Anti-ischemic effects of multivalent dendrimeric A 3 adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart

Bella Chanyshev; Asher Shainberg; Ahuva Isak; Alexandra Litinsky; Yelena Chepurko; Dilip K. Tosh; Khai Phan; Zhan Guo Gao; Edith Hochhauser; Kenneth A. Jacobson

doi:10.1016/j.phrs.2011.11.013

Anti-ischemic effects of multivalent dendrimeric A ₃ adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart

Bella Chanyshev, Asher Shainberg, Ahuva Isak, Alexandra Litinsky, Yelena Chepurko, Dilip K. Tosh, Khai Phan, Zhan Guo Gao, Edith Hochhauser, Kenneth A. Jacobson^*

^*Corresponding author for this work

Clinical Departments

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Adenosine released during myocardial ischemia mediates cardioprotective preconditioning. Multivalent drugs covalently bound to nanocarriers may differ greatly in chemical and biological properties from the corresponding monomeric agents. Here, we conjugated chemically functionalized nucleosides to poly(amidoamine) (PAMAM) dendrimeric polymers and investigated their effects in rat primary cardiac cell cultures and in the isolated heart. Three conjugates of A ₃ adenosine receptor (AR) agonists, chain-functionalized at the C2 or N ⁶ position, were cardioprotective, with greater potency than monomeric agonist Cl-IB-MECA. Multivalent amide-linked MRS5216 was selective for A ₁ and A ₃ARs, and triazole-linked MRS5246 and MRS5539 (optionally containing fluorescent label) were A ₃AR-selective. The conjugates protected ischemic rat cardiomyocytes, an effect blocked by an A ₃AR antagonist MRS1523, and isolated hearts with significantly improved infarct size, rate of pressure product, and rate of contraction and relaxation. Thus, strategically derivatized nucleosides tethered to biocompatible polymeric carriers display enhanced cardioprotective potency via activation of A ₃AR on the cardiomyocyte surface.

Original language	English
Pages (from-to)	338-346
Number of pages	9
Journal	Pharmacological Research
Volume	65
Issue number	3
DOIs	https://doi.org/10.1016/j.phrs.2011.11.013
State	Published - Mar 2012

Keywords

Adenosine receptor
Cardiomyocyte
Dendrimer
Ischemia
Isolated heart
Rat

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10.1016/j.phrs.2011.11.013

Cite this

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title = "Anti-ischemic effects of multivalent dendrimeric A 3 adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart",

abstract = "Adenosine released during myocardial ischemia mediates cardioprotective preconditioning. Multivalent drugs covalently bound to nanocarriers may differ greatly in chemical and biological properties from the corresponding monomeric agents. Here, we conjugated chemically functionalized nucleosides to poly(amidoamine) (PAMAM) dendrimeric polymers and investigated their effects in rat primary cardiac cell cultures and in the isolated heart. Three conjugates of A 3 adenosine receptor (AR) agonists, chain-functionalized at the C2 or N 6 position, were cardioprotective, with greater potency than monomeric agonist Cl-IB-MECA. Multivalent amide-linked MRS5216 was selective for A 1 and A 3ARs, and triazole-linked MRS5246 and MRS5539 (optionally containing fluorescent label) were A 3AR-selective. The conjugates protected ischemic rat cardiomyocytes, an effect blocked by an A 3AR antagonist MRS1523, and isolated hearts with significantly improved infarct size, rate of pressure product, and rate of contraction and relaxation. Thus, strategically derivatized nucleosides tethered to biocompatible polymeric carriers display enhanced cardioprotective potency via activation of A 3AR on the cardiomyocyte surface.",

keywords = "Adenosine receptor, Cardiomyocyte, Dendrimer, Ischemia, Isolated heart, Rat",

author = "Bella Chanyshev and Asher Shainberg and Ahuva Isak and Alexandra Litinsky and Yelena Chepurko and Tosh, {Dilip K.} and Khai Phan and Gao, {Zhan Guo} and Edith Hochhauser and Jacobson, {Kenneth A.}",

note = "Funding Information: This research was supported by the Intramural Research Program of the NIH, NIDDK . This work was also in part supported by The Adar Program for the Advancement of Research in Heart Function and the Horowitz Foundation at Bar-Ilan University. ",

year = "2012",

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doi = "10.1016/j.phrs.2011.11.013",

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T1 - Anti-ischemic effects of multivalent dendrimeric A 3 adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart

AU - Chanyshev, Bella

AU - Shainberg, Asher

AU - Isak, Ahuva

AU - Litinsky, Alexandra

AU - Chepurko, Yelena

AU - Tosh, Dilip K.

AU - Phan, Khai

AU - Gao, Zhan Guo

AU - Hochhauser, Edith

AU - Jacobson, Kenneth A.

N1 - Funding Information: This research was supported by the Intramural Research Program of the NIH, NIDDK . This work was also in part supported by The Adar Program for the Advancement of Research in Heart Function and the Horowitz Foundation at Bar-Ilan University.

PY - 2012/3

Y1 - 2012/3

N2 - Adenosine released during myocardial ischemia mediates cardioprotective preconditioning. Multivalent drugs covalently bound to nanocarriers may differ greatly in chemical and biological properties from the corresponding monomeric agents. Here, we conjugated chemically functionalized nucleosides to poly(amidoamine) (PAMAM) dendrimeric polymers and investigated their effects in rat primary cardiac cell cultures and in the isolated heart. Three conjugates of A 3 adenosine receptor (AR) agonists, chain-functionalized at the C2 or N 6 position, were cardioprotective, with greater potency than monomeric agonist Cl-IB-MECA. Multivalent amide-linked MRS5216 was selective for A 1 and A 3ARs, and triazole-linked MRS5246 and MRS5539 (optionally containing fluorescent label) were A 3AR-selective. The conjugates protected ischemic rat cardiomyocytes, an effect blocked by an A 3AR antagonist MRS1523, and isolated hearts with significantly improved infarct size, rate of pressure product, and rate of contraction and relaxation. Thus, strategically derivatized nucleosides tethered to biocompatible polymeric carriers display enhanced cardioprotective potency via activation of A 3AR on the cardiomyocyte surface.

AB - Adenosine released during myocardial ischemia mediates cardioprotective preconditioning. Multivalent drugs covalently bound to nanocarriers may differ greatly in chemical and biological properties from the corresponding monomeric agents. Here, we conjugated chemically functionalized nucleosides to poly(amidoamine) (PAMAM) dendrimeric polymers and investigated their effects in rat primary cardiac cell cultures and in the isolated heart. Three conjugates of A 3 adenosine receptor (AR) agonists, chain-functionalized at the C2 or N 6 position, were cardioprotective, with greater potency than monomeric agonist Cl-IB-MECA. Multivalent amide-linked MRS5216 was selective for A 1 and A 3ARs, and triazole-linked MRS5246 and MRS5539 (optionally containing fluorescent label) were A 3AR-selective. The conjugates protected ischemic rat cardiomyocytes, an effect blocked by an A 3AR antagonist MRS1523, and isolated hearts with significantly improved infarct size, rate of pressure product, and rate of contraction and relaxation. Thus, strategically derivatized nucleosides tethered to biocompatible polymeric carriers display enhanced cardioprotective potency via activation of A 3AR on the cardiomyocyte surface.

KW - Adenosine receptor

KW - Cardiomyocyte

KW - Dendrimer

KW - Ischemia

KW - Isolated heart

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