Ranolazine may exert its beneficial effects by increasing myocardial adenosine levels Article Swipe
D. Elizabeth Le
,
Catherine M. Davis
,
Kevin Wei
,
Yan Zhao
,
Zhiping Cao
,
Matthew A. Nugent
,
Kristin L. Scott
,
Lijuan Liu
,
Shanthi Nagarajan
,
Nabil J. Alkayed
,
Sanjiv Kaul
·
YOU?
·
· 2019
· Open Access
·
· DOI: https://doi.org/10.1152/ajpheart.00217.2019
YOU?
·
· 2019
· Open Access
·
· DOI: https://doi.org/10.1152/ajpheart.00217.2019
We hypothesized that ranolazine-induced adenosine release is responsible for its beneficial effects in ischemic heart disease. Sixteen open-chest anesthetized dogs with noncritical coronary stenosis were studied at rest, during dobutamine stress, and during dobutamine stress with ranolazine. Six additional dogs without stenosis were studied only at rest. Regional myocardial function and perfusion were assessed. Coronary venous blood was drawn. Murine endothelial cells and cardiomyocytes were incubated with ranolazine and adenosine metabolic enzyme inhibitors, and adenosine levels were measured. Cardiomyocytes were also exposed to dobutamine and dobutamine with ranolazine. Modeling was employed to determine whether ranolazine can bind to an enzyme that alters adenosine stores. Ranolazine was associated with increased adenosine levels in the absence (21.7 ± 3.0 vs. 9.4 ± 2.1 ng/mL, P < 0.05) and presence of ischemia (43.1 ± 13.2 vs. 23.4 ± 5.3 ng/mL, P < 0.05). Left ventricular end-systolic wall stress decreased (49.85 ± 4.68 vs. 57.42 ± 3.73 dyn/cm 2 , P < 0.05) and endocardial-to-epicardial myocardial blood flow ratio tended to normalize (0.89 ± 0.08 vs. 0.76 ± 0.10, P = nonsignificant). Adenosine levels increased in cardiac endothelial cells and cardiomyocytes when incubated with ranolazine that was reversed when cytosolic-5′-nucleotidase (cN-II) was inhibited. Point mutation of cN-II aborted an increase in its specific activity by ranolazine. Similarly, adenosine levels did not increase when cardiomyocytes were incubated with dobutamine. Modeling demonstrated plausible binding of ranolazine to cN-II with a docking energy of −11.7 kcal/mol. We conclude that the anti-adrenergic and cardioprotective effects of ranolazine-induced increase in tissue adenosine levels, likely mediated by increasing cN-II activity, may contribute to its beneficial effects in ischemic heart disease. NEW & NOTEWORTHY Ranolazine is a drug used for treatment of angina pectoris in patients with ischemic heart disease. We discovered a novel mechanism by which this drug may exhibit its beneficial effects. It increases coronary venous levels of adenosine both at rest and during dobutamine-induced myocardial ischemia. Ranolazine also increases adenosine levels in endothelial cells and cardiomyocytes in vitro, by principally increasing activity of the enzyme cytosolic-5′-nucleotidase. Adenosine has well-known myocardial protective and anti-adrenergic properties that may explain, in part, ranolazine’s beneficial effect in ischemic heart disease.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1152/ajpheart.00217.2019
- https://journals.physiology.org/doi/pdf/10.1152/ajpheart.00217.2019
- OA Status
- bronze
- Cited By
- 21
- References
- 52
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2995407177
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W2995407177Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1152/ajpheart.00217.2019Digital Object Identifier
- Title
-
Ranolazine may exert its beneficial effects by increasing myocardial adenosine levelsWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2019Year of publication
- Publication date
-
2019-12-13Full publication date if available
- Authors
-
D. Elizabeth Le, Catherine M. Davis, Kevin Wei, Yan Zhao, Zhiping Cao, Matthew A. Nugent, Kristin L. Scott, Lijuan Liu, Shanthi Nagarajan, Nabil J. Alkayed, Sanjiv KaulList of authors in order
- Landing page
-
https://doi.org/10.1152/ajpheart.00217.2019Publisher landing page
- PDF URL
-
https://journals.physiology.org/doi/pdf/10.1152/ajpheart.00217.2019Direct link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
bronzeOpen access status per OpenAlex
- OA URL
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https://journals.physiology.org/doi/pdf/10.1152/ajpheart.00217.2019Direct OA link when available
- Concepts
-
Ranolazine, Adenosine, Pharmacology, Medicine, Chemistry, Internal medicineTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
21Total citation count in OpenAlex
- Citations by year (recent)
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2025: 3, 2024: 4, 2023: 2, 2022: 2, 2021: 4Per-year citation counts (last 5 years)
- References (count)
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52Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.wall | 143 |
| abstract_inverted_index.were | 24, 42, 52, 64, 76, 79, 220 |
| abstract_inverted_index.when | 187, 194, 218 |
| abstract_inverted_index.with | 20, 35, 66, 86, 107, 189, 222, 232, 285 |
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| abstract_inverted_index.(0.89 | 168 |
| abstract_inverted_index.(21.7 | 114 |
| abstract_inverted_index.(43.1 | 129 |
| abstract_inverted_index.0.05) | 124, 158 |
| abstract_inverted_index.0.10, | 174 |
| abstract_inverted_index.57.42 | 150 |
| abstract_inverted_index.Point | 199 |
| abstract_inverted_index.blood | 56, 162 |
| abstract_inverted_index.cN-II | 202, 231, 258 |
| abstract_inverted_index.cells | 61, 184, 325 |
| abstract_inverted_index.heart | 14, 268, 287, 356 |
| abstract_inverted_index.novel | 292 |
| abstract_inverted_index.part, | 350 |
| abstract_inverted_index.ratio | 164 |
| abstract_inverted_index.rest, | 27 |
| abstract_inverted_index.rest. | 46 |
| abstract_inverted_index.which | 295 |
| abstract_inverted_index.(49.85 | 146 |
| abstract_inverted_index.0.05). | 139 |
| abstract_inverted_index.Murine | 59 |
| abstract_inverted_index.alters | 101 |
| abstract_inverted_index.angina | 281 |
| abstract_inverted_index.drawn. | 58 |
| abstract_inverted_index.during | 28, 32, 314 |
| abstract_inverted_index.dyn/cm | 153 |
| abstract_inverted_index.effect | 353 |
| abstract_inverted_index.energy | 235 |
| abstract_inverted_index.enzyme | 71, 99, 336 |
| abstract_inverted_index.levels | 75, 110, 179, 214, 307, 322 |
| abstract_inverted_index.likely | 254 |
| abstract_inverted_index.ng/mL, | 121, 136 |
| abstract_inverted_index.stress | 34, 144 |
| abstract_inverted_index.tended | 165 |
| abstract_inverted_index.tissue | 251 |
| abstract_inverted_index.venous | 55, 306 |
| abstract_inverted_index.vitro, | 329 |
| abstract_inverted_index.(cN-II) | 196 |
| abstract_inverted_index.Sixteen | 16 |
| abstract_inverted_index.aborted | 203 |
| abstract_inverted_index.absence | 113 |
| abstract_inverted_index.binding | 227 |
| abstract_inverted_index.cardiac | 182 |
| abstract_inverted_index.docking | 234 |
| abstract_inverted_index.effects | 11, 246, 265 |
| abstract_inverted_index.exhibit | 299 |
| abstract_inverted_index.exposed | 81 |
| abstract_inverted_index.levels, | 253 |
| abstract_inverted_index.release | 5 |
| abstract_inverted_index.stores. | 103 |
| abstract_inverted_index.stress, | 30 |
| abstract_inverted_index.studied | 25, 43 |
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| abstract_inverted_index.without | 40 |
| abstract_inverted_index.−11.7 | 237 |
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| abstract_inverted_index.Modeling | 88, 224 |
| abstract_inverted_index.Regional | 47 |
| abstract_inverted_index.activity | 209, 333 |
| abstract_inverted_index.conclude | 240 |
| abstract_inverted_index.coronary | 22, 305 |
| abstract_inverted_index.disease. | 15, 269, 288, 357 |
| abstract_inverted_index.effects. | 302 |
| abstract_inverted_index.employed | 90 |
| abstract_inverted_index.explain, | 348 |
| abstract_inverted_index.function | 49 |
| abstract_inverted_index.increase | 205, 217, 249 |
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| abstract_inverted_index.ischemic | 13, 267, 286, 355 |
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| abstract_inverted_index.mutation | 200 |
| abstract_inverted_index.patients | 284 |
| abstract_inverted_index.pectoris | 282 |
| abstract_inverted_index.presence | 126 |
| abstract_inverted_index.reversed | 193 |
| abstract_inverted_index.specific | 208 |
| abstract_inverted_index.stenosis | 23, 41 |
| abstract_inverted_index.Adenosine | 178, 338 |
| abstract_inverted_index.activity, | 259 |
| abstract_inverted_index.adenosine | 4, 69, 74, 102, 109, 213, 252, 309, 321 |
| abstract_inverted_index.assessed. | 53 |
| abstract_inverted_index.decreased | 145 |
| abstract_inverted_index.determine | 92 |
| abstract_inverted_index.increased | 108, 180 |
| abstract_inverted_index.increases | 304, 320 |
| abstract_inverted_index.incubated | 65, 188, 221 |
| abstract_inverted_index.ischemia. | 317 |
| abstract_inverted_index.kcal/mol. | 238 |
| abstract_inverted_index.measured. | 77 |
| abstract_inverted_index.mechanism | 293 |
| abstract_inverted_index.metabolic | 70 |
| abstract_inverted_index.normalize | 167 |
| abstract_inverted_index.perfusion | 51 |
| abstract_inverted_index.plausible | 226 |
| abstract_inverted_index.treatment | 279 |
| abstract_inverted_index.NOTEWORTHY | 272 |
| abstract_inverted_index.Ranolazine | 104, 273, 318 |
| abstract_inverted_index.Similarly, | 212 |
| abstract_inverted_index.additional | 38 |
| abstract_inverted_index.associated | 106 |
| abstract_inverted_index.beneficial | 10, 264, 301, 352 |
| abstract_inverted_index.contribute | 261 |
| abstract_inverted_index.discovered | 290 |
| abstract_inverted_index.dobutamine | 29, 33, 83, 85 |
| abstract_inverted_index.increasing | 257, 332 |
| abstract_inverted_index.inhibited. | 198 |
| abstract_inverted_index.myocardial | 48, 161, 316, 341 |
| abstract_inverted_index.open-chest | 17 |
| abstract_inverted_index.properties | 345 |
| abstract_inverted_index.protective | 342 |
| abstract_inverted_index.ranolazine | 67, 94, 190, 229 |
| abstract_inverted_index.well-known | 340 |
| abstract_inverted_index.dobutamine. | 223 |
| abstract_inverted_index.endothelial | 60, 183, 324 |
| abstract_inverted_index.inhibitors, | 72 |
| abstract_inverted_index.noncritical | 21 |
| abstract_inverted_index.principally | 331 |
| abstract_inverted_index.ranolazine. | 36, 87, 211 |
| abstract_inverted_index.responsible | 7 |
| abstract_inverted_index.ventricular | 141 |
| abstract_inverted_index.anesthetized | 18 |
| abstract_inverted_index.demonstrated | 225 |
| abstract_inverted_index.end-systolic | 142 |
| abstract_inverted_index.hypothesized | 1 |
| abstract_inverted_index.Cardiomyocytes | 78 |
| abstract_inverted_index.cardiomyocytes | 63, 186, 219, 327 |
| abstract_inverted_index.ranolazine’s | 351 |
| abstract_inverted_index.anti-adrenergic | 243, 344 |
| abstract_inverted_index.cardioprotective | 245 |
| abstract_inverted_index.nonsignificant). | 177 |
| abstract_inverted_index.dobutamine-induced | 315 |
| abstract_inverted_index.ranolazine-induced | 3, 248 |
| abstract_inverted_index.endocardial-to-epicardial | 160 |
| abstract_inverted_index.cytosolic-5′-nucleotidase | 195 |
| abstract_inverted_index.cytosolic-5′-nucleotidase. | 337 |
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| cited_by_percentile_year.min | 94 |
| corresponding_author_ids | https://openalex.org/A5109234653 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 11 |
| corresponding_institution_ids | https://openalex.org/I165690674, https://openalex.org/I4210144745 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.8199999928474426 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.92092496 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |