A new canine model of endotoxin shock

A new canine model of endotoxin shock has been developed in which spontaneous recovery of cardiovascular function is largely prevented, the haemodynamic effects of anaesthesia are minimized and intravascular volume replacement is given. This model has been evaluated using two groups of five adult mongrel dogs anaesthetized with alpha-chloralose and breathing spontaneously. Animals in one group were anaesthetized, instrumented and given Escherichia coli (E. coli) endotoxin intravenously, whilst those in the control group were subjected only to anaesthesia and instrumentation. E. coli endotoxin was given to dogs in the shock group as a bolus dose of 5 mg kg-1 followed by a continuous infusion at 2 mg kg-1 h-1. This produced immediate, severe, cardiovascular depression, with precipitous falls in mean arterial pressure (MAP), cardiac index (CI), stroke index (SI) and left ventricular (LV) dp/dt max. There were associated increases in systemic and pulmonary vascular resistances. Arterio-venous oxygen content difference (C(a-v)O2) increased after induction of shock, and animals developed a progressive metabolic acidosis. Increasing haemoconcentration occurred, as evidenced by a rising haematocrit (PCV). Hypovolaemia was reflected by a concurrent fall in pulmonary capillary wedge pressure (PCWP). One hour after induction of shock, intravascular volume replacement was given in the form of a colloidal gelatin solution, as a bolus dose of 10 ml kg-1, followed by a continuous infusion at 10 ml kg-1 h-1. Volume replacement reversed haemoconcentration, restored PCWP and produced some haemodynamic improvement, although in general, severe cardiovascular depression persisted throughout a three hour observation period. This severe endotoxin shock model has proved to be stable, reproducible and economical.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of naloxone on corticosterone response to stress

The effect of naloxone on the corticosterone response to restraint stress was examined. Naloxone (8 mg/kg, IP) did not alter basal corticosterone or the magnitude of the corticosterone response to restraint stress. Naloxone did, however, retard the fall in corticosterone following the end of restraint stress; thus the drug prolonged the stress response. These data suggest that endogenous opiates play a role in the restoration of corticosterone levels back to normal after stress.     

Effect of naloxone on the cardiovascular and sympathetic response to hypovolemic hypotension in the rat

Conscious rats were exposed to acute hypovolemic-hypotension by bleeding (5 ml/300 g body weight). Treatment with the opiate antagonist naloxone (7 mg/kg intra-arterial) following hemorrhage resulted in an increase of systolic blood pressure but not heart rate. Changes in plasma catecholamine levels did not differ between control and naloxone-treated animals. From these results we suggest that the ability of naloxone to improve blood pressure after hemorrhage is not due to increased sympatho-adrenomedullary activity.     

Myocardial failure with altered response to adrenaline in endotoxin shock

1 There is a growing concensus that myocardial performance in the early stages of experimental endotoxic and septic shock is relatively normal; however, recent reports have identified an intermediate phase of shock when myocardial dysfunction is clearly apparent.

2 The mechanism of dysfunction has become a subject of intense investigation. A current view is that altered myocardial responsiveness to circulating catecholamines may play an important role in the dysfunction observed after endotoxin administration. The present studies, in which an isolated working heart preparation of the dog was used, were designed to test this hypothesis. This particular experimental preparation was selected to provide an adequate interpretation of results; cardiac output, afterload, and concentrations of adrenaline reaching the coronary vascular bed were controlled in all experiments. Responses to infusions of adrenaline were recorded in the `steady-state' condition. Control (non-shocked) heart responses to adrenaline were highly reproducible in terms of inotropic, chronotropic and coronary vascular behaviour.

3 Results from the study document myocardial dysfunction within 4-6 h following an LD₇₀ endotoxin administration on the basis of increased left ventricular end diastolic pressure (LVEDP), decreased cardiac power and myocardial efficiency, and depressed negative and positive dP/dt parameters.

4 Findings suggest significantly altered responsiveness of the myocardium to infused adrenaline at rates of 1, 2, and 5 μg/min with concentrations between 10 and 1 ng/ml blood. LVEDP was elevated while calculated power and efficiency parameters remained significantly below control values during infusion of adrenaline in endotoxin-treated hearts. Depressions of responsiveness were interpreted to occur on the basis of failure to restore positive and negative dP/dt to normal values and depressed coronary blood flow responses during adrenaline administration. Increases in coronary flow were regularly less in experimental hearts than the controls. Heart rate responses to adrenaline in both failing and non-failing hearts were identical.

5 In conclusion, it is suggested that myocardial contractile and relaxation characteristics and coronary vascular responses to adrenaline infusion are depressed in endotoxin shock during the period of demonstrated myocardial dysfunction. No distinct causal relationships were observed between the altered myocardial responsiveness and pathogenesis of heart dysfunction since myocardial dysfunction and altered responsiveness to adrenaline were generally observed together. Myocardial oedema formation after endotoxin as previously reported by this laboratory may bear a relationship to the depressed negative dP/dt response to adrenaline.

     

Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock.

1. The present investigation compares the effects of intravenous infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) with that of an inhalation with NO gas in a porcine model of endotoxin (lipopolysaccharide, LPS) shock. In addition, the effects of the combination of these two treatments were also investigated. 2. Male pigs were anaesthetized and instrumented for the measurement of haemodynamic parameters. Blood samples were withdrawn at different time intervals for determination of blood gases, pH, and plasma levels of nitrite/nitrate and tumour necrosis factor. 3. Endotoxin infusion (15 micrograms kg-1 h-1 for 3 h) caused a progressive fall in mean arterial blood pressure (MABP) and cardiac output (CO) and a biphasic increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR). A continuous infusion of L-NMMA (0.1 mg kg-1 min-1) significantly attenuated the fall in MABP, but did not affect MPAP, CO and PVR. NO-inhalation (50 p.p.m.) did not affect MABP, but significantly blunted the biphasic increase in MPAP and PVR and significantly delayed the fall in CO. The combination of L-NMMA infusion (0.1 mg kg-1 min-1) with NO-inhalation (50 p.p.m.) completely prevented the fall in MABP, significantly improved CO, and attenuated the biphasic increase in MPAP and PVR. 4. Endotoxin also caused a decline in PaO2 and a rise of PaCO2. Infusion of L-NMMA neither affected the fall in PaO2 nor the increase in PaCO2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beneficial effects of magnolol in a rodent model of endotoxin shock

Magnolol is a compound extracted from the Chinese medicinal herb Magnolia officinalis. It has multiple pharmacological effects, notably as an anti-oxidant. The aim of this study was to evaluate the effects of magnolol on sepsis induced by intravenous (i.v.) administration of lipopolysaccharide (LPS; 10 mg/kg) in anaesthetized Wistar rats. Magnolol (4 μg/kg, i.v.) was administered at 30 min after LPS injection. Post-treatment with magnolol significantly attenuated the deleterious haemodynamic changes (e.g., hypotension and bradycardia) caused by LPS. Meanwhile, magnolol significantly inhibited the elevation of plasma levels of tumor necrosis factor alpha, glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase and blood urine nitrogen caused by LPS. The induction of inducible nitrous oxide (NO) synthase and the overproduction of NO and superoxide anions by LPS were also significantly reduced by post-treatment with magnolol. Moreover, the plasma level of the thrombin-antithrombin complex following administration of LPS was also reduced by post-treatment with magnolol. Thus, the beneficial effects of magnolol on LPS-induced sepsis result from its anti-inflammatory, anti-coagulatory, and anti-oxidant effects.     

扩容和麻黄碱对老年病人全麻诱导期循环功能的影响

目的 讨论使用预先扩容或麻黄碱对老年手术病人全麻诱导期对低血压和低心输出量的预防作用.方法 将90位ASAⅠ～Ⅱ级65岁以上老年患者随机分为三组:对照组(n=30),诱导时不给麻黄碱或扩容;麻黄碱组(n=30):麻醉诱导前给予麻黄碱;扩容组(n=30):诱导前给予羟乙基淀粉扩容.观察患者入室时(T1)、诱导后1 min...     

Comparison of the cardiovascular effects of meptazinol and naloxone following haemorrhagic shock in rats and cats.

The cardiovascular effects of the opioid mixed agonist-antagonist, meptazinol, and the opioid antagonist, naloxone, have been evaluated in conscious rats, anaesthetized rats and anaesthetized cats following the induction of haemorrhagic shock. The mean arterial pressure of conscious rats decreased by 17-29 mmHg following a haemorrhage of 20% of blood volume. Meptazinol (17 mg kg-1, i.m.) administered after haemorrhage evoked a rapid and sustained increase in mean arterial pressure to pre-haemorrhage levels. Naloxone (10 mg kg-1, i.v.) also increased mean arterial pressure to a level significantly higher than post-haemorrhage values. Neither haemorrhage nor subsequent drug treatments evoked significant changes in the heart rates of conscious rats. In anaesthetized rats, 20% haemorrhage evoked decreases in mean arterial pressure, heart rate and cardiac output. Blood flow to the heart, skin, skeletal muscle, kidneys, spleen and liver (arterial) was decreased. Meptazinol and naloxone increased blood pressure and total peripheral resistance, but did not significantly alter heart rate or cardiac output. Hepatic arterial flow decreased further in both drug and vehicle treated groups. In addition meptazinol slightly reduced skeletal muscle flow. In anaesthetized cats 40% haemorrhage decreased mean arterial pressure by 46 +/- 3 mmHg. An intravenous infusion of either meptazinol or naloxone (cumulative 2 mg kg-1, i.v.) partially restored blood pressure. In experimental animal models of haemorrhagic shock, meptazinol has a similar cardiovascular profile to naloxone. The established analgesic activity of meptazinol may confer an advantage in some shock states.     

多巴酚丁胺对犬内毒素休克的影响

目的：研究多巴酚丁胺在内毒素休克时所的作用。方法选用成年杂种犬１２只,随机分成２组,第一组（ｎ＝６）用２５０μｇ／ｋｇ持续静注内毒素３０分钟。第二组（ｎ＝６）除用同样的方法静注内毒素外,从第１２０ｍｉｎ起按１０μｇ．ｋｇ＾－１ｍｉｎ＾－１持续输注多巴酚丁胺至实验结束。两组动物从开始到结束,每隔半小时测定一次ＭＡＰ、ＣＶＰ、ＭＰＡＰ、ＰＡＷＰ、ＨＲ和ＣＯ,并计算出ＳＩ,ＳＶＲＩＰＶＲＩ,ＤＯ２,ＶＯ     

Decrease by naloxone of some electrocardiographic and biochemical changes following endotoxin induced shock in rats

Administration of endotoxin, a lipopolysaccharide extracted from cell walls of gram negative bacteria, elicited alterations in various metabolic parameters and in the electrocardiogram of rats. Cardiac glycogen and serum glucose were decreased, while serum pyruvate and acid phosphatase levels were increased. There was initial tachycardia followed by significant bradycardia and elevation of the ST segment in the animals with shock. Erythrocyte count, haemoglobin and haematocrit were not changed after shock. Treatment with naloxone caused significant decreases in the metabolic and electrocardiographic changes induced by endotoxin.     

Effects of florfenicol on early cytokine response and survival in a murine septic shock model

氟苯尼考对内毒素休克小鼠生存率和细胞因子的影响@张雪梅$Department of Pharmacology, College of Animal Science and Veterinary Medicine, Jilin University!Changchun 130062, Jilin, China;Department of Animal Medicine, Agricultural College of Yanbian University,     

The effect of sodium bicarbonate on propranolol-induced cardiovascular toxicity in a canine model

STUDY OBJECTIVE: To evaluate the potential utility of sodium bicarbonate in an established model of acute propranolol toxicity. METHODS: Two minutes after the completion of a propranolol infusion (10 mg/kg), a bolus of 1.5 mEq/kg of sodium bicarbonate solution (1 mEq/mL) followed by an infusion of 1.5 mEq/kg over the next 26 minutes (n = 6) or an equivalent timing and volume of 5% dextrose solution (n = 6) was administered in each dog. Targeted cardiovascular parameters included heart rate, mean arterial pressure, left ventricular dP/dtmax, and QRS interval. RESULTS: Propranolol infusion significantly depressed heart rate (p < 0.0001), mean arterial pressure (p < 0.0001), dP/dtmax (p < 0.0001) and prolonged the QRS interval (p < 0.0001). Sodium bicarbonate failed to significantly improve these targeted parameters when compared to control animals. CONCLUSION: In this canine model of propranolol toxicity, intravenous sodium bicarbonate appears to be an ineffective single therapy. Furthermore, these results may suggest a different mechanism of sodium channel blockade for propanolol than that of type IA antiarrhythmic agents.     

Supranormal natriuretic response to volume expansion in vagotomized and renal-denervated rats

1. To investigate the participation of both vagal cardiopulmonary baroreceptor activity and efferent renal sympathetic nerve activity (ERSNA) in the natriuretic response to saline volume expansion (SVE), three series of experiments were undertaken in anaesthetized rats. 2. In the first two series of experiments, the natriuretic (series A) and ERSNA (series B) responses to SVE were evaluated in both sham operated and cervical bilateral vagotomized rats. The acute experiment consisted of two baseline (BL) periods, treatment (sham control (CTR) or real cervical bilateral vagotomy), a volume expansion phase (Ringer's solution, 10% bodyweight) and a postexpansion phase. The results of these two series indicate that vagotomy significantly enhances basal ERSNA (37 +/- 8%; P < 0.05 vs BL) and significantly attenuates the renal sympathoinhibitory response (by approximately 50%; P < 0.05 vs CTR) but not the natriuretic response to SVE, suggesting the potential expression of a vagotomy induced compensatory natriuretic mechanism. 3. To assess this, the natriuretic response to SVE was evaluated in chronic sham operated or renal denervated groups of rats in which vagotomy was or was not performed (series C). There were no differences among groups in either systemic haemodynamics or plasma protein concentration. Vagotomy plus chronic renal denervation induced a supranormal natriuretic and diuretic response (approximately 30%; P < 0.01) to SVE when compared with similar natriuretic and diuretic responses of the remaining groups. 4. These data support the idea that, in intact rats on a normal sodium diet, neither cardiopulmonary baroreceptors nor renal nerves are necessary for the elimination of an acute intravenous isotonic sodium load and indicate that during SVE the activation of vagal cardiopulmonary baroreceptors exerts an inhibitory effect on both ERSNA and the expression of a natriuretic mechanism. Such a natriuretic mechanism is expressed only when SVE is induced in vagotomized rats (compensating for the vagotomy mediated antinatriuretic effects of an enhanced ERSNA), but is unmasked only when, in addition, renal nerves are chronically transected. All of this offers an efficient element of safety in eliminating an acute isotonic sodium load when cardiopulmonary baroreceptors are severed.     

Effects of a cytokine inhibitor, JTE-607, on the response to endotoxin in healthy human volunteers

It is generally regarded that the excessive production of cytokines plays an important role in the pathology of autoimmune diseases and septic shock. We have investigated the ability of JTE-607, a novel inhibitor of cytokine production, to modulate the inflammatory response to endotoxin in healthy human volunteers. Three cohorts of healthy male volunteers were recruited for a randomized, placebo-controlled, double-blind study. Within each cohort, 6 subjects received a single 8-hour intravenous infusion of JTE-607 (either 0.03, 0.1 or 0.3 mg/kg/h) and 3 subjects received a placebo infusion. Two hours after the start of the JTE-607 infusion, all subjects received a 30 unit/kg bolus infusion of endotoxin. JTE-607 administration resulted in the decrease in endotoxin-induced IL-10 production with mean % difference from placebo of − 79.5% (P = 0.040) and − 86.2% (P = 0.026) at 0.1 and 0.3 mg/kg/h dose, respectively. The production of endotoxin-mediated interleukin (IL)-1 receptor antagonist was significantly inhibited at 0.3 mg/kg/h dose with mean % difference from placebo of − 60% (P = 0.0037). Endotoxin-induced C-reactive protein decreased with the increasing dose of JTE-607 with mean % difference from placebo of − 32.1% (P = 0.322), − 82.9% (P = 0.0001) and − 90.3% (P < 0.0001) at 0.03, 0.1 and 0.3 mg/kg/h dose, respectively. In conclusion, this study describes a cytokine modulator JTE-607, which inhibits production of IL-10, IL-1ra and C-reactive protein in a human model of endotoxemia.     

Effects of naloxone on pethidine-induced neonatal depression. Part I--Intravenous naloxone.

Infants whose mothers had had pethidine during labour were given either naloxone 40 microgram or isotonic saline administered intravenously double-blind within one minute of birth. Peak alveolar carbon dioxide tension, carbon dioxide excretion, alveolar ventilation, feeding behaviour, and habituation to a specific sound stimulus were measured regularly up to 48 hours after birth. Alveolar carbon dioxide tension was significantly lower and alveolar ventilation significantly higher half an hour after birth in the naloxone-treated group than in the saline-treated group, but these differences between the groups were not significant at any other time, and there were no significant differences in sucking frequency or pressure, milk consumption, or habituation to the auditory stimulus.     

Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock.

1. This study investigates the role of tumour necrosis factor (TNF) in the induction of nitric oxide synthase (NOS) by bacterial endotoxin (lipopolysaccharide; LPS) in a rat model of endotoxin shock. 2. In anaesthetized rats, pretreatment with a monoclonal antibody for TNF (TNFab; 20 mg kg-1, s.c., at 16 h prior to LPS) ameliorated the fall in mean arterial blood pressure (MAP) in response to LPS (2 mg kg-1, i.v.). For instance, endotoxaemia for 180 min resulted in a fall in MAP from 114 +/- 6 (control) to 84 +/- 5 mmHg (P < 0.01; n = 7). In contrast, animals pretreated with TNFab prior to LPS injection maintained significantly higher MAP when compared to LPS-control (MAP at 180 min; 118 +/- 3 mmHg; P < 0.01, n = 5). 3. Three hours of endotoxaemia was also associated with a significant reduction of the contractile effects of noradrenaline (NA) (10(-8)-10(-6) M) on the thoracic aorta ex vivo. This hyporeactivity to NA was partially restored by in vitro treatment of the vessels with NG-nitro-L-arginine methyl ester (L-NAME, 20 min, 3 x 10(-4) M). Pretreatment of rats with TNFab (20 mg kg-1; at 16 h prior to LPS) significantly (P < 0.05) attenuated the LPS-induced hyporeactivity of rat aortic rings ex vivo. L-NAME did not enhance the contractions of aortic rings obtained from TNFab pretreated LPS-rats. 4. At 180 min after LPS there was a significant elevation of the induced NOS activity in the lung (5.14 +/- 0.57 pmol citrulline mg-1 min-1, n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of NG-nitro-L-arginine methyl ester on the cardiovascular system of the anaesthetized rabbit and on the cardiovascular response to thyrotropin-releasing hormone.

1. The effects of 300 mg kg-1 of the nitric oxide (NO) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on the regional blood flow, on the flow response to 1 mg kg-1 of thyrotropin-releasing hormone (TRH) and on cerebral blood flow autoregulation were studied in urethane anesthetized rabbits subjected to unilateral sectioning of the cervical sympathetic claim. The blood flow measurements were performed by the tracer microspheres method. 2. The cerebral arteriovenous difference in oxygen saturation (CAVOD) was measured before and after the administration of L-NAME and TRH in order to ascertain whether the effects on cerebral blood flow that were observed were secondary to changes in cerebral metabolism. 3. L-NAME caused a significant decrease in blood flow in several cerebral regions; CBFtot decreased to 72 +/- 4% of control (P < 0.001). An increase in blood pressure and a concurrent decrease in heart rate and cardiac output were noted. 4. In the eye, L-NAME caused a reduction in uveal blood flow which was more pronounced on the sympathetically intact side; in the retina the blood flow decreased to 50% of control on both sides. 5. The administration of TRH in animals pretreated with L-NAME caused a significant increase in blood pressure and cerebral blood flow. 6. In L-NAME-treated animals the CBF was not affected when the mean arterial blood pressure was increased by ligation of the abdominal aorta. 7. The CAVOD increased from 56.0 +/- 5.2 to 73.6 +/- 3.5%, 20 min after the administration of L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)     

A mechanistic model for the sex-specific response to nalbuphine and naloxone in postoperative pain

We develop a mechanistic model for post-operative pain and apply it to describe the pharmacodynamic effects of the kappa-opioids nalbuphine and naloxone administered either alone or in combination in patients after surgical removal of one or more madibular third molar teeth. Data were obtained from 6 clinical studies in which a total of 304 patients were intravenously administered single doses of 2.5, 5, 10 or 20 mg of nalbuphine. Some groups also received 0.2 or 0.4 mg of naloxone. A total of 3,040 Visual analog scale (VAS) pain ratings were recorded at 20 min intervals for 3 h after drug administration. We used a two-site indirect action model to describe early and late pain and to incorporate the effect of nalbuphine and naloxone on pain over time. A mixed effects statistical model was used to account for inter- and intra-individual variability. Our model estimated the population average baseline pain score in men to be lower than that in women (68 vs. 76 mm on the 100 mm VAS scale). The model confirmed a late increase in pain (anti-analgesia) and estimated the lag time for the start of anti-analgesia to be 73 min after study drug administration. The maximum early phase pain score is 81.6 mm while the maximum anti-analgesia is 16.1 mm. The nalbuphine dose required to reduce early pain by 50% (ED₅₀) was estimated to be 5.85 mg and the naloxone dose required to reduce late phase pain by 50% was estimated to be 0.5 mg. The model confirmed the results from conventional statistical analyses performed previously on individual studies.     

Mechanism of the protective effects of prostaglandins E1 and F2 alpha in canine endotoxin shock

Prostaglandins E₁ (PGE₁) and F_2α (PGF_2α) were studied for their ability to alter the course of a standardized endotoxin shock procedure in dogs. 3 hr after the administration of E. coli endotoxin, mean arterial blood pressure (MABP) was reduced 44% and cardiac output (CO) 60%. At this time plasma activities of the lysosomal protease, cathepsin D, increased 670%, and of a myocardial depressant factor (MDF), 310%. Dogs treated with PGF_2α had consistently higher MABP and CO, while plasma cathepsin D and MDF activities were moderately elevated. In addition, post-endotoxin survival was significantly improved. PGE₁-treated dogs exhibited a higher MABP and CO, while plasma cathepsin D and MDF activities were only slighly elevated, and survival time increased (p < 0.005). Furthermore, PGE₁, but not PGF_2α markedly reduced the rate of release of proteases from isolated hepatic and pancreatic lysosomes subjected to thermal activation. An enhanced release of splanchnic proteases appears to lead to the formation of MDF, a peptide involved in the pathophysiology of endotoxin shock. Prostaglandin E₁ may protect in endotoxin shock by suppressing the release of lysosomal proteases and the subsequent formation of MDF, whereas PGF_2α may protect either by circulatory support or by some secondary mechanism for preventing the release of lysosomal enzymes.     

The effects of meptazinol in comparison with pentazocine, morphine and naloxone in a rat model of anaphylactic shock.

The actions of meptazinol, pentazocine, morphine and naloxone on the cardiovascular changes accompanying anaphylactic shock were evaluated in ovalbumin-sensitized anaesthetized rats. Pretreatment with meptazinol and pentazocine prevented the fall in mean arterial pressure associated with antigen challenge, whereas morphine and naloxone attenuated but did not completely prevent, this change. None of the drugs significantly altered the antigen-induced decreases in heart rate. All the drugs partially reversed the fall in mean arterial pressure when given after antigen challenge although the activity of naloxone was less marked. Pretreatment with reserpine prevented the restoration of blood pressure by all drugs. Additional experiments with meptazinol showed that pretreatment with phentolamine prevented its pressor action. In pithed non-sensitized rats the frequency-pressor response curve to splanchnic stimulation was shifted to the left by meptazinol and shifted to the right by pentazocine, but the changes were small Morphine and naloxone had no significant effects. It was concluded that opioid mixed agonist-antagonists reverse the cardiovascular changes associated with anaphylactic shock. These effects appear to be mediated by facilitation of sympathetic neurotransmission.