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.