CXL 1020 is an
experimental drug 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), edema, leg or feet swelling, and Fatigue (medical), fatigue. ADHF is a common and ...
. 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 the solution phase. The conjugate base, NO−, nitroxide anion, is the redox re ...
donor; nitroxyl is the reduced,
protonated
In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry acid, i ...
version of
nitric oxide
Nitric oxide (nitrogen oxide 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 denoted by a dot in its che ...
.
Nitroxyl is capable of enhancing
left ventricular contractility without increasing
heart rate by modifying normal Ca
2+ cycling through the
sarcoplasmic reticulum as well as increasing the sensitivity of cardiac
myofilaments to Ca
2+.
Acute decompensated heart failure
Patients with acute decompensated heart failure have diminished left ventricular
systolic
Systole ( ) is the part of the cardiac cycle during which some chambers of the heart contract after refilling with blood. The term originates, via New Latin, from Ancient Greek (''sustolē''), from (''sustéllein'' 'to contract'; from ''sun ...
and/or
diastolic functioning.
Impaired
ventricular function
A ventricle is one of two large chambers 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 (heart), atrium, an adjacent chamb ...
can be a consequence of decreased sarcoplasmic reticulum Ca
2+ cycling and a corresponding decline in
cardiomyocyte
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
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 Ca
2+ 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 ga ...
found the sarcoplasmic reticulum of cardiac myocytes that is responsible for transporting Ca
2+ within the
cytosol 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 Ca
2+ from the cytosol of the cardiac myocyte.
Secondly, the nitroxyl group from CXL 1020 interacts with
ryanodine receptor
Ryanodine receptors (RyR for short) form a class of intracellular calcium channels in various forms of excitable animal tissue like 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 media ...
, which is the predominant form found in cardiac tissue.
Ryanodine receptors are located within the membrane of the sarcoplasmic reticulum and function to release Ca
2+ required for myofilament activation (Guyton, 2006). Nitroxyl interacts with RyR2 to increase the probability of Ryanodine receptor opening, thereby enhancing Ca
2+ 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 gro ...
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 Ca
2+, which in turn enhances the force of contraction. Its hypothesized that nitroxyl interacts with thiol groups present in myofilament proteins to increase the maximal Ca
2+ activated force of the myofilament, although the exact effect of nitroxyl on the myofilament is unknown.
References
{{Reflist
Drugs acting on the cardiovascular system