (29.6%; 14.5% to 50.3%) patients from the adrenaline injection alone group and 2/31 (6.5%; 1.1% to 22.9%) patients from the dual treatment group required operative intervention. The relative risk of this was lower in the dual treatment group (0.17; 0.03 to 0.87). Hospital stay was significantly shorter in the dual treatment group than the adrenaline injection alone group (4 v 6 days, P = 0.01). CONCLUSION: The addition of heat probe treatment after endoscopic adrenaline injection confers an advantage in ulcers with spurting haemorrhage.     

In vitro study of rat uterus after chronic formaldehyde exposure.

To measure cholinergic, adrenergic and tryptaminergic receptor activity of formaldehyde (HCHO) in rat uterus, albino rats were treated with 5 and 10 mg/kg, ip HCHO for 30 days. Acetylcholine (ACh) in doses 1.33, 2 and 3 micrograms/ml produced mild to moderate contraction of isolated rat uterus in control group. HCHO had no effect on isolated rat uterus per se, however it reduced ACh and carbachol induced contraction and presence of adrenaline influences in respect of ACh and carbachol activity. Adrenaline per se had no effect in control preparations, but reduced carbachol induced contraction. Propranolol had no effect on rat uterus; but its presence in the bathing medium increased activity of adrenaline. 5-Hydroxytryptamine (5-HT) had no effect of its own on isolated rat uterus but its presence in the bathing medium enhanced contractions of carbachol and oxytocin.     

Biogenic amine regulation of bovine luteal progesterone production in vivo

Biogenic amines were administered using osmotic pumps placed subcutaneously in the neck region of regularly cycling, non-lactating dairy cows on Days 9-11 (oestrus = Day 0) of the oestrous cycle. Blood samples were collected using indwelling jugular catheters and the plasma progesterone concentrations were measured. Samples were collected at 4-h intervals for the first 12 h of treatment and thereafter at 12-h intervals for the remainder of the 72-h treatment period. After administration of various doses of noradrenaline, adrenaline and serotonin (0.5-2.0 micrograms/kg/h) significant elevation of plasma progesterone was achieved at a dosage of 2.0 micrograms/kg/h (P less than 0.01). The response to adrenaline was greater than that observed for noradrenaline and serotonin (P less than 0.05). Within-treatment comparison to pretreatment samples showed plasma progesterone concentrations to increase within 4 h after the administration of noradrenaline, adrenaline and serotonin (P less than 0.05) and this enhancement was maintained throughout the treatment period (P less than 0.05). The elevation in plasma progesterone concentrations induced by noradrenaline, adrenaline and serotonin was independent of changes in circulating concentrations of luteinizing hormone. These results support a physiological role for endogenous biogenic amines in the control of bovine luteal progesterone production.     

Biological significance of elevated TNF levels: In vivo administration of monoclonal antibody against TNF following haemorrhage shock increases the capacity of macrophages to release TNF while restoring immuno-responsiveness

Haemorrhagic shock results in a severe depression of the cellular and humoral immunity, thus rendering the host increasingly susceptible to sepsis. To study the effect of elevated TNF release following haemorrhagic shock on depressed macrophage and splenocyte functions, C3H/HeN mice were pretreated intraperitoneally with either anti-murine TNF-Ab or saline. Twenty hrs later, mice were bled to and maintained at a mean BP of 35 mmHg for 60 min followed by adequate fluid resuscitation. Pretreatment with anti-TNF-Ab completely neutralized elevated TNF plasma levels following haemorrhage. This was associated with an increased (P < 0.05) capacity of pMø isolated 24 h after haemorrhagic shock to release TNF, while the ability to secrete IL-6 and PGE₂ was reduced. Haemorrhagic shock-induced suppression of pMø antigen presentation capacity and MHC class II antigen expression, as well as depression of splenocyte proliferation and lymphokine production was also attenuated (P < 0.05) by anti-TNF-Ab pretreatment. These data indicate that elevated circulating TNF levels play a pivotal role in the depression of essential macrophage and splenocyte functions following haemorrhagic shock.     

Effect of small doses of naloxone on the pulsatile secretion of prolactin in the crossbreed ewe during the non-breeding season

The objective of this work was to study the effect of small doses of naloxone (Nx) on the pulsatile secretion of prolactin (Pr). For this purpose 12 crossbreed ewes were selected and allocated to three groups of four. Group 1 was treated with two injections (at 7 and 19 h) of 40 microg of GnRH. Group 2 was treated with two i.m. injections (at 7 and 19 h) of 0.5mg of naloxone. And the control group 3 was sham treated with injections of 3 ml saline. Blood samples were taken at 20 min intervals during six consecutive hours after injections. When ewes were treated at 7h no significant changes were observed in concentrations of prolactin following treatment with GnRH. Values fluctuated between 200 and 210 ng/ml. In group 2 treated with naloxone there was no change in plasma Pr concentrations during the first 100 min of sampling, however 60 min after Nx treatment Pr decreased significantly (p<0.01) and thereafter Pr plasma levels were consistently less (p<0.001) than control and GnRH treated ewes for the duration of the experiment. The response of the three groups after the second injection (19 h): After the injection of GnRH plasma Pr levels followed much the same pattern observed after the initial treatment, Pr concentrations were similar to those of control ewes. Ewes treated with a second small dose of naloxone (0.5mg i.m.) however, showed a decrease in plasma Pr 60 min after the administration of the endogenous opioid antagonist. Thereafter Nx treated ewes had lesser (p<0.001) plasma Pr levels until the termination of the experiment. It was concluded that Nx an opioid antagonist administered in small intermittent doses can alter Pr plasma concentrations in the ewe, showing that endogenous opioids are important modulators of endocrine function and that the administration of small intermittent doses of opioid antagonists produce significant endocrine changes in ewes.