Evaluation of Sida cordifolia L. for its potential against thrombosis in experimental models.

Thrombosis, the formation of blood clots due to platelet aggregation, vascular injury or hypercoagulability, leads to cardiovascular pathologies including myocardial or cerebral infarction. Antiplatelet and thrombolytic agents have promising effects in ameliorating thromboembolism and dissolving blood clots. However, the associated limitations generate the need to explore agents from natural origin. The aim of the study was to explore the potential of aqueous methanolic extract (Sc.Cr) of an indigenous plant, Sida cordifolia L., traditionally used for cardiovascular complaints. Sc.Cr was evaluated by clot lysis assay, acute pulmonary embolism, carrageenan-induced tail vein thrombosis and ferric chloride-induced carotid arterial thrombosis models. Hemostasis parameters were increased in a dose-dependent manner. Histological studies showed restoration with clear alveolar spaces and less red blood cell congestion. Significant reduction in infarcted length of thrombus, escalation in coagulation parameters with a profound decrease in platelet count (PC) were observed. Arterial occlusion time was increased with a reduction in weight of thrombus dose-dependently with significant augmentation in PT and APTT. Sc.Cr was also analyzed for phytochemical constituents and antioxidant potential. The results demonstrated the antithrombotic and thrombolytic potential of Sc.Cr using in vitro and in vivo experimental models.

Kai­Xin­San suppresses matrix metalloproteinases and myocardial apoptosis in rats with myocardial infarction and depression.

Depression is often triggered by prolonged exposure to psychosocial stressors and associated with coronary heart disease (CHD). Matrix metalloproteinases (MMPs) are involved in the pathogenesis of various emotional and cardiovascular disorders. The purpose of this study was to investigate whether Kai­Xin­San (KXS), which may terminate the signaling of MMPs, exerts antidepressant­like and cardioprotective effects in a myocardial infarction (MI) plus depression rat model. Rats were randomly assigned to five groups: A normal control (control group), a celisc­injection of isopropyl adrenaline group (ISO group), depression (depression group), an ISO + depression (depression + ISO group), and an ISO + depression group treated with intragastric administration of 1,785 mg/kg KXS (KXS group). Behavioral changes, echocardiography, biochemical index, matrix metalloproteinase (MMP) and apoptosis­related proteins were assessed. Compared with the depression + ISO group, KXS significantly improved stress­induced alterations of behavioral parameters and protected the heart by enlarging the left ventricular (LV) fractional shortening (FS) and LV ejection fraction (EF). Moreover, KXS significantly attenuated ISO + depression­induced MMP­2 and MMP­9 expression at the mRNA and protein level and decreased TIMP in the heart compared to the complex model group. Myocardial apoptosis was significantly attenuated by KXS by regulating the Bcl­2/Bax axis. These results indicated that MI comorbid with depression may damage the MMP balance in the central and peripheral system, and KXS may have a direct anti­depressive and cardio­protective effect by regulating the level of MMPs and associated myocardial apoptosis. It is promising to further explore the clinical potential of KXS for the therapy or prevention of MI plus depression comorbidity disease.

Antithrombotic Activity of a New Hypoglycemic Compound Limiglidole in Mouse Model of Cell Thrombosis.

Antithrombotic activity of hypoglycemic compound limiglidole that exhibits antiplatelet activity 2-fold exceeded activity of antiplatelet agent acetylsalicylic acid in the mouse model of systemic collagen-epinephrine thrombosis. Limiglidole signifi cantly reduced the relative and mean area of blood clots in the sections of mouse lungs.

Protective effect of dry olive leaf extract in adrenaline induced DNA damage evaluated using in vitro comet assay with human peripheral leukocytes.

Excessive release of stress hormone adrenaline is accompanied by generation of reactive oxygen species which may cause disruption of DNA integrity leading to cancer and age-related disorders. Phenolic-rich plant product dry olive leaf extract (DOLE) is known to modulate effects of various oxidants in human cells. The aim was to evaluate the effect of commercial DOLE against adrenaline induced DNA damage in human leukocytes by using comet assay. Peripheral blood leukocytes from 6 healthy subjects were treated in vitro with three final concentrations of DOLE (0.125, 0.5, and 1mg/mL) for 30 min at 37°C under two different protocols, pretreatment and post-treatment. Protective effect of DOLE was assessed from its ability to attenuate formation of DNA lesions induced by adrenaline. Compared to cells exposed only to adrenaline, DOLE displayed significant reduction (P<0.001) of DNA damage at all three concentrations and under both experimental protocols. Pearson correlation analysis revealed a significant positive association between DOLE concentration and leukocytes DNA damage (P<0.05). Antigenotoxic effect of the extract was more pronounced at smaller concentrations. Post-treatment with 0.125 mg/mL DOLE was the most effective against adrenaline genotoxicity. Results indicate genoprotective and antioxidant properties in dry olive leaf extract, strongly supporting further explorations of its underlying mechanisms of action.

Protective effect of tomato against adrenaline-induced myocardial infarction in rats.

Lycopene, a carotenoid rich in tomato fruit (ripe), is an effective antioxidant and free radical scavenger. In this study n-hexane extract of tomato was evaluated for its protective action against oxidative stress in experimental myocardial infarction induced by administration of adrenaline in rats. Adrenaline produced significant elevation of malondialdehyde content of heart, an indicator of lipid peroxidation, with a significant rise in serum aspartate aminotransferase (AST) level and different grades of necrotic changes in myocardium. Rats were treated with two doses of n-hexane extract of tomato, intragastrically daily for one month prior to administration of adrenaline on the 31st and 32nd day. Pretreatment of tomato extract (1 mg/kg, 2 mg/kg) and vitamin E (50 mg/kg) significantly reduced the malondialdehyde concentration in heart and significantly lowered the serum AST level in adrenaline treated rats. Myocardial necrosis was significantly prevented by pretreatment. These results suggest that n-hexane extract of tomato possesses antioxidative property that may protect heart against catecholamine induced myocardial infarction.

[Safety of tumescent liposuction]. / Hohe Sicherheit der Tumeszenz-Liposuktion.

Liposuction surgery is increasing in frequency and is the most commonly performed cosmetic procedure to date. Regularly, complications and fatalities are reported by tabloids. The anaesthesiogical techniques used, however, are usually not reported. Tumescent liposuction has to be clearly separated from liposuction with intravenous sedation or under general anaesthesia. In tumescent liposuction, tumescent fluid containing saline, lidocaine and adrenaline is injected into the undesired fat deposits and the pain is controlled locally. In contrast, when liposuctions are performed either with intravenous sedation or under general anaesthesia, the patient is unconscious. In this study, the different anaesthesiological techniques currently used for liposuction were compared with each other. Reported fatalities were reviewed and it was determined, whether liposuction was performed as tumescent liposuction or if systemic sedation was used. To date, no fatalities were reported when tumescent liposuction was performed and a total of 396 457 liposuctions (including own unpublished data) was counted. Fatalities, however, were reported, when either intravenous sedation or general anaesthesia was performed, and a mortality rate of 2.6-19.1 per 100000 cases was counted. Liposuctions should therefore, whenever possible be performed as tumescent liposuction. Intravenous sedation or general anaesthesia should be more carefully considered.

Resistance of cholestatic rats against epinephrine-induced arrhythmia: the role of nitric oxide and endogenous opioids.

Short-term ligation of bile duct has been used as a model to study acute cholestasis and is associated with various cardiovascular abnormalities. We examined the role of nitric oxide (NO) and endogenous opioids on epinephrine-induced arrhythmia in 7-day bile duct-ligated (BDL) rats. Six groups of rats, each of which was subdivided into two subgroups (sham-operated and BDL), were examined. First group of animals were chronically treated with normal saline. In the second and third groups, single intraperitoneal administration of N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) or naltrexone (20 mg/kg) was performed 30 min before evaluation of epinephrine-induced arrhythmia. Two groups received chronic administration of low dose (3 mg/kg/day) or high dose (10 mg/kg/day) L-NAME; and the last group was treated chronically with naltrexone (20 mg/kg/day). Chronic drug administration was performed subcutaneously for 6 consecutive days following BDL or sham operation. After induction of arrhythmia by intravenous injection of 10 microg/kg epinephrine, mean arterial pressure and electrocardiogram were recorded for 1 min. Heart rate and mean arterial pressure were significantly lower in BDL rats (P<0.01). Chronic injection of naltrexone increased heart rate and mean arterial pressure in BDL (P<0.05). Chronic low dose L-NAME administration had no effect on baseline hemodynamic parameters. High dose L-NAME injection corrected hypotension in BDL rats, but not bradycardia (P<0.05). Epinephrine induced less arrhythmia in BDL rats (P<0.05). Acute and chronic injection of naltrexone had no effect on the resistance of BDL rats against epinephrine-induced arrhythmia. Although acute L-NAME administration enhanced arrhythmias in sham-operated rats (P<0.001), it had no effect on BDL animals. Chronic injection of low dose or high dose L-NAME, without having any effect on sham-operated animals, increased arrhythmias in BDL rats (P<0.01). This study showed that BDL animals are resistant against epinephrine-induced arrhythmia and this resistance depends on long-term NO overproduction.

Evaluation of the antidysrhythmic effects of delta- and kappa-opioid receptor agonists and antagonists on calcium chloride-, adrenaline- and ischemia/reperfusion-induced arrhythmias in rats.

This study was undertaken to evaluate the involvement of delta- and kappa-opioid receptors in both ischemia- and reperfusion-induced arrhythmias, and to elucidate some of the plausible mechanisms conferring antidysrhythmic effects on opioid delta- and kappa-receptor agonists and antagonists. Different models of arrhythmia (calcium chloride [CaCl(2)]-, adrenaline-, and ischemia/reperfusion-induced arrhythmias) were employed. The following opioid agonists, antagonists and blockers were used in the study: [D-Ala(2), D-Leu(5)]enkephalin (DADLE), a selective delta-receptor agonist; trans-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U-50488H), a selective kappa-receptor agonist; Naltriben Methanesul-fonate (NTB), a selective delta(2)-antagonist with kappa-receptor agonist-like activity; natrindole, a non-selective delta(1)- and delta(2)-receptor antagonist; nor-binaltorphimine dehydrochloride (nor-BNI), a selective kappa-receptor antagonist; chelerythrine, a selective protein kinase C inhibitor, and glibenclamide, a selective blocker of ATP-sensitive K channel. Although results of the morphometric, enzymatic, hemodynamic, electrocardiographic and pharmacodynamic studies undertaken suggest that both opioid delta(1)- and kappa-receptors are involved in the phenomenon of ischemic heart preconditioning (IPC), the antidysrhythmic effects of the opioids seem to be mediated mainly via kappa-receptors. The antidysrhythmic effect of U50488H was found to be a consequence of its beta-blocking activity (which is comparable to that of propranolol, a Class II antiarrhythmic drug) and its ability to prolong myocardial action potential (QT-interval prolongation, which is comparable to that of amiodarone, a Class III antiarrhythmic drug). The antidysrrhythmic effects of the opioid compounds examined were almost completely abolished by glibenclamide or chelerythrine pretreatment. No calcium-channel blocking activity was observed in this investigation. The present observations suggested that opioid receptors displaying well known analgesic properties may have the potential to protect the myocardium during cardiac ischemia at the early stages of myocardial infarction (when early arrhythmias are the most common causes of death).

[Effect of shenfu injection on microcirculation].

This study was aimed to assess the effect of Shenfu injection on different circulation state. Using a microcirculation microscope system, we observed mice's auricle micro-artery diameter, density of capillary, blood velocity in different circulation state (i.e. normal state, epinephrine or endotoxin induced microcirculation disturbance state) after administering Shenfu injection into their caudal vein, and we compared the Shenfu group with Shenmai group and Dexamethasone group. The results showed that Shenfu injection causes the auricle microartery diameter to enlarge and the density of capillary and blood velocity to increase in different microcirculation state, and such effect is especially notable on the epinephrine induced microcirculation disturbance group and endotoxin induced microcirculation disturbance group; the effect of Shenfu injection is stronger than that of Shenmai injection and similar to Dexamethasone injection. In addition, Shenfu injection was shown to have remarkable effect on resisting the lowering of limb temperature when the mice are attacked by endotoxin.

Flurbinitroxybutylester: a novel anti-inflammatory drug has enhanced antithrombotic activity.

We have recently shown that the introduction of a nitroxybutylester moiety into flurbiprofen, to form Flurbi-NO, results in a compound with markedly reduced undesired effects in the gastrointestinal tract. This effect has been shown to be linked to nitric oxide release from the Flurbi-NO. Here we have investigated whether this is associated with a reduction in platelet aggregability in vivo, as assessed in a mouse model of thromboembolism and a rat model of platelet aggregation, and found in both models that Flurbi-NO is more potent than flurbiprofen at inhibiting collagen-induced platelet aggregation. Further in vitro studies using human washed platelets and cells in culture suggest that this is due to the release of NO from Flurbi-NO following the action of (possibly plasma) esterases. Together with our earlier data, these results strongly suggest that Flurbi-NO and other members of this class of drugs, have particular potential as anti-thrombotic agents devoid of gastrointestinal side effects.

Effect of D-400, a herbal formulation, on blood sugar of normal and alloxan-induced diabetic rats.

Blood sugar levels of normal rats treated with D-400 showed significant reduction (P < 0.05) as compared to control groups. The fall was seen at one month and remained so uptill 3 months. Hyperglycemic response to adrenaline was significantly lowered (P < 0.05) following D-400 treatment. D-400 potentiated the hypoglycemia following tolbutamide treatment. Blood sugar remained persistently low in tolbutamide plus D-400 treated group after 3 and 4 hours (P < 0.05). In the alloxan-induced diabetic rats, a significant lowering of blood and urinary sugar was noticed on day 20, 30 and 40 following treatment with D-400 (P < 0.05). Liver glycogen depletion was significantly inhibited in the D-400 treated group (P < 0.025). D-400 has significantly potentiated (P < 0.05) the hypoglycemic action of insulin in alloxan-induced diabetic rats.

Effect of leaf extract from Clerodendron colebrookianum on blood pressure in rats.

Hypotensive effect of the extract of leaves of C. colebrookianum was investigated. An extremely bitter fraction was isolated, which gave positive test for alkaloids. The fraction produced fall of blood pressure in a dose dependent manner. The fall of blood pressure was blocked by atropine. Hypertensive effects of adrenaline and noradrenaline were slightly antagonised by the alkaloidal extract.

Mouse antithrombotic assay. Inhibition of platelet thromboembolism by disintegrins.

The mouse antithrombotic assay represents a model of fatal pulmonary thromboembolism induced by intravenous injection of collagen and epinephrine. Mice were protected by low doses of two disintegrins, albolabrin (10 micrograms/mouse) and eristostatin (0.6 micrograms/mouse), whereas high doses of a thrombin inhibitor and an inhibitor of von Willebrand Factor binding to glycoprotein Ib were not effective. Injection of collagen and epinephrine resulted in the drop of platelet count and accumulation of platelet aggregates in the lung that appears to be the immediate cause of death. Albolabrin or eristostatin administration did not prevent the decrease of platelet count. Injection of albolabrin resulted in the formation of smaller and reversible platelet aggregates in the lungs and decreased accumulation of 51Cr-labeled platelets in the lung suggesting that this disintegrin decreases formation of platelet aggregates in vivo. We compared the effects of albolabrin and erisostatin on platelet aggregation, tail bleeding time, and survival of challenged animals. Eristostatin was about 5 times more potent in inhibiting platelet aggregation in vitro than albolabrin and 38 times more potent than albolabrin in protecting animals from sudden death. Both disintegrins, at the same doses (0.6-5 micrograms/mouse), caused similar dose-dependent prolongation of the bleeding time; however, only eristostatin exerted a protective effect. In conclusion, a) the mouse antithrombotic assay is a suitable model to screen and to evaluate the potency of platelet fibrinogen receptor antagonists in vivo; b) the results of the antithrombotic assay correlate better with the inhibition of platelet aggregation in vitro than with the prolongation of bleeding time.

[The effect of alpha-tocopherol on conditioned reflex activity in adrenaline-induced myocardial dystrophy in rats]. / Vliianie al'fa-tokoferola na uslovnoreflektornuiu deiatel'nost' pri adrenalinovoi distrofii miokarda u krys.

Adrenolytic heart defect (AHD) proceeds with the breaking of higher adaptational reactions, i.e. the change of latent period of conditioned active prevention reaction and arising of retrograde amnesia. alpha-Tocopherol--antioxidant prevents the breaking of conditioned reflex activity and sharply reduces the mortality rate in AHD. More effective is the prophylaxis of the brain function breaking and lethality.

Antiarrhythmic effect of a new class 1 antiarrhythmic drug, AN-132, on ventricular arrhythmias in beagles.

Using two-stage coronary-ligation-, digitalis- and adrenaline-induced ventricular arrhythmias in beagles, antiarrhythmic effects of AN-132 were examined, and the minimum effective plasma concentration for each arrhythmia model was determined. AN-132 suppressed all the arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by 24-hour coronary ligation, 48-hour coronary ligation, digitalis, and adrenaline were 3.4-4.6, 1.5-2.3, 0.83, and 9.3 micrograms/ml, respectively. The concentration for adrenaline-induced arrhythmia was significantly higher than that of 24-hour coronary ligation arrhythmia, and it was also higher than that of digitalis arrhythmia. This pharmacologic profile is similar to those of pirmenol and mexiletine. Since AN-132 had no deleterious effects on the hemodynamics and the central nervous system, it may become a clinically useful antiarrhythmic drug.

[The action of an enzymatically stable Leu-enkephalin analog on the prostanoid content in the myocardium under stress- and adrenaline-induced damage]. / Vozdeistvie énzimoustoichivogo analoga lei-énkefalina na soderzhanie prostanoidov v miokarde pri stressornom i adrenalinom povrezhdenii.

The protective action of enzymatically stable analogue of Leu-enkephalin (D-ala-2-leu5-arg6), injected intraperitoneally, in the course of stress- and epinephrine induced myocardial damage was demonstrated in animal (129 white rats) experiments. Two effect of enkephalin were sufficient for the cardiac protection: enkephalin-stimulated prostacyclin biosynthesis and simultaneous inhibition of thromboxane production.