胍基丁胺对大鼠血流动力学的影响及其细胞机制

在麻醉大鼠研究静注胍基丁胺（ＡＧＭ）对血流动力学的影响,并初步探讨其机制。结果如下：（１）静注ＡＧＭ（１０ｍｇ／ｋｇ）后,ＨＲ,ＭＡＰ,ＬＶＰ,±ＬＶｄｐ／ｄｔｍａｘ,ＣＩ和ＴＰＲＩ均明显下降;（２）预先静注ＮＯＳ抑制剂ＬＮＮＡ（１５ｍｇ／ｋｇ）或腹腔内注射鸟苷酸环化酶抑制剂亚甲基蓝（５０ｍｇ／ｋｇ）,均不能阻断ＡＧＭ的降压作用;（３）预先静注咪唑啉受体和α２肾上腺素能受体阻断剂ｉｄａｚｏｘａｎ（２ｍｇ／ｋｇ）则可明显阻抑ＡＧＭ的降压效应。以上结果表明,ＡＧＭ对麻醉大鼠的降压机制,在于显著抑制心肌收缩性而使心输出量降低,以及舒张外周血管致使总外周阻力下降;此效应似主要由ＩＲ和／或α２ＡＲ所介导。     

Cannabinoid antagonist SR-141716 inhibits endotoxic hypotension by a cardiac mechanism not involving CB1 or CB2 receptors

Endocannabinoids and CB1 receptors have been implicated in endotoxin (LPS)-induced hypotension: LPS stimulates the synthesis of anandamide in macrophages, and the CB1 antagonist SR-141716 inhibits the hypotension induced by treatment of rats with LPS or LPS-treated macrophages. Recent evidence indicates the existence of cannabinoid receptors distinct from CB1 or CB2 that are inhibited by SR-141716 but not by other CB1 antagonists such as AM251. In pentobarbital-anesthetized rats, intravenous injection of 10 mg/kg LPS elicited hypotension associated with profound decreases in cardiac contractility, moderate tachycardia, and an increase in lower body vascular resistance. Pretreatment with 3 mg/kg SR-141716 prevented the hypotension and decrease in cardiac contractility, slightly attenuated the increase in peripheral resistance, and had no effect on the tachycardia caused by LPS, whereas pretreatment with 3 mg/kg AM251 did not affect any of these responses. SR-141716 also elicited an acute reversal of the hypotension and decreased contractility when administered after the response to LPS had fully developed. The LPS-induced hypotension and its inhibition by SR-141716 were similar in pentobarbital-anesthetized wild-type, CB1(-/-), and CB1(-/-)/CB2(-/-) mice. We conclude that SR-141716 inhibits the acute hemodynamic effects of LPS by interacting with a cardiac receptor distinct from CB1 or CB2 that mediates negative inotropy and may be activated by anandamide or a related endocannabinoid released during endotoxemia.     

Adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning

The purpose of this study was to determine whether the adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning. Regional stunning was produced by 15 min of coronary artery occlusion and 3 h of reperfusion (RP) in anesthetized open-chest pigs. In acute protection studies, animals were pretreated with saline, low-dose AMP-579 (15 microg/kg iv bolus 10 min before ischemia), or high-dose AMP-579 (50 microg/kg iv at 14 microg/kg bolus + 1.2 microg.kg(-1).min(-1) for 30 min before coronary occlusion). The delayed preconditioning effects of AMP-579 were evaluated 24 h after administration of saline vehicle or high-dose AMP-579 (50 microg/kg iv). Load-insensitive contractility was assessed by measuring regional preload recruitable stroke work (PRSW) and PRSW area. Acute preconditioning with AMP-579 dose dependently improved regional PRSW: 129 +/- 5 and 100 +/- 2% in high- and low-dose AMP-579 groups, respectively, and 78 +/- 5% in the control group at 3 h of RP. Administration of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.7 mg/kg) blocked the acute protective effect of high-dose AMP-579, indicating that these effects are mediated through A1 receptor activation. Delayed preconditioning with AMP-579 significantly increased recovery of PRSW area: 64 +/- 5 vs. 33 +/- 5% in control at 3 h of RP. In isolated perfused rat heart studies, kinetics of the onset and washout of AMP-579 A1 and A2a receptor-mediated effects were distinct compared with those of other adenosine receptor agonists. The unique nature of the adenosine agonist AMP-579 may play a role in its ability to induce delayed preconditioning against in vivo myocardial stunning.     

Electrophysiological action of ethacizin in acute myocardial ischemia in dogs

The effects of ethacizin on delayed activation of the ischemic myocardium by acute left anterior descending coronary artery occlusion were studied in dogs. Ethacizin, administered intravenously at a dose of 0.5 or 1 mg/kg depressed the conduction of excitation in the ischemic myocardium and significantly increased the incidence of ventricular fibrillation. Electrophysiological effects of ethacizin in acute myocardial ischemia, as well as its antiarrhythmic activity at the advanced stages of experimental myocardial infarction might be related to an intensive influence of ethacizin on fast inward sodium current in the myocardial fibers.     

Dexrazoxane provided moderate protection in a catecholamine model of severe cardiotoxicity

Positive effects of dexrazoxane (DEX) in anthracycline cardiotoxicity have been mostly assumed to be associated with its iron-chelating properties. However, this explanation has been recently questioned. Iron plays also an important role in the catecholamine cardiotoxicity. Hence in this study, the influence of DEX on a catecholamine model of acute myocardial infarction (100?mg/kg of isoprenaline by subcutaneous injection) was assessed: (i) the effects of an intravenous dose of 20.4?mg/kg were analyzed after 24?h, (ii) the effects were monitored continuously during the first two hours after drug(s) administration to examine the mechanism(s) of cardioprotection. Additional in vitro experiments on iron chelation/reduction and influence on the Fenton chemistry were performed both with isoprenaline/DEX separately and in their combination. DEX partly decreased the mortality, reduced myocardial calcium overload, histological impairment, and peripheral haemodynamic disturbances 24?h after isoprenaline administration. Continuous 2?h experiments showed that DEX did not influence isoprenaline induced atrioventricular blocks and had little effect on the measured haemodynamic parameters. Its protective effects are probably mediated by inhibition of late myocardial impairment and ventricular fibrillation likely due to inhibition of myocardial calcium overload. Complementary in vitro experiments suggested that iron chelation properties of DEX apparently did not play the major role.     

Cardiovascular effects of mycotoxin T-2 after topical application in rats

Evidence has been mounting that trichothecenes cause cardiac lesions and cardiovascular effects in general. T-2 toxin, dissolved in dimethyl sulfoxide, was applied in doses of 0, 1.0, 2.0 mg/kg to the skin of Sprague-Dawley rats. Twenty-four hours later, the cardiac function of the animals was assessed, followed by killing and histological examination. It was found that the arterial blood pressure values were lower in the 2.0 mg/kg group, the peak intraventricular pressure was lower in both the 1.0 and 2.0 mg/kg groups, and the resting systolic and diastolic blood pressure values of the 2.0 mg/kg group were lower than the 0 and 1.0 mg/kg groups. The 1.0 and 2.0 mg/kg groups had significantly lower epinephrine-stimulated intraventricular pressure values, indicating reduced contractility. Extended Q-T intervals in electrocardiograms of the 1.0 and 2.0 mg/kg groups suggested also impaired contractility. The histological examination gave equivocal results. It is concluded that topical applications of small doses of T-2 toxin have a noticeable negative effect on cardiovascular function.     

Effect of potassium channel modulators on toxicity of Cleistanthus collinus

The study was conducted to determine the effects of boiled extract of Cleistanthus collinus on rats by observing ECG changes and electrolyte levels in serum and urine. Influence of minoxidil and glibenclamide on Cleistanthus collinus induced toxicity was determined. ED50 for arrhythmia, changes in contractility and heart rate were recorded using the isolated frog heart. Cleistanthus at low doses caused transient tachycardia and increase in contractility and at high dose caused arrhythmia and cardiac arrest in rat. LD50 was found to be 1690 mg/kg. Minoxidil potentiated cardiac toxicity, whereas glibenclamide did not produce any significant change. High concentration of potassium in Cleistanthus extract hindered comparison of its levels. There was excretion of sodium even in the presence of hyponatraemia. Cleistanthus at low dose caused transient tachycardia and increase in contractility and at high dose caused arrhythmia and cardiac arrest in isolated frog heart. ED50 for arrhythmia was found to be 1406 mg/kg. Acute toxicity was mainly due to depressive cardiac activity of Cleistanthus. It also caused renal failure. Potassium channel modulators did not have important role in acute cardiac toxicity treatment. Probably in chronic toxicity, electrolyte level changes are involved and potassium channel modulators might have a role.     

Circulatory consequences of reduced endogenous nitric oxide production during small-volume resuscitation

Hypertonic small-volume resuscitation transiently restores the cardiovascular function during various circulatory disturbances. Nitric oxide (NO) is an important mediator of flow-induced peripheral and central hemodynamic changes, and therefore, we hypothesized that a decreased endogenous NO production could influence the consequences and the effectiveness of hypertonic fluid therapy. The main goal of this study was to outline and compare the circulatory effects small volume hypertonic saline-dextran (HSD, 7.5% NaCl-10% dextran; 4 ml/kg iv) infusion with (n=7) or without (n=7) artificially diminished NO production in normovolemic anesthetized dogs. HSD administration significantly increased cardiac index (CI), coronary flow (CF) and myocardial contractility, and elevated plasma nitrite/nitrate (NOx) and endothelin-1 (ET-1) levels. However, the late (2 h) postinfusion period was characterized by significantly decreased myocardial NO synthase (NOS) and enhanced myeloperoxidase activities. Pre-treatment with the non-selective NOS inhibitor N-nitro-L-arginine (NNA, 4 mg/kg) immediately increased cardiac contractility, and the HSD-induced CI and CF elevations and the positive inotropy were absent. Additionally, plasma ET-1 levels increased and NOx levels were significantly decreased. In conclusion, our results demonstrate that HSD infusion leads to preponderant vasoconstriction when endogenous NO synthesis is diminished, and this could explain the loss of effectiveness of HSD resuscitation in NO-deficient states.     

Impaired in vivo myocardial reactivity to norepinephrine in diabetic rats

The effects of long-term diabetes with and without insulin treatment on in vivo myocardial contractile activity were studied under basal conditions and as a function of intravenously infused norepinephrine. Diabetes was induced by iv injection of streptozotocin (50 mg/kg). Insulin-treated diabetic rats received 5 units per day of isophane insulin suspension. The duration of the study was 8 weeks. In vivo myocardial contractility measurements were performed in ketamine-xylazine-anesthetized rats using a miniature catheter-tip pressure transducer advanced through the right carotid artery into the left ventricle. Peak positive dP/dt and intraventricular developed pressure were comparable among the groups when measured under basal conditions; however, the magnitude of the response to variable doses of norepinephrine (6 X 10(-12) to 6 X 10(-8) mole/kg body wt) were significantly diminished in diabetic rats, but the sensitivity was unchanged. Negative dP/dt was decreased under basal conditions and in response to norepinephrine in diabetic rats. Insulin treatment to diabetic rats prevented these changes, but heart rate was elevated. These results demonstrate that the in vivo cardiovascular reactivity of diabetic rats to norepinephrine is significantly attenuated.     

The reduction of myocardial damage and leukocyte polymorphonuclear accumulation following coronary artery occlusion by the tyrosine kinase inhibitor tyrphostin AG 556

We investigated the effects of tyrophostin AG 556, a tyrosine kinase inhibitor, on the phenomenon of leukocyte accumulation during ischaemia and reperfusion of the myocardium. Male anaesthetized rats were subjected to total occlusion (45 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham myocardial ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK) serum Tumor Necrosis Factor (TNF-alpha) and Interleukin 6 (IL-6), cardiac intercellular adhesion molecule-1 (ICAM-1) and TNF-alpha expression and myocardial contractility (left ventricle dP/dt(max)) were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial necrosis, increased serum CPK activity (196.5 +/- 19 U/100 ml, at the end of reperfusion) and myeloperoxidase activity (MPO, a marker of leukocyte accumulation) both in the area-at-risk (4.5 +/- 0.5 U/g/tissue) and in necrotic area (8.2 +/- 1.2 U/g/tissue), reduced myocardial contractility (1,706 +/- 52 mmHg/s, at the end of reperfusion) and induced a marked increase in the serum levels of TNF-alpha (1,950 +/- 97 pg/ml, at 1 h of reperfusion) and IL-6 (998 +/- 16 U/ml, at the end of reperfusion). Finally, myocardial ischaemia-reperfusion injury also increased cardiac mRNA for TNF-alpha and ICAM-1 in the myocardium-at risk. Tyrphostin AG 556 (0.5, 1 and 2 mg/kg subcutaneously 5 min after the onset of reperfusion) lowered myocardial necrosis and myeloperoxidase activity in the area-at-risk (1.5 +/- 0.2 U/g/tissue, following the highest dose) and in necrotic area (2.9 +/- 0.3 U/g/tissue following the highest dose), decreased serum CPK activity (96 +/- 9 U/100 ml, at the end of reperfusion), lowered serum TNF-alpha and IL-6, increased myocardial contractility (2,096 +/- 88 mmHg s, at the end of reperfusion) and reduced cardiac mRNA levels for TNF-alpha and ICAM-1. The present data suggest that tyrosine kinase inhibitors protect against myocardial ischaemia-reperfusion injury by reducing leukocyte accumulation to the ischaemic myocardium.     

Participation of central and peripheral mu- and delta opiate receptors in anti-arrhythmia action of enkephalins]

It was found, that injection of delta-receptors agonist dalargin before the occlusion of left anterior coronary artery in rats prevented the decrease of ventricular fibrillation threshold (VFT). An injection of naloxone in dose 0.5 mg/kg (for the blockade of mu-receptors only) had no influence on the VFT. Naloxone in dose 1 mg/kg (for the blockade peripheric mu- and delta-receptors) decreased VFT. An intraventricular infusion of dalargin (10 mkg) induced bradycardia and an increase of VFT. It was assumed that anti-arrhythmic effects of enkephalins in acute myocardial ischemia could be realized by an activation of peripheric delta-receptors and central mu-receptors.     

Protective effect of labedipinedilol-A, a novel dihydropyridine-type calcium channel blocker, on myocardial apoptosis in ischemia-reperfusion injury

The effects of labedipinedilol-A, a novel dihydropyridine-type calcium channel blocker with alpha-/beta-adrenoceptor blocking activities, on myocardial infarct size, apoptosis and necrosis in the rat after myocardial ischemia/reperfusion (45 min/120 min) were investigated. Ten minutes prior to left coronary artery occlusion, rats were treated with vehicle or labedipinedilol-A (0.25 or 0.5 mg/kg, i.v.). In the vehicle group, myocardial ischemia-reperfusion induced creatine kinase (CK) release and caused cardiomyocyte apoptosis, as evidenced by DNA ladder formation and terminal dUTP deoxynucleotidyltransferase nick end-labeling (TUNEL) staining. Treatment with labedipinedilol-A (0.25 or 0.5 mg/kg) reduced infarct size significantly compared to vehicle group (18.75+/-0.65% and 8.27+/-0.29% vs. 41.72+/-0.73%, P<0.01). Labedipinedilol-A also reduced the CK, CK-MB, lactate dehydrogenase (LDH) and troponin T levels in blood. In addition, labedipinedilol-A (0.5 mg/kg) significantly decreased TUNEL positive cells from 19.21+/-0.52% to 9.73+/-0.81% (P<0.01), which is consistent with absence of DNA ladders in the labedipinedilol-A group. Moreover, labedipinedilol-A pretreatment also decreased calcium content in ischemic-reperfused myocardial tissue. In conclusion, these results demonstrate that labedipindielol-A, through reduction of calcium overload and apoptosis, exerts anti-infarct effect during myocardial ischemia-reperfusion and would be useful clinically in the prevention of acute myocardial infarction.     

Pentobarbital versus medetomidine-ketamine-fentanyl anaesthesia: effects on haemodynamics and the incidence of ischaemia-induced ventricular fibrillation in swine

The present study was performed to compare haemodynamic variables at baseline and the incidence of ventricular fibrillation during the early phase of ischaemia in swine during pentobarbital or medetomidine-ketamine-fentanyl anaesthesia. Twenty-two swine (mean +/- SD: 29+/- 3 kg) were anaesthetized with sodium pentobarbital (induction with 36 mg/kg intraperitoneally, and maintenance with 5-20 mg/kg/h intravenously [i.v.]) and 6 swine (27+/- 3 kg) were anaesthetized with ketamine and fentanyl (premedicated with medetomidine 0.1 mg/kg and ketamine 10 mg/kg intramuscularly, induction with ketamine 20 mg/kg and fentanyl 0.025 mg/kg i.v., and maintenance with ketamine 20 mg/kg/h and fentanyl 0.025 mg/kg/h i.v.). After a stabilization period of 30 min, the left anterior descending coronary artery (LAD) was occluded for 10 min. Haemodynamic data and occurrence of ventricular fibrillation were recorded. The ischaemic area was measured by fluorescing microspheres. Swine anaesthetized with medetomidine-ketamine-fentanyl had significantly lower heart rate, myocardial contractility, peak left ventricular pressure, arterial blood pressure, aortic blood flow, myocardial blood flow and cardiac index at baseline, than swine anaesthetized with pentobarbital. Whereas none of the swine anaesthetized with pentobarbital fibrillated during the LAD occlusion, ventricular fibrillation occurred in 83% of the animals anaesthetized with medetomidine-ketamine-fentanyl (P< 0.001). No significant difference was found in size of ischaemic area between the two groups. Thus, we show a depression in haemodynamic variables at baseline and a higher incidence of ventricular fibrillation during the early phase of ischaemia in swine anaesthetized with medetomidine-ketamine-fentanyl compared to swine anaesthetized with pentobarbital.     

Anti-necrosogenic action of natural and synthetic antioxidants in coronary occlusive myocardial infarct

The synthetic liposoluble antioxidant BAT. 120 mg/kg, was found to produce markedly protective effects in a rat model of coronary occlusive myocardial infarction, whereas the water soluble BAT analogue, 4-Oxy-3,5-ditretbutylphenyl phosphonic acid sodiate (SFN-6), 100 mg/kg, displayed no protective effects. The natural antioxidant beta-carotene capable of displaying antioxidative activity at low partial O2 pressures was shown to reduce the size of postinfarct scar by 34% when given in a dose of 20 mg/kg. The synthetic antioxidants, BAT and SFN-6 given in doses of 100 to 120 mg/kg each decreased antioxidant enzyme activities in the intact or infarct-related myocardium. beta-carotene was found to lack inhibitory effects on the myocardial antioxidant enzymes, thus enhancing its cardioprotective properties.     

Some mechanisms of nonspecific antiarrhythmic action of phosphocreatine in acute myocardial ischemia

Using isotope-labeled microspheres (diameter 15 microns) it was shown that phosphocreatine at a dose of 300 mg/kg does not affect the myocardial blood flow in the ischemic zone during acute occlusion (5 min) of the left anterior descending coronary artery (LAD) in dogs. Intravenous administration of NaCl hypertonic solution which contained the same amount of Na+ as 300 mg/kg of phosphocreatinine disodium salt prevented the development of ventricular fibrillation during acute LAD occlusion in dogs. Under these conditions excitation conduction velocity significantly increased. Experiments in isolated intraventricular rabbit septum have showed that the addition of phosphocreatine or phosphocreatinine to the perfusion medium at a concentration of 10 mmole/liter increased excitation conduction velocity in ischemic myocardium. However, when changes in perfusate Na+ and Ca2+ concentration produced by addition of phosphocreatine or phosphocreatinine were compensated, these compounds do not affect excitation conduction velocity. On the other hand, the alterations similar to those produced by the addition of phosphocreatine or phosphocreatinine led to the same increase of excitation conduction velocity. The results obtained indicate an important role of the changes of blood plasma ionic composition on intravenous administration of phosphocreatine in electrophysiological and antiarrhythmic effects of this substance during acute myocardial ischemia.     

Corticotropin-releasing factor acts centrally to suppress stimulated gastric contractility in the rat

The effects of intracisternal (i.c.) and intravenous (i.v.) administration of corticotropin-releasing factor (CRF) on gastric contractility stimulated by i.c. injection of the TRH analog RX77368 [p-Glu-His-(3,3'-dimethyl)-Pro-NH2], 2-deoxy-D-glucose (2DG) and i.v. infusion of carbachol were evaluated in rats under urethane anesthesia. Gastric contractility was monitored using acutely implanted extraluminal force transducers sutured to the corpus of the stomach. I.c. injection of CRF (6.3-210 pmol) resulted in a dose dependent suppression of gastric contractility stimulated by RX77368 (260 pmol) and 2DG (6 mg). Gastric inhibitory response to i.c. CRF was rapid in onset and lasted at least 45 min. Carbachol (200 mg/kg/h)-induced stimulation of gastric contractility was not modified by i.c. injection of CRF. The stimulation of contractility caused by both i.v. carbachol and i.c. 2DG were completely inhibited by atropine (1 mg/kg, i.v.). CRF (210 pmol) given i.v. suppressed RX77368-stimulated gastric contractions, but was less than 1/10 as potent as administered i.c. I.v. CRF (210 pmol) did not alter 2DG- or carbachol-induced gastric contractions. These results demonstrate that the i.c. administration of CRF acts within the brain to inhibit gastric contractility elicited by vagus-dependent mechanisms.     

Effect of Inula racemosa root extract on cardiac function and oxidative stress against isoproterenol-induced myocardial infarction

The cardioprotective potential of Inula racemosa root hydroalcoholic extract against isoproterenol-induced myocardial infarction was investigated in rats. The rats treated with isoproterenol (85 mg/kg, s.c.) exhibited myocardial infarction, as evidenced by significant (P < 0.05) decrease in mean arterial pressure, heart rate, contractility, relaxation along with increased left ventricular end diastolic pressure, as well as decreased endogenous myocardial enzymatic and non-enzymatic antioxidants. Isoproterenol also significantly (P < 0.05) induced lipid peroxidation and increased leakage of myocyte injury marker enzymes. Pretreatment with I. racemosa extract (50, 100 or 200 mg/kg per day, p.o.) for 21 consecutive days, followed by isoproterenol injections on days 19th and 20th significantly (P < 0.05) improved cardiac function by increasing the heart rate, mean arterial pressure, contractility and relaxation along with decreasing left ventricular end diastolic pressure. Pretreatment with I. racemosa also significantly (P < 0.05) restored the reduced form of glutathione and endogenous antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase from the heart, which were depleted after isoproterenol administration. In addition to restoration of antioxidants, I. racemosa significantly (P < 0.05) inhibited lipid peroxidation and prevented the leakage of myocytes specific marker enzymes creatine phosphokinase-MB and lactate dehydrogenase from the heart. Thus, it is concluded that I. racemosa protects heart from isoproterenol-induced myocardial injury by reducing oxidative stress and modulating hemodynamic and ventricular functions of the heart. Present study findings demonstrate the cardioprotective effect of I. racemosa and support the pharmacological relevance of its use and cardioprotection mechanism in ischemic heart disease as well as substantiate its traditional claim.     

Amiodarone inhibits interleukin 6 production and attenuates myocardial injury induced by viral myocarditis in mice

A recent study has shown that amiodarone inhibits the production of cytokines in vitro. This study was performed to examine the effects of amiodarone on survival, heart weight-to-body-weight ratio (HW/BW), myocardial lesions and cytokines production in a murine model of viral myocarditis induced by the encephalomyocarditis virus (EMCV). Four-week-old male DBA/2 mice were inoculated with the EMCV. To examine its effect on survival and HW/BW on day 14, mice were administered oral amiodarone (30 mg/kg) or the vehicle only once daily, starting 4 days before inoculation of the virus. The effects of amiodarone on histopathologic changes in myocardial lesions and myocardial cytokine production were studied in mice treated with amiodarone (10 mg/kg or 30 mg/kg) or vehicle, and killed day 7. The survival rate on day 14 was significantly higher in the amiodarone-treated mice than in the control mice. The HW/BW, histopathologic score of cellular infiltration and myocardial interleukin 6 concentration were significantly lower in the amiodarone-treated group than in the control group. Likewise, myocardial necrotic area was significantly smaller in the amiodarone group than in the control group. This study suggests that the beneficial effects of amiodarone in viral myocarditis may be mediated by decreasing interleukin 6 production in myocardial tissue.     

The interaction between myocardial depressant factors in endotoxemic cardiac dysfunction: role of TNF-alpha in TLR4-mediated ICAM-1 expression

Multiple pro-inflammatory mediators contribute to cardiac dysfunction caused by bacterial lipopolysaccharide (LPS). The rapid TNF-alpha response is likely involved in the induction of down-stream myocardial depressant factors. Studies by our laboratory and others indicate an important role for ICAM-1 in endotoxemic cardiac dysfunction through leukocyte-independent mechanisms. The purpose of this study was to determine: whether ICAM-1 knockout improves cardiac function during endotoxemia and whether TLR4 and TNF-alpha regulate LPS-induced myocardial ICAM-1 expression. METHODS AND RESULTS: Mice were treated with Escherichia coli LPS (0.5mg/kg iv). Myocardial ICAM-1 levels were analyzed by immunoblotting and left ventricular developed pressure (LVDP) was assessed by the Langendorff technique. In wild-type mice, peak ICAM-1 levels were observed at 4h when myocardial contractility was depressed. Myocardial contractility was improved following LPS in mice lacking functional TLR4, TNF-alpha or ICAM-1. TLR4 mutation abolished ICAM-1 expression with abrogation of precedent TNF-alpha response. Similarly, TNF-alpha knockout reduced myocardial ICAM-1 level following LPS treatment. CONCLUSIONS: ICAM-1 contributes to the mechanism of endotoxemic cardiac dysfunction. TNF-alpha is involved in the regulation of myocardial ICAM-1 expression by TLR4.     

Protamine is a low molecular weight polycationic amine that produces actions on cardiac muscle

Protamine is a polycationic amine used clinically to reverse heparin overdose. Here we characterized the actions of protamine on the cardiovascular system of anesthetized rats and in isolated Langendorff rat hearts in order to define a possible mechanism of action on cardiovascular tissue. In anesthetized rats, protamine reduced blood pressure in a dose-dependent fashion and reduced heart rate. Only at a dose of 32 mg/kg did protamine increase the Q-aT interval of the electrocardiogram (EKG) to 62 +/- 6 msec from a control of 54 +/- 5 msec (p < 0.05). Protamine dose-dependently reduced cardiac output by 74 +/- 5% and stroke volume by 62 +/- 15 %, suggesting that it directly affects cardiac contractility. An analysis of blood chemistry suggests that protamine does not alter plasma electrolyte or serum enzyme levels at the doses administered. Protamine produced aberrant rhythms in normal rat hearts when administered between 1-32 mg/kg. The P-Q segment of the EKG for each of the arrhythmic complexes was reduced to 24 +/- 1 msec compared to 32 +/- 3 msec in normal EKG complexes suggestive of anomalous atrio-ventricular or pre-excitation conduction. Isolated rat heart studies confirmed that protamine produced a reduction in cardiac contractility. Our studies suggest that the cardiovascular depressant actions of protamine result from a direct effect on the heart and that protamine may produce aberrant conduction within the heart which may result in deleterious effects in heart function, especially conditions associated with myocardial disease.