title: A calcium channel blocker, benidipine, improves cell membrane fluidity in human subjects via a nitric oxide-dependent mechanism. An electron paramagnetic resonance investigation.
abstract: Recent studies have revealed that benidipine, a long-acting dihydropyridine-type of calcium (Ca) channel blocker, may exert its protective effect against vascular disorders by increasing nitric oxide (NO) production. The purpose of the present study was to investigate the effects of benidipine and NO on the membrane function in human subjects. We measured the membrane fluidity of erythrocytes by using an electron paramagnetic resonance (EPR) and spin-labeling method. Benidipine decreased the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (h(o)/h(-1)) for 16-NS obtained from EPR spectra of erythrocyte membranes in a dose-dependent manner in normotensive volunteers. The finding indicated that benidipine increased the membrane fluidity and improved the microviscosity of erythrocytes. The effect of benidipine was significantly potentiated by the NO donor, S-nitroso-n-acetylpenicillamine, and by the cyclic guanosine 3', 5'-monophosphate (cGMP) analog, 8-bromo-cGMP. In contrast, the change evoked by benidipine was counteracted by the NO synthase inhibitors, N(G)-nitro-L-arginine-methyl-ester and asymmetric dimethyl-L-arginine. These results demonstrated that benidipine increased the membrane fluidity of erythrocytes, at least in part, via the NO- and cGMP-dependent mechanism. Furthermore, the data strongly suggest that benidipine might have a beneficial effect on the rheologic behavior of erythrocytes and the improvement of the microcirculation in humans.
authors.affiliation: Division of Cardiology, Department of Medicine, Wakayama Medical University, Wakayama 641-8509, Japan. tsudak@mail.wakayama-med.ac.jp
authors.forename: Kazushi
authors.initials: K
authors.lastname: Tsuda
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nishio
mesh_terms: D000368:Aged; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D002462:Cell Membrane / Q000187:drug effects*; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives; D004095:Dihydropyridines / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004912:Erythrocytes / Q000187:drug effects* / Q000648:ultrastructure; D005260:Female; D018056:Hemorheology / Q000187:drug effects; D006801:Humans; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects*; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage; D010396:Penicillamine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014783:Viscosity / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; C061004:benidipine; C018524:N,N-dimethylarginine; D001120:Arginine; D010396:Penicillamine; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester