缓激肽对兔血浆、组织丙二醛含量及超氧化物歧化酶活性的延迟性影响

目的 :观察缓激肽 （BK）对血浆、组织超氧化物歧化酶 （SOD）活性的影响 ,探讨 BK对心肌保护作用的机制。方法 :采用兔缺血再灌注模型 ,分别给予缺血再灌注、缺血再灌注加 BK、缺血再灌注加 BK及 HOE140处理。测定处理后 2 4h的血浆、组织丙二醛 （MDA）含量及 SOD的活性。结果 :与对照组相比 ,BK组 MDA含量明显降低 ,Mn SOD活性明显升高。结论 :BK能够增强 2 4h后兔血浆、组织 SOD活性 ,从而对缺血再灌注心肌具有保护作用。     

Effects of angiotensin II on the cardiac responses to sympathetic nerve stimulation in dogs

In anesthetized dogs with the left cardiac sympathetic nerves and both vagal nerves intact, angiotensin II (AII) induced a substantial, dose-dependent increase in arterial blood pressure and small increments in cardiac cycle length and ventricular contractile force. In dogs in which the cardiac sympathetic and vagal nerves had been interrupted, AII produced similar increases in blood pressure and larger increases in contractile force, but it decreased the cardiac cycle length. In both groups of dogs, AII augmented substantially the positive inotropic responses to sympathetic nerve stimulation, but it enhanced the positive chronotropic responses only slightly. However, AII did not appreciably prolong the cardiac responses to sympathetic nerve stimulation, nor did it alter significantly the cardiac responses to norepinephrine infusions. Hence, at the dosage levels used, AII probably did not inhibit the neuronal uptake of norepinephrine appreciably nor did it enhance the responsiveness of the cardiac effector sites to norepinephrine. Therefore, the potentiation of the cardiac responses to sympathetic nerve stimulation by AII in these experiments was probably achieved principally by facilitating norepinephrine release from the adrenergic nerve terminals in the heart.     

Portal hypertensive response to bradykinin in inflamed or cirrhotic rat livers is mediated by B2-type receptors

BACKGROUND: We have shown that the portal hypertensive response to bradykinin in normal rats is mediated by B2 receptors. METHODS: By using isolated and exsanguinated rat liver perfusion, we studied the portal hypertensive response to bradykinin or des-Arg9-bradykinin (B1 agonist) in inflamed or cirrhotic rat livers. Livers were perfused with bovine serum albumin Krebs-Henseleit buffer (pH 7.4; 37 degrees C) at a constant flow rate, in the absence or presence of des-Arg9[Leu8]-bradykinin or HOE 140 (B1 and B2 receptor antagonists, respectively). Bradykinin (140 nmol) or des-Arg9-bradykinin was injected as a bolus via the afferent route to the liver. RESULTS: Basal perfusion pressure in liver-cirrhotic rats was higher than in normal rats. In normal, inflamed, or liver-cirrhotic rats, the presence of the B1 antagonist did not change the portal hypertensive response to bradykinin, while the B2 antagonist abolished this response. A 140-nmol dose of des-Arg9-bradykinin did not change the perfusion pressure; 700 nmol of this B1 agonist produced an insignificant perfusion pressure increase. The perfusion pressure increase induced by bradykinin in cirrhotic livers was lower than in normal livers. CONCLUSIONS: The portal hypertensive response to bradykinin in inflamed or cirrhotic rat livers is mediated by B2 receptors, but not B1 receptors, and there is a contracting hyporeactivity to bradykinin in cirrhotic rat livers.     

The effects of cocaine and metanephrine on the cardiac responses to sympathetic nerve stimulation in dogs.

The effects of infusions of cocaine (COC) and metanephrine (MET) on the inotropic and chronotropic responses to cardiac sympathetic nerve stimulation were studied in open-chest, anesthetized dogs. COC blocks the neuronal uptake of norepinephrine (NE), whereas MET blocks the extraneuronal uptake. Both blocking agents slightly enhanced the inotropic but not the chronotropic responses. COC prolonged the cardiac responses significantly, particularly the chronotropic responses, whereas MET had no appreciable effect on the durations of these responses. Hence, it appears that the neuronal uptake mechanism plays a major role in the dissipation of neurally released NE in the heart, but that the extra-neuronal uptake mechanism plays only a minor role in its dissipation. In contrast to the results in certain other tissues, the combined effects of COC and MET on the cardiac responses were no greater or more prolonged than the sum of the effects produced by each agent acting alone.     

组织型激肽释放酶对脑缺血再灌注大鼠缺血脑组织缓激肽及其受体表达的影响

目的 探讨组织型激肽释放酶(tissue kallikrein,TK)对脑缺血再灌注大鼠缺血脑组织缓激肽、缓激肽B1受体(bradykinin B1 rgceptor,B1R)和缓激肽B2受体(bradykinin B2 receptor,B2R)表达的影响.方法 54只SD大鼠随机分为3组,每组18只.3组分别为假手术组;生理盐水(normal saline,NS)处理组(Ns组):NS 2 ml/(kg·d),连用3 d;TK(处理组(TK组):TK 17.5×10-3U/(kg·d),连用3 d.3 d后分别进行神经功能缺损评分、脑梗死体积测定.酶联免疫吸附法检测缺血区缓激肽含量;采用逆转录聚合酶链反应和Western印迹法分别检测缺血脑组织B1R、B2R mRNA和蛋白表达.结果 与NS组比较,TK组神经功能缺损显著减轻[(6.17±1.17)分对(8.17 4±1.33)分,t=2.000,P=0.004],脑梗死体积明显缩小[(29.67±3.78)%对(37.50±6.72)%,t=0.078,P=0.005];缺血脑组织缓激肽含量升高[(9.25 4±1.13)对(15.53±1.68),t=6.283,P:0.000];B2RmRNA表达显著上调[(1.21±0.17)对(2.15±0.20),t=0.943,P=0.000),而B1R mRNA表达上调不明显[(0.51±0.05)对(0.57±0.06),t=0.058,P=0.141)];B2R蛋白表达显著上调[(1.15±0.16)对(1.88 4±0.21),t=0.737,P=0.0001,B1R蛋白表达上调不明显[(0.50±0.04)对(0.53±0.05),t=1.326,P=0.214].结论 TK 对脑缺血再灌注大鼠具有保护作用,能使缺血脑组织缓激肽含量增高,B2R表达上调,而对B1R表达影响不大.由此推测,B2R在TK保护缺血脑组织中发挥着主要作用.     

Effect of nipradilol on silent myocardial ischemia,plasma beta-endorphin,and bradykinin in chronic stable angina

Hypothesis: This study was undertaken to investigate the effect of nipradilol on the total ischemic burden and on plasma levels of beta-endorphin and bradykinin. Methods: Sixteen patients with chronic stable angina were subjected to exercise treadmill testing and 24-h ambulatory electrocardiogram (ECG). Results: Nipradilol significantly decreased both mean heart rate and mean pressure rate product at submaximal and maximal exercise. It significantly improved exercise-induced maximal ST-segment depression from ?2.7 ± 0.5 mm to ?1.3 ± 0.6 mm (p<0.05) and reduced the number of leads with significant ST-segment depression (4.0 ± 1.2 vs. 2.0 ± 1.8, p<0.05). Silent ischemic episodes recorded in 24-h ambulatory ECG were significantly decreased by nipradilol administration, concomitantly with a decrement of mean heart rate and observed maximal heart rate. Patients with exercise-induced silent myocardial ischemia showed significantly increased plasma levels of beta-endorphin during both the placebo and nipradilol phases of the study. However, during the nipradilol phase, bradykinin did not change significantly at rest and at peak exercise. Conclusion: Nipradilol effectively controls exercise-induced myocardial ischemia and silent myocardial ischemic episodes, and does not influence the response of plasma levels of beta-enduced silent myocardial ischemia.     

Reflexogenic neuronal and humoral responses to selective stimulation of low-pressure cardiopulmonary receptors in man.

This study was conducted to determine the relative importance of efferent muscle sympathetic nerve activity (MSA), vasopressin (ADH) and atrial natriuretic peptide (ANP) in the short-term neurohumoral response to moderate changes in low-pressure cardiopulmonary receptor activity. The low-pressure receptors were stimulated and unloaded, respectively, by autotransfusion of blood (450 ml) and the application of lower body negative pressure (LBNP, -20 mmHg), and in 11 healthy men we measured MSA in the left peroneal nerve, indirect blood pressure, ECG, central venous pressure (CVP) and venous plasma concentrations of ANP and ADH (radioimmunoassay). Total MSA rose by 30% during LBNP and decreased during a rapid autotransfusion of blood, and the changes in MSA were significantly related to changes in CVP. The plasma concentrations of ADH and ANP were not significantly affected by either procedure. It is suggested that during moderate short-term changes in venous return, MSA responded more rapidly and/or at a lower threshold than the ADH and ANP systems.     

Effect of acute hypoxia on cardiac function in alloxan-diabetic dogs

Summary The aim of the present study was to examine the left ventricular and haemodynamic parameters during acute hypoxia induced by carbon monoxide intoxication and/or after norepinephrinc administration in metabolically healthy and alloxan-diabetic dogs. In metabolically healthy animals after carbon monoxide intoxication followed by norepinephrine administration myocardial oedema occurred with a concomitant elevation of diastolic stiffness in the left ventricular wall, resulting in impaired cardiac performance. In the alloxan-diabetic animals no myocardial oedema developed and therefore no further increase of the originally elevated left ventricular diastolic stiffness could be observed. Close correlations were demonstrable between the enhanced water content and diastolic stiffness of the left ventricular wall in metabolically healthy animals as well as between the myocardial contractile force and cardiac output index in both control and diabetic dogs. In contrast to the controls, following norepinephrine administration per se decrease of cardiac performance could be observed in the alloxan-diabetic animals. Based on these results, it can be concluded that an increase of left ventricular diastolic stiffness impairs the cardiac performance in acute hypoxia following norepinephrine administration both in control and in diabetic animals, even if different reasons are responsible for it.     

极化液给予时机对缺血/再灌注犬心脏功能及心肌损伤的影响

目的:探讨不同时间开始给予极化液（葡萄糖-胰岛素-钾液,G IK）对犬心肌缺血/再灌注（M I/R）后心脏功能及心肌细胞损伤的影响。方法:制备犬M I/R模型,心肌定量缺血（左前降支血流量降低80%）50 m in,再灌注4 h。分别于:①再灌注前30 m in（再灌注前）、②再灌注即刻（再灌注时）、③再灌注后1 h（再灌注后）给予G IK。观察对动脉血压、心率、左室压的影响及测定心大静脉血清乳酸脱氢酶（LDH）、肌酸激酶（CK）活性,再灌注结束后检测心肌梗死率或细胞凋亡指数。结果:与再灌注后组相比,再灌注前组和再灌注时组可明显改善再灌注后左室收缩及舒张功能,降低血清CK、LDH活性,减少心肌梗死范围[分别为（5.9±1.1）%和（5.2±0.8）%vs（9.1±1.2）%,均P<0.01]、抑制心肌细胞凋亡的发生[（4.6±0.9）%和（3.7±1.1）%vs（8.9±2.3）%,均P<0.05]。结论:再灌注早期给予G IK可降低M I/R引起的心肌细胞损伤,促进再灌注后心脏功能的恢复,在再灌注后1 h给予G IK对心脏的上述保护作用则明显减弱。     

Diuretic and Natriuretic Responses to Anf in the Presence and Absence of Renal Nerves in Doca-Salt Hypertensive Rats

To determine if renal nerves contributes in the renal response to atrial natriuretic factor (ANF) in DOCA-salt hypertensive rats, diuretic and natriuretic responses to ANF were measured in Inactin (0.1 g/kg, i.p) anesthetized rats with unilateral renal denervation. Rats were assigned to either a control group (108±6 mmHg), or one of two DOCA-salt groups (injected with deoxycorticosterone acetate, DOCA, 25 mg/week, and given 0.9% saline to drink for 4 weeks); a) DOCA-salt group (137±6 mmHg) and b) DOCA-salt-BPC group (with blood pressure controlled at the level of the femoral artery (102±3 mmHg) by an occluder on the abdominal aorta proximal to the right renal artery). Urine flow and sodium excretion in response to ANF infusion (0.3 μg/min/kg) were measured from intact and denervated kidneys of control and DOCA-salt treated rats.

ANF infusion produced a significant increase in diuresis and natriuresis in all three groups of rats. Urine flow and sodium excretion in response to ANF were significantly less in the intact kidney but not the denervated kidneys of the DOCA-salt rats compared to control rats. These results indicate that renal nerves contribute to the blunted renal responses to ANF in DOCA-salt rats. Renal responses also were significantly smaller in both intact and denervated kidneys of DOCA-salt-BPC rats (in which arterial pressure was reduced) compared to DOCA-salt rats. Overall, these results indicate that both renal nerves and arterial pressure determine the natriuretic and diuretic actions of ANF in DOCA-salt hypertensive rats.     

Evaluation of changes in epicardial blood flow in experimental animals by cardiothermography

When exposed to ambient air, the heart loses heat and its epicardialtemperature becomes mainly perfusion dependent. Cardiothermographywas used in this study to identify the extent and degree ofepicardial cooling following reduction of coronary blood flowin 21 open chested dogs. The cold-ischemic area was easily identifiedby the dark color, reflecting lower epicardial temperature.Differences in temperature could be accurately identified (±0.2 °C) by isotherm analysis. Six unipolar ECG electrodeswere sutured to the epicardium 2–3 mm apart, between thenormal and the ischemic zone. Following complete occlusion ofthe left anterior descending coronary artery (LAD), a cold areawas detected within 11.7 ± 2.3 s. Within 60 s the ischemicarea reached its maximum size. Myocardial cooling was 2.0 ±0.4 °C from control state and reached its lowest value within2 min. The zone of myocardial cooling corresponded preciselyin all dogs with the ischemic area detected by ECG. ST elevationat the border of the ischemic zone was 4.5 ± 2.0 m Vwhile toward the ischemic zone it was 14.1 ± 4.6 m V.Cooling of the epicardium was seen when coronary blood flowwas reduced beyond 40–50%; this coincided with the ECGST elevation. Further decrease of coronary blood flow increasedthe size of the ischemic area. Between 70–100% of coronaryblood flow reduction, the size of the ischemic zone did notchange although there was a slight further drop in the temperatureat complete occlusion. The capability of cardiothermographyto detect changes in the size of the ischemic area was testedunder two interventions. Hypotension, induced by bleeding, causeda marked increase in the size of the cold-ischemic area in fourdogs after LAD occlusion, while elevation of blood pressureafter LAD occlusion induced by methoxamine caused a decreasein the size ofischemic area in six out of eight dogs studied.It is concluded that changes in epicardial temperature are usefulindicators of myocardial ischemia, and that cardiothermographycan assess the degree and extent of myocardial ischemia in experimentalanimals.     

Coronary collaterals: Role in restoration of blood flow and preservation of cardiac function during exercise

Summary Chronically instrumented dogs were studied at rest and during exercise on two occasions 10–12 weeks apart. The left circumflex coronary artery (LCf) was initially constricted in all dogs. By the time of the second study the LCf was still patent in 9 dogs and had become occluded in 6. In the dogs with chronic coronary occlusion, collaterals restored myocardial flow to normal both at rest and during exercise, and there were no adverse hemodynamic effects when running. Conversely, in dogs with constricted but patent LCfs collateral development was inadequate to return ischemic flows to normal following transient coronary occlusion, and occlusion during exercise produced significant myocardial failure. Thus coronary collaterals can compensate for decreased antegrade coronary flow.This study was supported by National Heart, Lung and Blood Institute Grant HL-17809.     

Metabolic and haemodynamic responses to adrenaline in normal dogs

Summary The metabolic and haemodynamic effects of adrenaline were investigated in 6 intact anaesthetized dogs, which were subjected to an infusion of adrenaline. The dose given was similar to the endogenous production rate of adrenaline in experimental myocardial infarction. Adrenaline infusion (0.8, 1.17 or 1.05g · kg^–1. min^–1) over two hours led to a variable rise in blood level of this amine, regardless of the rate of infusion. Dogs with high blood adrenaline (over 3.5 ng·ml^–1) exhibited haemodynamic deterioration, i.e a rise in peripheral vascular resistance together with a fall in cardiac output and external cardiac work. Dogs with low blood adrenaline showed little change in peripheral vascular resistance, a rise in cardiac output and external cardiac work. The myocardial consumption of each of the substrates lactate, pyruvate, glucose and FFA was measured, and its equivalent oxygen consumption expressed as a percentage of the total myocardial oxygen consumption. No relationship was found between myocardial utilisation of individual substrates and the type of haemodynamic response. Thus in intact dogs exposed to adrenaline excess, similar to that found in acute myocardial infarction, the different types of haemodynamic response cannot be attributed to the type of substrate utilization by the myocardium, but to different rates of clearance of adrenaline. Low clearance rates lead to high blood adrenaline levels and an unfavourable response of the cardiovascular system.

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Zusammenfassung An 6 narkotisierten Hunden wurden die metabolischen und hämodynamischen Auswirkungen einer Adrenalin-Infusion untersucht. Die Dosierung stimmte weitgehend mit der endogenen Produktionsrate von Adrenalin bei experimentellem Herzinfarkt überein. Eine Adrenalin-Infusion (0,8; 1,17 oder 1,05 g/kg) über 2 Stunden führte zu einem variablen Anstieg des Blutspiegels von Adrenalin. Hunde mit einem hohen Blutspiegel (über 3,5 g · kg^–1 · min^–1) zeigten hämodynamische Störungen, d. h. einen Anstieg des peripheren Widerstandes, verbunden mit einem Abfall des Herzminutenvolumens und der äußeren Herzarbeit. Hunde mit niedrigem Blutspiegel zeigten nur geringe Änderungen des peripheren Widerstandes sowie einen Anstieg des Herzminutenvolumens und der äußeren Herzarbeit. Der myokardiale Verbrauch der Substrate Laktat, Pyruvat, Glucose und freie Fettsäuren wurde gemessen und der äquivalente Sauerstoffverbrauch als Prozentsatz des gesamten myokardialen Sauerstoffverbrauchs ausgedrückt. Es wurde keine Beziehung zwischen myokardialer Utilisation der einzelnen Substrate und der Art der hämodynamischen Reaktion gefunden. Ähnlich wie beim akuten Myokardinfarkt können auch bei Hunden unter starkem Adrenalineinfluß die verschiedenen hämodynamischen Reaktionstypen nicht auf die Art der Substratutilisation im Myokard bezogen werden, sondern auf unterschiedliche Geschwindigkeiten der Adrenalin-Elimination. Niedrige Eliminationsgeschwindigkeit führt zu hohen Adrenalinblutspiegeln und ungünstigen Reaktionen des kardiovaskulären Systems.

     

Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury

Vagal nerve stimulation (VS) has been reported to improve the survival after both acute and chronic myocardial infarction through the release of neurotransmitter ACh. However, the precise mechanism behind its beneficial effect is still unknown. In this study, we demonstrate the upregulation of tumor necrosis factor-alpha (TNF-α) and its cell survival TNF receptor-2 (TNFR2) as the mechanism behind VS induced myocardial protection.We investigated the effects of efferent VS on myocardial ischemic injury with in vivo and in vitro mouse models. In in vivo hearts VS significantly increased the expression of TNF-α both at the messenger and protein level after 3-hours of myocardial ischemia. In the in vitro studies ACh treatment before hypoxia, induced a significant upregulation of TNF-α compared to the untreated cardiomyocytes. Immunofluorescence analysis confirmed the synthesis of TNF-α by cardiomyocytes both in vivo and in vitro. VS also significantly reduced the myocardial infarct size (23.9 ± 5.7% vs. 56 ± 1.9%) and activated the cell survival Akt cascade system. Further, ACh upregulated the cell survival TNFR2 expression, while downregulating the cell destructive TNF receptor 1 (TNFR1) expression. These results were confirmed using the TNF receptors deficient mice, where the VS mediated protection was lost both in vivo and in vitro in TNFR2 (TNFR2^-/-) and TNF receptors double knock out (TNFR1^-/-2^-/-) mice.VS and ACh protects the heart against acute ischemia or hypoxic injury by differentially regulating the TNF receptor subtypes.     

氯化锂毛果芸香碱癫痫鼠模型B1与B2激肽受体表达研究

目的检测B1与B2激肽受体在氯化锂毛果芸香碱致癫痫鼠模型海马中的表达变化并探讨其作用机制。方法选择清洁雄性Wistar大鼠35只，随机分为空白对照组5只；实验组15只，将氯化锂毛果芸香碱腹腔注射法制作癫痫模型，分为6h，5、60天时间点，每时间点5只；生理盐水对照组15只，腹腔注射剂量相等的生理盐水，按实验组相应的时间点，每时间点5只。相应时间点处死大鼠取海马标本，应用RTPCR方法检测海马齿状回、CA1、CA3区的B1与H2激肽受体的表达变化，并进行组间比较。结果6h、5天时间点实验组较生理盐水对照组B1激肽受体mRNA表达均显著上调，差异有显著性意义（P〈0．05），60天时差异无显著性意义（P〉0．05）；实验组各时间点均较60天生理盐水对照组B2激肽受体mRNA表达显著上调，差异有显著性意义（P〈0．05）；生理盐水对照组与空白对照组比较，B1与B2激肽受体mRNA表达差异无显著性意义（P〉0．05）。结论B1与B2激肽爱体tuRNA表达失衡在癫痫的发生、发展过程中可能起着重要的作用。     

Thermomechanical facilitation of swallowing evoked by electrical nerve stimulation in cats

Application of a cold metal probe to the anterior faucial pillar has been reported to improve swallowing in some patients with dysphagia. Although a variety of stimuli contribute to the initiation of swallowing, the effects of a controlled, cold-thermal stimulus combined with mechanical stimulation have not been examined. It is known that simultaneous stimulation of the glossopharyngeal nerve (IX) and the superior laryngeal nerve may summate to facilitate swallowing in the cat. The goal of this study was to determine whether thermomechanical stimulation of the mucosa innervated by IX would interact with threshold electrical stimulation of the internal laryngeal nerve (ILN) to augment the swallowing response in cats. Four experimental conditions were tested over 24 trials in 4 pentobarbital-anesthetized cats. These included electrical stimulation of ILN, mechanical stimulation of the anterior faucial pillar with a thermode at ambient (room) temperature, concurrent ambient-mechanical and electrical stimulation, and concurrent cold-mechanical and electrical stimulation. Tissue was cooled to 8.9°C during cold-mechanical-electrical stimulation and 25.3°C during ambient-mechanical-electrical and ambient-mechanical alone stimulation. Ambient-mechanical stimulation alone did not produce swallowing. However, both forms of thermomechanical-electrical stimulation elicited a significantly greater number of swallows than did electrical stimulation alone. Therefore, mechanical stimulation with a thermode was capable of modifying the swallowing response in neurologically intact cats. Differences between stimulation with a probe at ambient and at cold temperatures were not significant.