Abstract 18400: Intravenous Ranolazine Relieves Ischemia by Increasing Myocardial Adenosine Levels
Background: The mechanism by which ranolazine (RAN) reduces stress-induced myocardial ischemia is not fully understood.
Hypothesis: RAN relieves myocardial ischemia through the cardioprotective effects of adenosine(ADEN).
Methods: Non-flow limiting stenosis was created in the LAD in 17 open-chest dogs. We compared regional myocardial function (echo radial strain) and perfusion (myocardial blood volume), and regional ADEN level in the absence and presence of intravenous RAN at rest and during dobutamine stress. ADEN level from the supernatant of murine cardiac endothelial cells subjected to oxygen glucose deprivation to stimulate ischemia before and after addition of RAN was also measured alone (n=5) and in the presence of the cytosolic-5’-nucleotidase inhibitor thymidine 5’ monophosphate (TMP) (n=6) and the ecto-adenosine deaminase inhibitor pentostatin (n=4). ADEN is produced from 5’AMP via cytosolic-5’-nucleotidase and is converted to inosine via ecto-adenosine deaminase.
Results: In the presence of RAN, LAD percent regional strain increased significantly during stress compared with rest (9.74% ± 4.47 vs. 2.07% ± 2.74, p<0.05). RAN increased myocardial blood volume at rest (0.93 ± 0.03 vs. 1.14 ± 0.06, p<0.001) but not during stress (0.99 ± 0.07 vs. 0.97 ± 0.05, p=NS). ADEN level increased by 2-fold at rest (10.6 ng/mL ± 2.1 vs. 21.7 ng/mL ± 4.3, p<0.05) and during stress (20.5 ng/mL ± 3.2 vs. 43.1 ng/mL ± 13.3, p<0.05). In vitro, RAN increased ADEN level, which was reversed with TMP and further increased with pentostatin (Figure 1).
Conclusions: RAN induced myocardial ADEN synthesis via cytosolic-5’-nucleotidase and prevented ADEN degradation via ecto-adenosine deaminase during ischemic stress. The increased availability of ADEN during exercise-induced ischemia in the presence of RAN maintained myocardial blood volume, resulting in angina relief. This is the first observation of this novel mechanism of action of RAN during intravenous administration.
Author Disclosures: D.E. Le: None. C.M. Davis: None. K.S. Wei: None. K.L. Lyon Scott: None. Y. Zhao: None. M. Nugent: None. S. Kaul: None.
- © 2016 by American Heart Association, Inc.