N-hydroxy-pyrroline modification of verapamil exhibits antioxidant protection of the heart against ischemia/reperfusion-induced cardiac dysfunction without compromising its calcium antagonistic activity

Rajarsi Mandal, Vijay Kumar Kutala, Mahmood Khan, Iyyapu K. Mohan, Saradhadevi Varadharaj, Arun Sridhar, Cynthia A. Carnes, T. Kalai, K. Hideg, Periannan Kuppusamy

Research output: Contribution to journalArticle

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Abstract

Any clinical intervention (e.g., coronary angioplasty, thrombolysis) used to reintroduce blood flow to an ischemic region of the myocardium is accompanied by a complex enzymatic cascade of reactions resulting in severe injury to the heart, termed myocardial ischemia/reperfusion (I/R) injury. In this study, we evaluated the ability of H-3010 (1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H- pyrrole-3-carboxylic acid (2-(3,4-dimethoxyphenyl)-5-([2-(3,4-dimethoxyphenyl) ethyl]-methylamino)-2-isopropylpentyl)-amide), a pyrroline modification of verapamil (2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethylmethyl-amino]- 2-(1-methylethyl)pentanenitrile), to protect the heart against I/R-mediated injury. Isolated perfused rat hearts pretreated with verapamil and H-3010 were subjected to 30 min of global no-flow ischemia followed by 45 min of reperfusion. The recovery (expressed as a percentage of preischemic baseline) in contractile function (left ventricular developed pressure) of hearts subjected to I/R was significantly higher in hearts treated with H-3010 at 5 μM (51.0 ± 6.4%) as well as at 50 μM (75.1 ± 7.4%) as compared with verapamil at 5 μM (32.2 ± 3.7%) or untreated control hearts (18.1 ± 2.8%). Creatine kinase release was significantly attenuated in hearts treated with H-3010 (45.7 ± 4.5 U/liter) as compared with untreated controls (131.5 ± 6.4 U/liter). Similar trends were also observed for lactate dehydrogenase release as well. A marked reduction in percent area of infarction was observed in the H-3010 group (11.7 ± 1.6%) compared with verapamil (25.1 ± 2.9%) and control (41.3 ± 1.9%) groups. Additional in vitro studies showed a marked decrease in reactive oxygen species generation with H-3010. In conclusion, our data clearly demonstrated that the verapamil derivative, H-3010, significantly decreased I/R-induced cardiac dysfunction. This can be attributed to the combined benefits of the pyrroline moiety (antioxidant) and the parent verapamil component (antiarrhythmic) in the protection of the heart from I/R-induced injury.

Original languageEnglish
Pages (from-to)119-127
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume323
Issue number1
DOIs
Publication statusPublished - Oct 2007

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Verapamil
Reperfusion
Ischemia
Antioxidants
Calcium
Reperfusion Injury
Heart Injuries
Myocardial Reperfusion Injury
Ventricular Pressure
Creatine Kinase
pyrroline
1-hydroxy-2,2,5,5-tetramethyl-2,5-diydro-1H-pyrrole-3-carboxylic acid (2-(3,4-dimethoxyphenyl)-5-((2-(3,4-dimethoxyphenyl)ethyl)methylamino)-2-isopropylpentyl)amide
Angioplasty
L-Lactate Dehydrogenase
Amides
Infarction
Myocardial Ischemia
Reactive Oxygen Species
Myocardium

ASJC Scopus subject areas

  • Pharmacology

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N-hydroxy-pyrroline modification of verapamil exhibits antioxidant protection of the heart against ischemia/reperfusion-induced cardiac dysfunction without compromising its calcium antagonistic activity. / Mandal, Rajarsi; Kutala, Vijay Kumar; Khan, Mahmood; Mohan, Iyyapu K.; Varadharaj, Saradhadevi; Sridhar, Arun; Carnes, Cynthia A.; Kalai, T.; Hideg, K.; Kuppusamy, Periannan.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 323, No. 1, 10.2007, p. 119-127.

Research output: Contribution to journalArticle

Mandal, Rajarsi ; Kutala, Vijay Kumar ; Khan, Mahmood ; Mohan, Iyyapu K. ; Varadharaj, Saradhadevi ; Sridhar, Arun ; Carnes, Cynthia A. ; Kalai, T. ; Hideg, K. ; Kuppusamy, Periannan. / N-hydroxy-pyrroline modification of verapamil exhibits antioxidant protection of the heart against ischemia/reperfusion-induced cardiac dysfunction without compromising its calcium antagonistic activity. In: Journal of Pharmacology and Experimental Therapeutics. 2007 ; Vol. 323, No. 1. pp. 119-127.
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abstract = "Any clinical intervention (e.g., coronary angioplasty, thrombolysis) used to reintroduce blood flow to an ischemic region of the myocardium is accompanied by a complex enzymatic cascade of reactions resulting in severe injury to the heart, termed myocardial ischemia/reperfusion (I/R) injury. In this study, we evaluated the ability of H-3010 (1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H- pyrrole-3-carboxylic acid (2-(3,4-dimethoxyphenyl)-5-([2-(3,4-dimethoxyphenyl) ethyl]-methylamino)-2-isopropylpentyl)-amide), a pyrroline modification of verapamil (2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethylmethyl-amino]- 2-(1-methylethyl)pentanenitrile), to protect the heart against I/R-mediated injury. Isolated perfused rat hearts pretreated with verapamil and H-3010 were subjected to 30 min of global no-flow ischemia followed by 45 min of reperfusion. The recovery (expressed as a percentage of preischemic baseline) in contractile function (left ventricular developed pressure) of hearts subjected to I/R was significantly higher in hearts treated with H-3010 at 5 μM (51.0 ± 6.4{\%}) as well as at 50 μM (75.1 ± 7.4{\%}) as compared with verapamil at 5 μM (32.2 ± 3.7{\%}) or untreated control hearts (18.1 ± 2.8{\%}). Creatine kinase release was significantly attenuated in hearts treated with H-3010 (45.7 ± 4.5 U/liter) as compared with untreated controls (131.5 ± 6.4 U/liter). Similar trends were also observed for lactate dehydrogenase release as well. A marked reduction in percent area of infarction was observed in the H-3010 group (11.7 ± 1.6{\%}) compared with verapamil (25.1 ± 2.9{\%}) and control (41.3 ± 1.9{\%}) groups. Additional in vitro studies showed a marked decrease in reactive oxygen species generation with H-3010. In conclusion, our data clearly demonstrated that the verapamil derivative, H-3010, significantly decreased I/R-induced cardiac dysfunction. This can be attributed to the combined benefits of the pyrroline moiety (antioxidant) and the parent verapamil component (antiarrhythmic) in the protection of the heart from I/R-induced injury.",
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AU - Khan, Mahmood

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AU - Varadharaj, Saradhadevi

AU - Sridhar, Arun

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