ABSTRACT
We studied some features of blood and lymph microcirculation in the brain, heart, and liver of female rats with developed alcoholic cardiomyopathy. In female rats after 24-week forced consumption of 10% ethanol solution, the size and inotropic function of the heart were measured by echocardiography. Microcirculation in the brain, myocardium, and liver was assessed by laser Doppler flowmetry using LAKK-OP2 and LAZMA-D computerized laser analyzers. Using spectral wavelet analysis, we determined the absolute and normalized to total perfusion amplitudes of microcirculation oscillations reflecting various regulatory mechanisms. Intact animals served as controls. In rats of the experimental group, alcoholic cardiomyopathy completely developed. Under these conditions, the index of microcirculation in the brain, myocardium, and liver significantly decreased. At the same time, there was a redistribution in the brain between shunting and nutritive blood flow in favor of the latter. In the myocardium and liver, this ratio did not change.
Subject(s)
Cardiomyopathy, Alcoholic , Rats , Female , Animals , Microcirculation/physiology , Heart , Brain , Liver , Laser-Doppler FlowmetryABSTRACT
The mechanisms underlying the antiarrhythmic action of compound trihydrochloride N1-(2,3,4-trimethoxy)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethane-diamine (code ALM-802) were studied in vitro. The experiments were performed on a culture of rat hippocampal neurons. The electrical activity of neurons was recorded by the patch-clamp method in the whole cell configuration. It is shown that the compound ALM-802 effectively blocks potential-dependent Na+ and K+ channels and does not affect the activity of potential-dependent Ca2+ channels. The inhibition of currents through these channels is dose-dependent; the IC50 of Na+ and K+ channels were 94±4 and 67±3 µM, respectively. These findings indicate that compound ALM-802 combines the properties of class I and class III antiarrhythmic agents according to the Vaughan-Williams classification.
Subject(s)
Anti-Arrhythmia Agents , Neurons , Rats , Animals , Anti-Arrhythmia Agents/pharmacology , Action PotentialsABSTRACT
The cardioprotective activity of ALM-802 compound was demonstrated in model experiments simulating postinfarction chronic heart failure in rats forming in 90 days after anterior transmural myocardial infarction. ALM-802 decreased the left ventricle and improved its inotropic function (p=0.038). This effect was observed in case of systematic administration of ALM-802 over 28 days (starting from day 91 after infarction modeling). This is apparently the minimum time for the cardioprotective effect of ALM-802 to prevent or treat the resulting heart failure, because short-term systematic therapy (15 days) produced no positive effect.
Subject(s)
Heart Ventricles/metabolism , Myocardial Infarction/metabolism , Animals , Chronic Disease , Disease Models, Animal , Heart Failure/genetics , Heart Failure/metabolism , Male , Myocardial Infarction/genetics , RatsABSTRACT
The anxiolytic and analgesic properties of compound ALM-802, a cardiotropic linear methoxyphenyltriazaalkane derivative, combining pharmacophore elements of p-FOX inhibitors trimetazidine and ranolazine were studied in vivo. In the elevated plus-maze test, ALM-802 after acute intraperitoneal administration in doses of 1-8 mg/kg dose-dependently prevented the development of anxiety in BALB/c mice. Chronic intraperitoneal administration of ALM-802 in a dose of 2 mg/kg to alcohol-preferring rats attenuated anxiogenesis induced by ethanol withdrawal. ALM-802 demonstrated antinociceptive activity in C57BL/6 mice during thermal stimulation of nociceptors in the hot plate test and during modeling of visceral pain in the acetic acid writhing test. Thus, ALM-802 exhibits anxiolytic and analgesic properties in the dose range corresponding to its anti-ischemic and antiarrhythmic effects.
Subject(s)
Nociception/drug effects , Trimetazidine/therapeutic use , Animals , Anxiety/drug therapy , Anxiety/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Nociceptors/metabolism , Pain/drug therapy , Pain/metabolismABSTRACT
The mechanisms underlying cardioprotective activity of compound ALM-802 were studied in experiments on rats with chronic post-infarction heart failure. Real-time PCR showed that compound ALM-802 (daily intraperitoneal injections in a dose of 2 mg/kg for 28 days starting from day 91 after myocardial infarction modeling) restored the expression of genes encoding ß1- (p=0.00001) and ß2-adrenoreceptors (p=0.01) and type 2 ryanodine receptors (p=0.008) in the myocardium that was reduced in control animals. These effects can serve as the basis for the ability of the compound to reduce the intensity of remodeling and increase the inotropic function of the left heart ventricle shown earlier in this model.
Subject(s)
Heart Failure/drug therapy , Heart Failure/metabolism , Receptors, Adrenergic/metabolism , Animals , Cardiotonic Agents/therapeutic use , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Male , Myocardium/metabolism , RNA, Messenger/metabolism , Rats , Ryanodine Receptor Calcium Release Channel/metabolismABSTRACT
A translational rat model of chronic heart failure was employed to examine the cardioprotective effect of fabomotizole hydrochloride. Fabomotizole therapy for 28 days (15 mg/kg/day intraperitoneally) restored inotropic function of the left ventricle and increased ejection fraction from 54±3 to 65±3% (p=0.001). The inotropic function returned to normal against the background of significantly reduced myocardial expression of angiotensin (p=0.01) and glucocorticoid (p=0.03) receptors and significant increased expression of sigma-1 receptors (p=0.04). Inhibition of abnormal expression of angiotensin and glucocorticoid receptors responsible for activation of the pathological cascades underlying the postinfarction remodeling of the left ventricle as well as activation of the expression of cytoprotective sigma-1 receptors are viewed as the key features of the cardioprotective action of fabomotizole hydrochloride.
Subject(s)
Benzimidazoles/therapeutic use , Heart Failure/drug therapy , Angiotensins/metabolism , Animals , Echocardiography , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Rats , Receptors, Glucocorticoid/metabolism , Receptors, sigma/metabolism , Sigma-1 ReceptorABSTRACT
Anti-ischemic activity of fabomotizole hydrochloride was studied on the model of subendocardial ischemia in rats with endothelial dysfunction. Endothelial dysfunction was modeled by intragastric administration of methionine (3 g/kg, once a day for 7 days). Acute subendocardial ischemia was induced in narcotized rats by intraperitoneal injection of isoproterenol (20 µg/kg/min over 5 min). Fabomotizole hydrochloride (intraperitoneally, 15 mg/kg) significantly reduced isoproterenol-induced ST segment depression in animals with endothelial dysfunction and with intact vasculature.
Subject(s)
Benzimidazoles/pharmacology , Cardiotonic Agents/pharmacology , Endocardium/drug effects , Endothelium, Vascular/drug effects , Morpholines/pharmacology , Myocardial Ischemia/prevention & control , Animals , Animals, Outbred Strains , Disease Models, Animal , Endocardium/physiopathology , Endothelium, Vascular/physiopathology , Isoproterenol/adverse effects , Isoproterenol/antagonists & inhibitors , Male , Methionine/adverse effects , Methionine/antagonists & inhibitors , Myocardial Ischemia/chemically induced , Myocardial Ischemia/physiopathology , Rats , Treatment OutcomeABSTRACT
We created a translational model of chronic heart failure in rats that developed in 3 months after reproducing experimental anterior transmural myocardial infarction. The model simulated the basic clinicodiagnostic criteria of this disease: impaired contractility and dilatation of heart ventricles, signs of venous congestion, elevated plasma content of biochemical markers, and abnormal overexpression of AT1aR and ß-adrenoceptors.
Subject(s)
Disease Models, Animal , Heart Failure/physiopathology , Heart Ventricles/physiopathology , Myocardial Infarction/physiopathology , Myocardium/pathology , Animals , Animals, Outbred Strains , Biomarkers/metabolism , Echocardiography , Gene Expression , Heart Failure/diagnostic imaging , Heart Failure/genetics , Heart Failure/metabolism , Heart Ventricles/diagnostic imaging , Heart Ventricles/metabolism , Hemodynamics/physiology , Humans , Male , Myocardial Contraction/physiology , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/genetics , Myocardial Infarction/metabolism , Myocardium/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptors, Adrenergic, beta-1/genetics , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-2/genetics , Receptors, Adrenergic, beta-2/metabolism , Translational Research, Biomedical/methodsABSTRACT
Anti-ischemic activity of N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino] ethyl}-1,2-ethanediamine (ALM-802) based on the structure of standard p-FOX inhibitors trimetazidine and ranolazine was studied on the model of endocardial ischemia in intact rats and animals with endothelial dysfunction. Acute endocardial myocardial ischemia was caused by infusion of isoproterenol (20 µg/kg/min intravenously). Endothelial dysfunction in rats was modeled by inducing hyperhomocysteinemia (3 g/kg methionine intragastrically one a day over 7 days). The reference drugs trimetazidine (30 mg/kg, intravenously) and ranolazine 10 mg/kg, intravenously) that were effective only in intact rats. In contrast, ALM-802 (2 mg/kg, intravenously) showed a pronounced anti-ischemic effect in animals with endothelial dysfunction, which suggests that the mechanisms of its cardioprotective action differ from those known for p-FOX inhibitors.
Subject(s)
Hyperhomocysteinemia/drug therapy , Myocardial Infarction/drug therapy , Ranolazine/therapeutic use , Trimetazidine/therapeutic use , Animals , Electrophysiology , Hyperhomocysteinemia/chemically induced , Isoproterenol/toxicity , Male , Myocardial Infarction/chemically induced , RatsABSTRACT
The effectiveness of antibody-based release-active preparations Impaza (antibodies to eNOS), Tenoten (antibodies to brain-specific protein S-100), Dietressa (antibodies to type 1 cannabinoid receptor), Brizantin (combined preparation, antibodies to brain-specific protein S-100 and type 1 cannabinoid receptor), and Divaza (combined preparation, antibodies to brain-specific protein S-100 and eNOS) in the prevention of vertigo was studied on the model of intermittent accumulation of Coriolis accelerations (ICCA). Modification of activity of vestibular receptors and signal systems by release-active preparations contributed to an increase in ICCA tolerance time. Combined preparation Impaza possessed the most significant antinaupathic properties. Brizantin was less potent in this respect.
Subject(s)
Antibodies/therapeutic use , Space Motion Sickness/prevention & control , Acceleration/adverse effects , Adolescent , Adult , Coriolis Force , Double-Blind Method , Drug Combinations , Female , Humans , Male , Middle Aged , Nausea/etiology , Nausea/physiopathology , Nausea/prevention & control , Nitric Oxide Synthase Type III/immunology , Primary Dysautonomias/etiology , Primary Dysautonomias/physiopathology , Primary Dysautonomias/prevention & control , Receptor, Cannabinoid, CB1/immunology , S100 Proteins/immunology , Severity of Illness Index , Space Motion Sickness/etiology , Space Motion Sickness/physiopathology , Vestibule, Labyrinth/drug effects , Young AdultABSTRACT
Anti-sea-sickness effect of a new homeopathic drug [see text] and its influence on operator's working capacity during Coriolis acceleration was evaluated in blind placebo-controlled investigation conducted in practically healthy volunteers with low vestibular resistance. For comparison "Dimenhydrinate" was used. The investigation has demonstrated that [see text] has rather strong anti-sea-sickness effect, is comparable with dimenhydrinate effectiveness and prevents the development of disorders in sensory-and-motor and cognitive functions during the influence of static-and- kinetic loads. According to the data obtained the protective action of [see text] is most likely connected with adaptive effect on organs and systems that form the functional protective system against sea-sickness. The negative influence of the drug on CNS complex functions was not observed that allows recommending its prophylactic use in subjects with low sea-sickness resistance including the operators.