Misplaced Pages

CXL 1020

Article snapshot taken from Wikipedia with creative commons attribution-sharealike license. Give it a read and then ask your questions in the chat. We can research this topic together.
Experimental drug

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. Nitroxyl is capable of enhancing left ventricular contractility without increasing heart rate by modifying normal Ca cycling through the sarcoplasmic reticulum as well as increasing the sensitivity of cardiac myofilaments to Ca.

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 Ca 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 Ca Cycling

There are two mechanisms through which CXL 1020 is able to enhance the movement of Ca 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 Ca 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 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 Ca required for myofilament activation (Guyton, 2006). Nitroxyl interacts with RyR2 to increase the probability of Ryanodine receptor opening, thereby enhancing Ca 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 Ca, 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 activated force of the myofilament, although the exact effect of nitroxyl on the myofilament is unknown.

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.
  2. ^ 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 Ca-cycling". Frontiers in Bioscience. E2 (2): 614–626. doi:10.2741/e118. PMC 3057191. PMID 20036906.
  3. ^ 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. ^ 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.
Category: