CXL 1020
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CXL 1020 is an
experimental drug An experimental drug is a medicinal product (a drug or vaccine) that has not yet received drug approval, approval from governmental regulatory agency, regulatory authorities for routine use in human medicine, human or veterinary medicine. A medicin ...
that is being investigated as a treatment for
acute decompensated heart failure Acute decompensated heart failure (ADHF) is a sudden worsening of the signs and symptoms of heart failure, which typically includes difficulty breathing (dyspnea), leg or feet swelling, and fatigue. ADHF is a common and potentially serious cause ...
. CXL 1020 functions as a
nitroxyl Nitroxyl (common name) or azanone (IUPAC name) is the chemical compound HNO. It is well known in the gas phase. Nitroxyl can be formed as a short-lived intermediate in solution. Its conjugate base, NO−, the nitroxide anion, is the reduced form o ...
donor; nitroxyl is the reduced,
protonated In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), usually denoted by H+, to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brà ...
version of
nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
. Nitroxyl is capable of enhancing
left ventricular A ventricle is one of two large chambers located toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in t ...
contractility Contractility refers to the ability for self- contraction, especially of the muscles or similar active biological tissue *Contractile ring in cytokinesis *Contractile vacuole *Muscle contraction **Myocardial contractility *See contractile cell fo ...
without increasing
heart rate Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...
by modifying normal Ca2+ cycling through the
sarcoplasmic reticulum The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kep ...
as well as increasing the sensitivity of cardiac
myofilament Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the ''contractile proteins'' and titin is an elastic protein. The myofilaments act togeth ...
s to Ca2+.


Acute decompensated heart failure

Patients with acute decompensated heart failure have diminished left ventricular
systolic Systolic is an adjective describing something pertaining to a systole, part of the cardiac cycle. Systolic may also refer to: Physiology and medical *Systolic hypertension *Systolic heart murmur Mathematics *Systolic geometry Technology *Systoli ...
and/or
diastolic Diastole ( ) is the relaxed phase of the cardiac cycle when the chambers of the heart are refilling with blood. The contrasting phase is systole when the heart chambers are contracting. Atrial diastole is the relaxing of the atria, and ventricul ...
functioning. Impaired
ventricular function A ventricle is one of two large chambers located toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in t ...
can be a consequence of decreased sarcoplasmic reticulum Ca2+ cycling and a corresponding decline in
cardiomyocyte Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
contraction. Reduced ventricular functioning limits the ability of the ventricles to fill with blood and pump blood to the rest of the body.


Sarcoplasmic reticulum Ca2+ Cycling

There are two mechanisms through which CXL 1020 is able to enhance the movement of Ca2+ in and out of the sarcoplasmic reticulum. Sarcoplasmic reticulum CaATPase (SERCA) is an energy-dependent
ion pump An ion pump (also referred to as a sputter ion pump) is a type of vacuum pump which operates by sputtering a metal getter. Under ideal conditions, ion pumps are capable of reaching pressures as low as 10−11 mbar. An ion pump first ionizes ...
found the sarcoplasmic reticulum of cardiac myocytes that is responsible for transporting Ca2+ within the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
back in to the lumen of the sarcoplasmic reticulum. The nitroxyl group that is donated by CXL 1020 initiates glutathiolation of SERCA at the cysteine 674 site, which in turn activates ATP-dependent Ca2+ transport. Therefore, stimulation of SERCA leads to accelerated uptake of Ca2+ from the cytosol of the cardiac myocyte. Secondly, the nitroxyl group from CXL 1020 interacts with
ryanodine receptor Ryanodine receptors (RyR) make up a class of high-conductance, intracellular calcium channels present in various forms, such as animal muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissu ...
s (RyR), specifically
RyR2 Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the ''RYR2'' gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major med ...
, which is the predominant form found in cardiac tissue. Ryanodine receptors are located within the membrane of the sarcoplasmic reticulum and function to release Ca2+ required for myofilament activation (Guyton, 2006). Nitroxyl interacts with RyR2 to increase the probability of Ryanodine receptor opening, thereby enhancing Ca2+ release from the sarcoplasmic reticulum. It is thought that nitroxyl modifies RyR2 function through its interaction with
thiol group In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...
s present in the receptor, although the exact mechanism is unknown.


Cardiac myocyte contractility

Nitroxyl has also been shown to increase the sensitivity to cardiac myocytes to Ca2+, which in turn enhances the force of contraction. Its hypothesized that nitroxyl interacts with thiol groups present in myofilament proteins to increase the maximal Ca2+ activated force of the myofilament, although the exact effect of nitroxyl on the myofilament is unknown.


References

{{Reflist Drugs acting on the cardiovascular system