HMR 1883

Last updated

HMR 1883 (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3 methylthiourea) and its sodium salt HMR 1098, are experimental anti-arrhythmic drugs classified as sulfonylthiourea compounds. [1] Their main purpose is to treat ventricular fibrillation caused by myocardial ischemia. They were synthesized via structural modifications to glibenclamide, an antidiabetic drug. [1] Both HMR 1883 and glibenclamide act by inactivating the ATP-sensitive potassium channels (KATP) responsible for potassium efflux. [2] Unlike glibenclamide, HMR 1883 has been suggested to target selectively the Kir6.2/SUR2A KATP subtype, found mostly in the membranes of cardiac cells. [3] However, data showing that HMR 1098 inhibits the Kir6.2/SUR1 KATP subtype found in insulin-secreting pancreatic beta cells challenges this view. [4]

Contents

Mechanism

Hypoxia provokes potassium efflux from cardiac muscles cells via the activation of ATP-sensitive potassium channels (KATP). [5] Potassium efflux from cardiac cells decreases action potential duration and results in non-uniform repolarization of the cardiac cells. [6] The heterogeneous repolarization of the cardiac tissue permits reentry of action potentials into conducting pathways, which manifests as malignant arrhythmias in the heart. [6] HMR 1883 is a cardioselective ATP-sensitive potassium channel antagonist that prevents the potassium efflux, hence correcting the non-uniform refractory period in the ischemic tissue. A uniform refractory period corrects the conductance problems in the heart and prevents the re-entry arrhythmias.

Side effects

HMR 1883 attenuates is chemically induced arrhythmias with little to no side effects as a result of having a higher affinity for the cardiac tissue KATP subtype than any other subtype found in the body. [2] In contrast, glibenclamide interacts with many KATP channels throughout the body resulting in many side effects. In particular its interaction with coronary smooth muscle cells and pancreatic-β cells cause decreased coronary blood flow, hyperinsulinemia, and hypoglycemia. [2] Since KATP channels only become activated during periods of low ATP and High ADP, HMR 1883 only affects hypoxic tissue and has no negative effect on the normal tissue. [2] Activation of the KATP channels on cardiac mitochondria is involved in ischemic preconditioning that results in protection for the heart. [7] It was shown that HMR 1883 did not interfere with the mitochondrial protective mechanisms in both rat [8] and rabbit [9] models. By not inhibiting the mitochondrial KATP channel subtype, HMR 1883 can treat cardiac arrhythmias while permitting mitochondrial protective mechanisms.

Research

HMR 1883 has been shown to attenuate and decrease ventricular fibrillation in anesthetized pigs, [10] rats [11] and conscious dogs. [10] Its sodium salt, HMR 1098, has been shown to decrease ventricular fibrillation in rabbit hearts, [12] anesthetized rats [13] and dogs. [14]

Related Research Articles

<span class="mw-page-title-main">Ventricular fibrillation</span> Rapid quivering of the ventricles of the heart

Ventricular fibrillation is an abnormal heart rhythm in which the ventricles of the heart quiver. It is due to disorganized electrical activity. Ventricular fibrillation results in cardiac arrest with loss of consciousness and no pulse. This is followed by sudden cardiac death in the absence of treatment. Ventricular fibrillation is initially found in about 10% of people with cardiac arrest.

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.

<span class="mw-page-title-main">Torsades de pointes</span> Type of abnormal heart rhythm

Torsades de pointes, torsade de pointes or torsades des pointes is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram (ECG). It was described by French physician François Dessertenne in 1966. Prolongation of the QT interval can increase a person's risk of developing this abnormal heart rhythm, occurring in between 1% and 10% of patients who receive QT-prolonging antiarrhythmic drugs.

<span class="mw-page-title-main">Glibenclamide</span> Chemical compound

Glibenclamide, also known as glyburide, is an antidiabetic medication used to treat type 2 diabetes. It is recommended that it be taken together with diet and exercise. It may be used with other antidiabetic medication. It is not recommended for use by itself in type 1 diabetes. It is taken by mouth.

Cardioplegia is a solution given to the heart during cardiac surgery, to minimize the damage caused by myocardial ischemia while the heart is paused.

<span class="mw-page-title-main">Levosimendan</span> Pharmaceutical drug

Levosimendan (INN) is a calcium sensitizer used in the management of acutely decompensated congestive heart failure. It is marketed under the trade name Simdax. Overall the drug has a two fold mechanism of action. It leads to greater inotropy by increasing the calcium sensitivity as it binds to troponin and this results in a greater positive inotrophic force. Secondly, the drug is able to open ATP sensitive potassium channels in vascular smooth muscle cells, and the vascular dilatory effects of the drug lead to a decreased preload and afterload, putting less work on the heart. This drug is in the process of review by the FDA but has not been approved for use in the United States yet.

Ischemic preconditioning (IPC) is an experimental technique for producing resistance to the loss of blood supply, and thus oxygen, to tissues of many types. In the heart, IPC is an intrinsic process whereby repeated short episodes of ischaemia protect the myocardium against a subsequent ischaemic insult. It was first identified in 1986 by Murry et al. This group exposed anesthetised open-chest dogs to four periods of 5 minute coronary artery occlusions followed by a 5-minute period of reperfusion before the onset of a 40-minute sustained occlusion of the coronary artery. The control animals had no such period of “ischaemic preconditioning” and had much larger infarct sizes compared with the dogs that did. The exact molecular pathways behind this phenomenon have yet to be fully understood.

An ATP-sensitive potassium channel is a type of potassium channel that is gated by intracellular nucleotides, ATP and ADP. ATP-sensitive potassium channels are composed of Kir6.x-type subunits and sulfonylurea receptor (SUR) subunits, along with additional components. KATP channels are widely distributed in plasma membranes; however some may also be found on subcellular membranes. These latter classes of KATP channels can be classified as being either sarcolemmal ("sarcKATP"), mitochondrial ("mitoKATP"), or nuclear ("nucKATP").

In molecular biology, the sulfonylurea receptors (SUR) are membrane proteins which are the molecular targets of the sulfonylurea class of antidiabetic drugs whose mechanism of action is to promote insulin release from pancreatic beta cells. More specifically, SUR proteins are subunits of the inward-rectifier potassium ion channels Kir6.x. The association of four Kir6.x and four SUR subunits form an ion conducting channel commonly referred to as the KATP channel.

K<sub>ir</sub>6.2 Protein-coding gene in the species Homo sapiens

Kir6.2 is a major subunit of the ATP-sensitive K+ channel, a lipid-gated inward-rectifier potassium ion channel. The gene encoding the channel is called KCNJ11 and mutations in this gene are associated with congenital hyperinsulinism.

<span class="mw-page-title-main">KCNJ8</span> Protein-coding gene in humans

Potassium inwardly-rectifying channel, subfamily J, member 8, also known as KCNJ8, is a human gene encoding the Kir6.1 protein. A mutation in KCNJ8 has been associated with cardiac arrest in the early repolarization syndrome.

<span class="mw-page-title-main">Tedisamil</span> Chemical compound

Tedisamil (3,7-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo-3,3,1-nonane) is an experimental class III antiarrhythmic agent currently being investigated for the treatment of atrial fibrillation. Tedisamil blocks multiple types of potassium channels in the heart resulting in slowed heart rate. While the effects of tedisamil have been demonstrated in both atrial and ventricular muscle, repolarization is prolonged more efficiently in the atria. Tedisamil is administered intravenously and has a half-life of approximately 8 –13 hours in circulation. Tedisamil is being developed as an alternative to other antiarrhythmics as incidence of additional arrhythmic events is lower compared to other class III agents. Tedisamil also has significant anti-ischemic properties and was initially investigated as a potential treatment for angina until its antiarrhythmic effects were discovered. Tedisamil is manufactured by Solvay Pharmaceuticals Inc. under the proposed trade name Pulzium.

<span class="mw-page-title-main">TAN-67</span> Chemical compound

TAN-67 (SB-205,607) is an opioid drug used in scientific research that acts as a potent and selective δ-opioid agonist, selective for the δ1 subtype. It has analgesic properties and induces dopamine release in nucleus accumbens. It also protects both heart and brain tissue from hypoxic tissue damage through multiple mechanisms involving among others an interaction between δ receptors and mitochondrial K(ATP) channels.

<span class="mw-page-title-main">CP-532,903</span> Chemical compound

CP-532,903 is a selective adenosine A3 subtype receptor agonist. It has antiinflammatory effects and has been shown to reduce superoxide generation in damaged tissues, and protects against tissue damage following myocardial ischemia, mediated via an interaction with ATP-sensitive potassium channels.

<span class="mw-page-title-main">Celivarone</span> Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

<span class="mw-page-title-main">F15845</span> Cardiac drug

F15845 is a cardiac drug proposed to have beneficial effects for the treatment of angina pectoris, arrhythmias and ischemia by inhibiting the persistent sodium current. The drug, currently in phase II of clinical trials, targets the persistent sodium current with selectivity and produces minimal adverse effects in current experimental studies.

<span class="mw-page-title-main">Rottlerin</span> Chemical compound

Rottlerin (mallotoxin) is a polyphenol natural product isolated from the Asian tree Mallotus philippensis. Rottlerin displays a complex spectrum of pharmacology.

<span class="mw-page-title-main">Benign early repolarization</span> Medical condition

Benign early repolarization (BER) or early repolarization is found on an electrocardiogram (ECG) in about 1% of those with chest pain. It is diagnosed based on an elevated J-point / ST elevation with an end-QRS notch or end-QRS slur and where the ST segment concave up. It is believed to be a normal variant.

<span class="mw-page-title-main">Oxymatrine</span> Chemical compound

Oxymatrine is one of many quinolizidine alkaloid compounds extracted from the root of Sophora flavescens, a Chinese herb. It is very similar in structure to matrine, which has one less oxygen atom. Oxymatrine has a variety of effects in vitro and in animal models, including protection against apoptosis, tumor and fibrotic tissue development, and inflammation. Furthermore, oxymatrine has been shown to decrease cardiac ischemia, myocardial injury, arrhythmias, and improve heart failure by increasing cardiac function.

Diallyl trisulfide (DATS), also known as Allitridin, is an organosulfur compound with the formula S(SCH2CH=CH2)2. It is one of several compounds produced by hydrolysis of allicin, including diallyl disulfide and diallyl tetrasulfide; DATS is one of the most potent.

References

  1. 1 2 Heinrich C. Englert, Uwe Gerlach, Heinz Goegelein, Jens Hartung, Holger Heitsch, Dieter Mania, and Sabine Scheidler. 2001. Cardioselective KATP Channel Blockers Derived from a New Series of m-Anisamidoethylbenzenesulfonylthioureas J. Med. Chem. 44 (7):1085–1098
  2. 1 2 3 4 Billman, G. E., Englert, H. C., & Schoelkens, B. A. (1998) HMR 1883, a novel cardioselective inhibitor of the ATP- sensitive potassium channel; Part II: effects on susceptibility to ventricular fibrillation induced by myocardial ischemia in conscious dogs. J Pharmacol Exp Therap 286, 1465−1473
  3. ↑ Suzuki, M., Li, R. A., Miki, T., Uemura, H., Sakamoto, N., Ohmoto-Sekine, Y., Tamagawa, M., Ogura, T., Seino, S., Marban, E., & Nakaya, H. (2001). Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice. Circ Res 88, 570−577.
  4. ↑ Hai Xia Zhang, Alejandro Akrouh, Harley T Kurata, Maria Sara Remedi, Jennifer S Lawton, Colin G Nichols. 2011. HMR 1098 is not an SUR isotype specific inhibitor of heterologous or sarcolemmal KATP channels. J. Mol. Cell. Cardiol. 50(3):552-560
  5. ↑ Wilde, A. A. M. (1993). Role of ATP-sensitive K+ channel current in ischemic arrhythmias. Cardiovasc Drugs Ther 7, 521−526.
  6. 1 2 Harris, A. S., Bisteni, A., Russell, R. A., Brigham, J. C., & Firestone, J. E. (1954). Excitory factors in ventricular tachycardia resulting from myocardial ischemia: potassium a major excitant. Science 119, 200−203
  7. ↑ Gross, G. J., & Fryer, R. M. (1999). Sarcolemmal versus mitochondrial ATP-sensitive K+ channels and myocardial preconditioning. Circ Res 84, 973−979.
  8. ↑ Fryer, R. M., Eells, J. T., Hsu, A. K., Henry, M. M., & Gross, G. J. (2000). Ischemic preconditioning in rats: role of mitochondrial KATP channel in preservation of mitochondrial function. Am J Physiol Heart Circ Physiol 278, H305−H312.
  9. ↑ Sato, T., & Marban, E. (2000). The role of mitochondrial KATP channels in cardioprotection. Bas Res Cardiol 95, 285−289
  10. 1 2 Bohn, H., Englert, H. C., & Schoelkens, B. A. (1998). The KATP channel blocker HMR 1883 attenuates the effects of ischemia on MAP duration and improves survival during LAD occlusion in anesthetized pig. Br J Pharmacol 124, 23P.
  11. ↑ Wirth, K. J., Klaus, E., Englert, H. G., Scholkens, B. A., & Linz, W. (1999b). HMR 1883, a cardioselective K(ATP) channel blocker, inhibits ischaemia- and reperfusioninduced ventricular fibrillation in rats. Naunyn-Schmiedeberg's Arch Pharmacol 360, 295−300.
  12. ↑ Behrens, S., Zabel, M., Janssen, A., Barbierato, M., & Schultheiss, H. P. (2001). Influence of a new ATP-sensitive potassium-channel antagonist (HMR 1098) on ventricular fibrillation inducibility during myocardial ischemia. Eur Heart J 22(abstract suppl), 546.
  13. ↑ Vajda, S., Baczko, I., & Lepran, I. (2007). Selective cardiac plasma-membrane KATP channel inhibition is defibrillatory and improves survival during acute myocardial ischemia and reperfusion. Eur J Pharmacol 577, 115−123.
  14. ↑ Zhu, B. M., Miyamoto, S., Nagawa, Y., Wajima, T., & Hashimoto, K. (2003). Effect of sarcolemmal K-ATP blocker HMR 1098 on arrhythmias induced by programmed electrical stimulation in canine old myocardial infarction model: comparison with glibenclamide. J Pharmacol Sci 93, 106−113.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.