CN110917195A - The muscle relaxant acalciumchloride (Alcuronium chloride) can be used as antiarrhythmic drug - Google Patents
The muscle relaxant acalciumchloride (Alcuronium chloride) can be used as antiarrhythmic drug Download PDFInfo
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- acalciumchloride
- arrhythmia
- chloride
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- zacopride
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/5545—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having eight-membered rings not containing additional condensed or non-condensed nitrogen-containing 3-7 membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Abstract
The invention discloses application of acalciumchloride in preparation of a medicament for treating arrhythmia. The invention discovers that the acaroconium chloride can be effectively used as I for the first timeK1The specific agonist has similar effect to zacopride, and can be used for preparing medicaments with anti-arrhythmia effect, thereby providing a new way for effective and safe treatment.
Description
Technical Field
The invention relates to a cardiovascular disease medicament, in particular to application of muscle relaxant acalciumchloride in preparing a medicament for treating arrhythmia.
Background
Arrhythmia refers to the abnormality of heart beat frequency and rhythm, and serious arrhythmia is one of the main causes of death of patients with cardiovascular diseases. The mechanism for forming severe arrhythmia is complex and often not single, but at the very least, there is a change in the functional activity of myocardial ion channels, and thus the change in ion current affects the occurrence and morphology of action potential. Those drugs that are able to change the action potential may thus have an arrhythmogenic risk or an antiarrhythmic effect.
The current antiarrhythmic drugs applied clinically are almost all various ion channel blockers, the main targets of the antiarrhythmic drugs act on Na, Kv and Ca ion channels, and the drugs for treating the tachyarrhythmia are divided into four types according to the action of the drugs on the ion channels and receptors:
class I: sodium channel blockers
Ⅰa: moderate intensity (moderate blockade of sodium channels), quinidine, procainamide
Ⅰb: mild blockade of sodium channels, lidocaine, phenytoin sodium, mexiletine, tocainide
Ⅰc: severe blockade of sodium channels, propafenone, flecainide
The medicine can block sodium channel, change the conduction of unidirectional tissue area and eliminate reentry.
β receptor blockers, such as propranolol, which cause reduced 4-phase depolarizing current and reduced autonomy.
Class III: the action potential time course prolonging medicine (potassium channel blocking medicine) such as amiodarone can inhibit Kv channel, reduce the outflow of repolarization 3-phase potassium ions, obviously prolong the action potential time course, prolong the effective refractory period and eliminate the reentry.
And IV: calcium channel blockers, such as verapamil and diltiazem, block calcium channels, reduce the influx of action potential 4-phase calcium ions, reduce the autonomy of slow-reacting cells, and can be used to treat supraventricular arrhythmias.
The four main treatments for tachyarrhythmia
At present, any antiarrhythmic drug has certain arrhythmogenic effect. Class i drugs can induce reentry by blocking sodium channels and slowing conduction; class iii drugs induce long QT syndrome by prolonging the time course of action potential. This has attracted attention and it is urgent to find new and safer treatments. After the middle of the nineties, great progress is made in treating various kinds of arrhythmia by cardiac catheter interventional technology, and a new direction for treating arrhythmia is developed. However, interventional therapy has a range of indications, and therefore, for most patients with cardiac arrhythmias, drug therapy is still the primary method of treatment or an essential component.
The causes of arrhythmia caused by antiarrhythmic drugs are manifold, and many scholars think that a new thought should be developed to search for new drugs.
Inward rectifier potassium channel (I)K1)The load current is the most dominant background outward current of the myocardium and is involved in the maintenance of Resting Potential (RP) and repolarization at the end of the myocardial Action Potential (AP) 3 phase (fig. 1). Regulation IK1The stability of resting membrane potential and action potential repolarization of cardiac muscle are influenced, so that the excitability of cardiac muscle and the occurrence of arrhythmia are deeply influenced.
IK1The drug is a new target of the anti-arrhythmia drug. However, none of the current antiarrhythmic drugs in clinical use is IK1As a main target. The reason for this comes from two aspects: one is that to date there is no highly selective IK1A blocker or an agonist. Lack of necessary pharmacological tools greatly limits IK1Study of relationship to arrhythmia; secondly, although many experimental studies confirm that I is blockedK1Can effectively inhibit reentry arrhythmia, but block IK1The risks involved are also obvious. Theoretically, IK1The inhibition will make the membrane depolarize, the excitability and autonomy of the cell increase, and the trigger activity such as depolarization (DAD) after the easy change delay; i isK1The inhibition of the membrane increases the membrane resistance, amplifies the membrane potential fluctuation caused by transmembrane current, and causes the instability of the membrane potential; inhibition of IK1It also prolongs action potential time course (APD), leading to long QT syndrome. Numerous studies have demonstrated thatK1The acquired or absent function of (a) is involved in the development of arrhythmia and pathological remodeling. But has been due to lack of high selectivity IK1Blockers or agonists, and methods for altering myocardial I using transgenics or gene knock-outsK1Expression, far from physiological state, makes the relevant studies extremely restrictive. In 2012, Wu Bo Wei professor topic group reported a I for the first timeK1The selective agonist, zacopride, by agonism IK1Can increase the negative value of resting potential (hyperpolarization) and slightly shorten the action potential time course (Liu QH, Li XL, Xu YW, Lin YY, Cao JM, Wu BW. A Novel Discovery of I)K1Channel Agonist: Zacopride Selectively Enhances IK1Current and pressesTriggered Arrhythmias in the rat J Cardiovasc Pharmacol, 2012, 59(1): 37-48.). But has no significant effect on other major ion channels or exchangers affecting action potential, such as Ito, ICa-L, INa/Ca, Iump, IK (guinea pig) and the like. Using this tool medicine, IK1The role in cardiac arrhythmias is gradually elucidated. The subject group firstly proves moderate agitation I on an acute myocardial ischemia model and a chronic arrhythmia model after myocardial infarction of ratsK1The channel has inhibitory effect on ischemic arrhythmia.
Ischemic arrhythmias are the more common and more dangerous arrhythmias in the clinic. Various types of myocardial ischemia can induce arrhythmia, mainly ventricular arrhythmia, which is the main reason for early death of patients with myocardial infarction; in people who survive an acute myocardial infarction, more than 50% still die from fatal ventricular arrhythmias. Cardiac arrhythmias arising during myocardial ischemia and myocardial infarction have also been demonstrated with IK1Is concerned with the decline. The study shows that the myocardium I of the rat chronic animal myocardial infarction modelK1The reduction is 20%; and chronic myocardial infarction rabbit non-infarct zone ventricular myocyte IK1Is also obviously reduced; pinto et al demonstrated that the reduction in subendocardial Purkinje fiber resting potential in the ischemic area of the dog myocardium was due to IK1The result is reduced. Kiesecker et al in human cardiomyocytes demonstrate that endothelin can significantly inhibit IK1This effect is an important mechanism of endothelin-induced ischemic arrhythmia. Myocardial ischemia time IK1The down regulation and/or the function weakening reduce the conductance of the resting potassium, so that the resting potential (negative value) is reduced, the excitation conduction is slowed down, and the reentry is easy to form; decreased potassium conductance also causes instability of membrane potential and increased abnormal autonomic activity, which are important causes of cardiac arrhythmias occurring during myocardial ischemia (both acute and chronic).
However, until now, only zacopride I has been usedK1Specific agonists are publicly reported. Establishment of the stimulated myocardium IK1The theoretical relationship with antiarrhythmic is still weak, and a new I needs to be found urgentlyK1A specific agonist.
Disclosure of Invention
At present, any antiarrhythmic drug has certain arrhythmogenic effect, and the drug is used as IK1 agonist, possibly having antiarrhythmic effect, can become a new way of effective and safe treatment. In this regard, the inventors analyzed and considered that IK1The selective agonist zacopride (zacopride), via agonism IK1The negative value of the resting potential can be increased (hyperpolarization), and the action potential time course is slightly shortened. In this regard, a drug relocation platform based on omics big data seeks zacopride effect analogues, a human colorectal cancer cell line HCT116 is used, zacopride incubation is performed for 24h, and row transcriptome sequencing (RNA-seq) is performed to verify the differential expression analysis results of two groups "Ctl _ VS _ Za _1 (control VS zacopride 1 μ M) and Ctl _ VS _ Za _40 (control VSzacopride 40 μ M)", and after the differential results are consistent, two groups of differential genes are obtained: 226 difference genes in the Ctl _ VS _ Za _1 group are up-regulated by 187 and down-regulated by 39; the Ctl _ VS _ Za _40 group of differential genes has 302 genes, 250 genes are up-regulated and 52 genes are down-regulated. The two groups of differentially expressed genes are introduced into a drug relocation platform based on transcriptome data, and finally the obtained acalciumchloride may have similar effects with zacopride, and is not reported in documents.
Therefore, the research of the invention finds that the acaroconium chloride can be effectively used as IK1A specific agonist having a similar effect to zacopride. Therefore, a new drug can be expected to be developed.
Therefore, the invention provides the application of the acalciumchloride in preparing the medicine for treating arrhythmia.
Wherein the medicine is capsule, microcapsule, liposome, granule, injection, tablet, or oral liquid.
Preferably, the dosage of the acaroconium chloride is 0.06-6 mg/kg.
Further, acalciumchloride is used in combination with a sodium channel blocker, an β receptor blocker, a potassium channel blocker, and a calcium channel blocker.
The invention discovers that the acaroconium chloride can be effectively used as I for the first timeK1A specific agonist having an effect similar to zacopride,can be used for preparing medicaments with anti-arrhythmia effect, thereby providing a new way for effective and safe treatment.
Drawings
Figure 1 is involved in the formation of ion channels and corresponding phases of myocardial Action Potentials (AP).
FIG. 2 shows that acalciumchloride can increase the resting potential and shorten the action potential time course.
Figure 3 acalcium chloride (Alcuronium chloride) up-regulates rat left ventricular myocyte IK1 protein expression (. P < 0.05).
Detailed Description
The invention is further illustrated below with reference to specific embodiments.
The experimental method comprises the following steps: detecting the influence of the acalciumchloride on the resting potential and the action potential of the myocardial cells of the adult rat on the myocardial cells of the left ventricle
(1) The experimental method comprises the following steps: patch clamp whole cell recording, voltage clamp mode recording membrane current, current clamp mode recording membrane potential.
(2) And (3) observation indexes are as follows: ventricular muscle resting potential (RMP), Action Potential Amplitude (APA) and time course (APD) of rats before and after drug action50，APD90) A change in (c).
Example one, the effect of the muscle relaxant acalcium chloride (Alcuronium chloride) on resting and action potentials of the left ventricular myocytes.
Due to IK1Is the main ion flux that determines resting potential (RMP) levels and Action Potential (AP) 3-phase end repolarization, we first observed the effect of the muscle relaxant acac chloride on resting and action potentials of left ventricular myocytes.
(1) Acute separation of rat left ventricular cardiomyocytes by collagenase method
Healthy adult male SD rats (with the weight of 220-250 g) are selected, pentobarbital sodium (40 mg/kg) is injected into the abdominal cavity for anesthesia, the heart is taken out quickly after the carotid artery is exsanguinated and is placed in a calcium-free Taiwan liquid (precooling at 4 ℃ and oxygen saturation at 100%), and the heart is hung in a Langendorff perfusion device for perfusion after being trimmed quickly (the perfusion liquid is filled with oxygen at 100% in the whole process and is filled into coronary arteries through the aorta in a retrograde manner)). Perfusing for 8-10 min (without calcium Taiwanese solution), and then changing the solution (collagenase solution) for circulating perfusion for 15-20 min. Perfusion conditions: the room temperature and the perfusion liquid are kept constant at 37 ℃ all the time, and the perfusion pressure is 80 cmH 2O. Dividing prepared KB liquid into A, B parts, observing that heart muscle tissues become large and soft, rapidly cutting off the left ventricle when the coronary vessel edge is unclear, rapidly washing with the liquid A, then placing the left ventricle into the liquid A, shearing the left ventricle to 2-3mm3 small blocks in an ophthalmic scissors, and lightly blowing and beating the left ventricle for 3-5 min by using a glass pipette (the tip is round and smooth so as to avoid damaging muscle cells). And filtering the solution A (a filter screen with the aperture of 150 mu m), placing the filtrate in the solution B, standing for 2-3 hours (at room temperature), and then carrying out an experiment.
(2) Whole cell patch clamp recordings
Blowing off the cells standing in the high-potassium KB solution, performing gradient calcium recovery (the final concentration is 1.8 mmol/L), sucking 2-3 drops of cell suspension according to the cell density, dripping the cell suspension into a cell pool containing about 1 ml of the desktop solution, standing for 10 min, and perfusing with the desktop solution at the flow rate of 2 ml/min after the cells are fully attached to the wall. And filling the glass electrode with the corresponding electrode internal liquid, wherein the resistance is about 2-5M omega after the glass electrode is filled with the liquid. Rod-shaped myocardial cells with smooth surfaces, clear transverse striations, no autonomous contraction and no overlapping with surrounding cells are selected as experimental cells. Negative pressure suction forms high-resistance (> 1G omega) sealing, electrode capacitance compensation is carried out, negative pressure membrane rupture is carried out after the electrode capacitance compensation is stabilized for 2-3 min, and the influence of drugs with different concentrations on rat ventricular myocytes RMP and AP is respectively observed in a current clamp mode.
(3) As shown in fig. 2, acalciumchloride dose-dependently increased the resting potential and shortened the end repolarization time of the action potential (APD 90).
Example II Acrocuronium chloride (Alcuronium chloride) upregulates rat left ventricular myocytes IK1Protein expression
In rat ventricular myocytes, Kir2.1 is component IK1The most predominant subset of channel proteins. The expression of Kir2.1 protein was detected by incubating rat left ventricular myocytes isolated by collagenase method with 10. mu. mol/L of acammonium chloride for 24 hours. Acalciumchloride can up-regulate rat ventricular myocyte IK1Protein expression (P)<0.05) (FIG. 3), indicating that acalciumchloride can be used as IK1An agonist of (4).
The research result shows that the action characteristics of the ammonium chloride (Alcuronium chloride) on the action potential conform to IK1The agonist is characterized and confirmed to be I by immunoblottingK1An agonist. Moderate enhancement IK1The mechanism of resisting ischemic arrhythmia is that ① resting potential negative value is increased to reverse membrane depolarization caused by pathological factor, reduce excitability of cell, ② increase availability of sodium channel, raise myocardial conduction speed in ischemic area and eliminate reentry [19 ]]③ it can increase membrane conductivity, reduce abnormal membrane potential fluctuation caused by membrane current change, and increase electrical stability of membrane, ④ shorten action potential time course (APD) to prevent early-late depolarization (EAD) and trigger arrhythmia caused by it.
Therefore, the application of the ammonium chloride (Alcuronium chloride) can be used as a novel antiarrhythmic drug and has the function of resisting ventricular arrhythmia.
It will be understood that modifications and variations can be made by persons skilled in the art in light of the above teachings and all such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.
Claims (4)
1. Application of acalciumchloride in preparing medicine for treating arrhythmia is disclosed.
2. The use of claim 1, wherein: the medicine is capsule, microcapsule, liposome, granule, injection, tablet, or oral liquid.
3. The use of claim 1, wherein: the dosage of the acaroconium chloride is 0.06-6 mg/kg.
4. The use of claim 1 wherein the acaroconium chloride is used in combination with a sodium channel blocker, an β receptor blocker, a potassium channel blocker, a calcium channel blocker.
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