CXL 1020

Acute decompensated heart failure

Patients with acute decompensated heart failure have diminished left ventricular systolic and/or diastolic functioning. Impaired ventricular function can be a consequence of decreased sarcoplasmic reticulum Ca2+ cycling and a corresponding decline in cardiomyocyte 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 found the sarcoplasmic reticulum of cardiac myocytes that is responsible for transporting Ca2+ within the cytosol back in to the lumen of the sarcoplasmic reticulum. 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 receptors (RyR), specifically RyR2, 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 groups 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

References

1. Del Rio, Carlos. (April 2011). "CXL-1020, A Novel Hno Donor, Decreases Myocardial Loading and Enhances Load-Independent Lusitropy and Inotropy Via A ?-Ar/Ace Independent Mechanism". JACC.
2. Kohr, Mark. (March 2011). "Nitroxyl enhances myocyte Ca2+ transients by exclusively targeting SR Ca²⁺-cycling". Frontiers in Bioscience.
3. Dai, Tieying. (2007). "Nitroxyl increases force development in rat cardiac muscle". Journal of Physiology.
4. Wang, Mengjun. (2009). "Intravenous Infusion of CXL-1020, a Novel Nitroxyl (HNO) Donor, Improves Left Ventricular Systolic and Diastolic Function in Dogs with Advanced Heart Failure". Circulation.
5. Lancel, Steve. (2009). "Nitroxyl Activates SERCA in Cardiac Myocytes via Glutathiolation of Cysteine 674". Circulation Research.
6. Tocchetti, Carlo. (2007). "Nitroxyl Improves Cellular Heart Function by Directly Enhancing Cardiac Sarcoplasmic Reticulum Ca 2+ Cycling". Circulation Research.