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

J Pharmacol Exp Ther. 2007 Oct;323(1):119-27. doi: 10.1124/jpet.107.127167. Epub 2007 Jul 23.


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 microM (51.0 +/- 6.4%) as well as at 50 microM (75.1 +/- 7.4%) as compared with verapamil at 5 microM (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Calcium Channel Blockers / chemistry
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels / metabolism
  • Free Radical Scavengers / chemistry
  • Free Radical Scavengers / pharmacology*
  • In Vitro Techniques
  • Male
  • Molecular Structure
  • Myocardial Contraction / drug effects*
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / prevention & control
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Patch-Clamp Techniques
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Superoxides / metabolism
  • Verapamil / analogs & derivatives*
  • Verapamil / chemistry
  • Verapamil / pharmacology*


  • 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
  • Calcium Channel Blockers
  • Calcium Channels
  • Free Radical Scavengers
  • Pyrroles
  • Superoxides
  • Verapamil