ABSTRACT
We studied the mechanisms of action of imidazobenzimidazole derivative RU-1117 on calcium homeostasis in myocytes isolated from rat thoracic aorta. In therapeutic concentrations, RU-1117 increased the content of free calcium ions due to their mobilization from intracellular depot via the IP3-dependent mechanisms. Antagonists of angiotensin II AT1-receptors irbesartan and, to greater extent, eprosartan abolished the calcium-mobilizing action of RU-1117. Selective antagonist of endothelin ETA-receptors sitaxsentan and alpha1-adrenoceptor agonist prazosin produced no effect on calcium mobilization caused by novel local anesthetic RU-1117.
Subject(s)
Anesthetics, Local/pharmacology , Benzimidazoles/pharmacology , Muscle, Smooth, Vascular/drug effects , Vasoconstrictor Agents/pharmacology , Animals , Calcium/metabolism , Cells, Cultured , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/metabolism , RatsABSTRACT
Conformation and kinetic characteristics of the interactions of local anesthetics lidocaine (xycaine), tetracaine (dicaine), bupivacaine, and new RU-1117 compound with proven anesthetic activity with Visiton (1% hydroxypropylmethylcellulose in phosphate buffer) were studied. It was found that complex formation between the local anesthetics and hydroxypropylmethylcellulose is a time-dependent reversible process. The equilibrium is attained within 2.5-8.0 h and depends on the chemical nature of local anesthetic.
Subject(s)
Anesthetics, Local/chemistry , Methylcellulose/analogs & derivatives , Hypromellose Derivatives , Kinetics , Methylcellulose/chemistry , Molecular Conformation , Solutions , WaterABSTRACT
We studied kinetic parameters of interaction of local anesthetics (lidocaine, tetracaine, bupivacaine, and two novel agents with proved local anesthetic potency RU-353 and RU-1117) with human serum albumin. Complexation of local anesthetics with human serum albumin is a time-dependent and reversible process; equilibrium was attained within 1.5-4.5 h depending on chemical nature of local anesthetics.
Subject(s)
Anesthetics, Local/chemistry , Serum Albumin/chemistry , Benzimidazoles/chemistry , Bupivacaine/chemistry , Humans , Kinetics , Lidocaine/chemistry , Tetracaine/chemistryABSTRACT
Voltage clamp and concentration jump experiments performed on Purkinje cells isolated from rat cerebellum showed that novel imidazobenzoimidazole derivative RU-353 increased the amplitude of GABA-activated chlorine current in a dose-dependent manner (EC50=15 microM for the currents activated by 1 microM GABA). RU-353 shifted the GABA dose-response curve to the left, but produced no effect on the maximum response (EC50 in control and in the presence of 30 microM RU-353 were 6.9 and 2.0 microM, respectively).
Subject(s)
Benzimidazoles/pharmacology , Ion Channels/metabolism , Purkinje Cells/drug effects , gamma-Aminobutyric Acid/pharmacology , Animals , Drug Synergism , GABA-A Receptor Agonists , Ion Channels/drug effects , Purkinje Cells/physiology , Rats , Receptors, GABA-A/drug effectsABSTRACT
Conduction anesthesia of the vagus nerve produced by procaine (0.5%), marcaine (0.25%), richlocaine (0.5%), and imidazobenzoimidazole derivative RU-353 (0.25%) was compared in acute experiments on cats. RU-353 produced the most long-term local anesthesia (assessed by inhibition of cardiochronotropic effect of vagus nerve).
Subject(s)
Anesthesia, Conduction , Anesthetics, Local/pharmacology , Benzimidazoles/pharmacology , Bupivacaine/pharmacology , Piperidines/pharmacology , Procaine/pharmacology , Animals , Cats , Drug Evaluation, Preclinical , Vagus Nerve/drug effectsABSTRACT
We demonstrated a dose-dependent inhibitory effect of novel imidazobenzoimidazole derivatives RU-353 and RU-563 on cerebral blood flow and systemic blood pressure in narcotized rats. The effects of RU-353 increased, while the effect of RU-563 decreased with increasing the dose.
Subject(s)
Benzimidazoles/pharmacology , Cerebrovascular Circulation/drug effects , Lidocaine/pharmacology , Animals , Dose-Response Relationship, Drug , Male , Rats , Rats, WistarABSTRACT
We propose a new method for evaluation of conduction anesthesia in animals: by the degree of prolongation of cardiac cycle during vagus nerve stimulation by solitary electric discharges synchronous to the dominant ECG wave, proximally from the site of anesthetic application on the nerve.
Subject(s)
Anesthesia, Conduction/standards , Animals , CatsABSTRACT
Eight types of peaks were revealed in the cardiac rhythm spectrum during acute experiments on vagotomized cats. Some peaks had no physiological nature and resulted from specificity of ECG processing by Fourier analysis, while others reflected myogenic reaction of the sinoatrial node (length-dependence of automaticity) to changes in venous return caused by respiratory-induced and other variations of the blood flow in the cardiovascular system.
Subject(s)
Electrocardiography , Heart Rate/physiology , Animals , Cats , Chloralose/administration & dosage , Fourier Analysis , Heart/innervation , Heart Rate/drug effects , Narcotics/administration & dosage , Pentobarbital/administration & dosage , VagotomyABSTRACT
Experiments on random-bred albino rats showed that application of local anesthetic RU-353 to the dorsal nuclei of the vagus nerve produced edematous or antiedematous effects in the lungs. Our findings open new vistas in prevention of centrogenous forms of water imbalance in the lungs.
Subject(s)
Anesthetics, Local/adverse effects , Anesthetics, Local/therapeutic use , Medulla Oblongata/drug effects , Pulmonary Edema/chemically induced , Pulmonary Edema/drug therapy , Animals , Medulla Oblongata/pathology , RatsABSTRACT
We compared the effects of local anesthetics procaine, amethocaine (dicaine), bupivacaine, and a new agent RU-1148 on hydrolytic activity of human plasma butyrylcholinesterase. The butyrylcholinesterase-blocking activity of the test substances decreased in the following order: bupivacaine>amethocaine>procaine>RU-1148. The study of the capacity of these agents to form complexes with human plasma proteins and serum albumin showed that RU-1148 in therapeutic concentrations was transported by human serum albumin,beta-globulin, and acid glycoproteins. Study of the mechanisms of pharmacodynamic interactions between clonidine and RU-1148 demonstrated good prospects of their combined use.
Subject(s)
Anesthetics, Local/pharmacokinetics , Benzimidazoles/pharmacokinetics , Butyrylcholinesterase/blood , Cholinesterase Inhibitors/pharmacokinetics , Blood Proteins/metabolism , Fluorescent Dyes/metabolism , Humans , Platelet Aggregation , Serum Albumin/metabolismABSTRACT
We studied the mechanisms of combined action of clonidine and local anesthetics amethocaine and imidazo-benzimidazole derivative RU-1117. In contrast to amethocaine, RU-1117 in therapeutic concentrations binds to imidazoline receptors and, to a lesser extent, to alpha(2A)-adrenoceptors on human platelets. Clonidine and RU-1117 produce opposite effects on platelet aggregation induced by ADP in low concentrations. Our results suggest that the pharmacodynamic interaction of clonidine and RU-1117 is associated with their ability to activate the imidazolinergic system.
Subject(s)
Anesthetics, Local/pharmacology , Benzimidazoles/pharmacology , Clonidine/pharmacology , Adenosine Diphosphate/metabolism , Adrenergic alpha-Agonists/pharmacology , Benzimidazoles/chemistry , Blood Platelets/drug effects , Blood Platelets/metabolism , Humans , Imidazoline Receptors , Inhibitory Concentration 50 , Platelet Aggregation/drug effects , Protein Binding , Receptors, Adrenergic, alpha-2/metabolism , Receptors, Drug/chemistry , Tetracaine/pharmacology , Time FactorsABSTRACT
We studied parameters of specific binding for various ligands of imidazole receptors and alpha2-adrenoceptors on human platelets. Pharmacological activity of compounds was evaluated by their effects on platelet aggregation induced by ADP in low concentrations (0.125-1.5 microM). In contrast to alpha2-adrenoceptor agonist norepinephrine inducing reversible aggregation of cells, selective stimulation of imidazole receptors with moxonidine produced a disaggregation effect. The data suggest that human platelets can be used as an experimental test system for screening and study of molecular mechanisms underlying the influence of new compounds.
