CXL 1020 is an experimental drug that is being investigated as a treatment for acute decompensated heart failure. CXL 1020 functions as a nitroxyl donor; nitroxyl is the reduced, protonated version of nitric oxide.[1] Nitroxyl is capable of enhancing left ventricular contractility without increasing heart rate by modifying normal Ca2+ cycling through the sarcoplasmic reticulum[2] as well as increasing the sensitivity of cardiac myofilaments to Ca2+.[3]

Acute decompensated heart failure

Patients with acute decompensated heart failure have diminished left ventricular systolic and/or diastolic functioning.[4] Impaired ventricular function can be a consequence of decreased sarcoplasmic reticulum Ca2+ cycling and a corresponding decline in cardiomyocyte contraction.[2] 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.[2] 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.[5] 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.[6] 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.[6]

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.[3]

References

  1. ↑ Del Rio, Carlos; Yukie Ueyama; Robert L. Hamlin; John Reardon; Reza Mazhari (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. 57 (17): E326. doi:10.1016/s0735-1097(11)60326-4. Archived from the original on 2014-01-15. Retrieved 2012-03-12.
  2. 1 2 3 Kohr, Mark; Nina Kaludercic; Carlo Tocchetti; Wei Dong Gao; David Kass; Paul Janssen; Nazareno Paolocci; Mark Ziolo (March 2011). "Nitroxyl enhances myocyte Ca2+ transients by exclusively targeting SR Ca2+-cycling". Frontiers in Bioscience. E2 (2): 614–626. doi:10.2741/e118. PMC 3057191. PMID 20036906.
  3. 1 2 Dai, Tieying; Ye Tian; Carlo Tocchetti; Tatsuo Katori; Anne Murphy; David Kass; Nazareno Paolocci; Wei Dong Gao (2007). "Nitroxyl increases force development in rat cardiac muscle". Journal of Physiology. 580 (3): 951–960. doi:10.1113/jphysiol.2007.129254. PMC 2075441. PMID 17331988.
  4. ↑ Wang, Mengjun; Reza Mazhari; Itamar Ilsar; Alice Wang; Michael Sabbah; Hani Sabbah (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. 120: S582.
  5. ↑ Lancel, Steve; Jingmei Zhang; Alicia Evangelista; Mario Trucillo; XiaoYong Tong; Deborah Siwik; Richard Cohen; Wilson Colucci (2009). "Nitroxyl Activates SERCA in Cardiac Myocytes via Glutathiolation of Cysteine 674". Circulation Research. 104 (6): 720–723. doi:10.1161/circresaha.108.188441. PMC 3046805. PMID 19265039.
  6. 1 2 Tocchetti, Carlo; Wang Wang; Jeffrey Froehlich; Sabine Huke; Miguel Aon; Gerald Wilson; Giulietta Di Benedetto; Brian O'Rourke; Wei Dong Gao; David Wink; John Toscano; Manuela Zaccolo; Donald Bers; Hector Valdivia; Heping Cheng; David Kass; Nazareno Paolocci (2007). "Nitroxyl Improves Cellular Heart Function by Directly Enhancing Cardiac Sarcoplasmic Reticulum Ca 2+ Cycling". Circulation Research. 100 (1): 96–104. doi:10.1161/01.res.0000253904.53601.c9. PMC 2769513. PMID 17138943.
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