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Protective effect of darodipine, a calcium antagonist, on rat cardiomyocytes against oxygen radical‐mediated injury
Author(s) -
Matucci Rosanna,
Francesca Ottaviani Maria,
Barbieri Mario,
Cerbai Elisabetta,
Mugelli Alessandro
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701525
Subject(s) - electrophysiology , calcium , chemistry , antagonist , oxygen , biophysics , medicine , endocrinology , pharmacology , receptor , biochemistry , biology , organic chemistry
1 We used electrophysiological and electron spin resonance (e.s.r.) techniques to study the mechanism of the protective effect of darodipine on rat isolated cardiomyocytes exposed to an exogenous source of oxygen free radicals (OFR). 2 The L‐type calcium current ( I Ca,L ), action potential and cell shortening were measured in patch‐clamped cells in the whole‐cell configuration. I Ca,L blockade by darodipine was concentration‐dependent, peak current being reduced by 20% with 50 n M and by 58% with 100 n M darodipine. The lowest concentration of darodipine did not affect action potential or twitch profile. 3 Exposure to OFR‐generating solution (5 m M dihydroxyfumarate, DHF) caused the appearance of electrophysiological alterations and/or spontaneous activity in 73% of cells ( n =26) within 5 min; action potential duration (APD) was prolonged (195±16 ms vs 140±6 ms in the control) and maximum diastolic potential (MDP) was reduced (−59.5±2.6 mV vs −69.8±0.8 mV in the control) ( P <0.05, n =25). 4 A 2 min pretreatment with 50 n M darodipine significantly reduced the incidence of these arrhythmogenic events following a 5 min exposure to OFR (36% of cells, n =14; P <0.05 vs nonpretreated cells). Pretreatment with darodipine also prevented APD prolongation caused by OFR (137±12 ms after DHF vs 117±6 ms before DHF n =14, not significant) but not the decrease of MDP (−63.4±2.5 mV after DHF vs −70.9±1.0 mV before DHF, P <0.05). 5 The e.s.r. spectra obtained from the DHF‐DMPO solution in the absence of darodipine demonstrated the presence of two components corresponding to two DMPO adducts. The addition of darodipine (50–500 n M ) led to a concentration‐dependent decrease in intensity of the signals, the intensity of the DMPO‐COO. − adduct being decreased more than that of the DMPO‐OH. adduct. 6 Our results demonstrate that darodipine dose‐depentently blocks I Ca,L in rat isolated cardiomyocytes. Furthermore it exerts protective effects against free‐radical‐induced electrophysiological alterations independently of its calcium antagonistic properties; this effect is possibly due to trapping of specific radical species.