title: N-hydroxy-pyrroline modification of verapamil exhibits antioxidant protection of the heart against ischemia/reperfusion-induced cardiac dysfunction without compromising its calcium antagonistic activity.
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 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.
authors.affiliation: Davis Heart and Lung Research Institute, Ohio State University, 420 West 12th Avenue, Room 114, Columbus, OH 43210, USA.
authors.forename: Rajarsi
authors.initials: R
authors.lastname: Mandal
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.forename: Iyyapu K
authors.initials: IK
authors.lastname: Mohan
authors.forename: Saradhadevi
authors.initials: S
authors.lastname: Varadharaj
authors.forename: Arun
authors.initials: A
authors.lastname: Sridhar
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Carnes
authors.forename: Tamás
authors.initials: T
authors.lastname: Kálai
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014700:Verapamil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C523976:1-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; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D016166:Free Radical Scavengers; D011758:Pyrroles; D013481:Superoxides; D014700:Verapamil