title: R 56865 delays cellular electrical uncoupling in ischemic rabbit papillary muscle.
abstract: The compound R56865 protects the heart from irreversible ischemic damage. The proposed mechanism of its action is a reduction of Ca2+ overload secondary to a reduction of intracellular Na+, caused by blockade of the Na(+)-channel. In addition, cardioprotection is ascribed to blockade of the Na(+)-sensitive K(+)-channel (IK-Na). We tested whether R 56865 delays cellular electrical uncoupling, one aspect of irreversible ischemic damage that is due to Ca2+ overload. Also, we studied whether the Na(+)-channel and IK-Na are involved in cardioprotection by relating delay of the onset of cellular electrical uncoupling to changes of conduction velocity and action potential duration (APD80), respectively. Experiments were performed with isolated perfused rabbit papillary muscles that were treated with 1 microM R 56865 for 45 min prior to ischemia. Uncoupling started at 15.0 +/- 0.8 min (mean +/- S.E.M., n = 12) of ischemia in the control group and at 23.4 +/- 1.7 min in the R 56865 group (n = 9, P < 0.005 vs control). R 56865 tended to decrease conduction velocity and to increase APD80 during pre-treatment, but these changes were not statistically significant. During ischemia, conduction velocity was statistically not different between the R 56865 group and the control group. APD80 was significantly longer in the R 56865 than in the control group during the first 7 min of ischemia and similar after that. We conclude that R 56865 delays the onset of cellular uncoupling during ischemia and that this effect is not related to changes of conduction velocity and at most in part to changes of APD80.
authors.affiliation: Department of Clinical and Experimental Cardiology, University of Amsterdam, The Netherlands.
authors.forename: H L
authors.initials: HL
authors.lastname: Tan
authors.forename: A O
authors.initials: AO
authors.lastname: Netea
authors.forename: M E
authors.initials: ME
authors.lastname: Sleeswijk
authors.forename: P
authors.initials: P
authors.lastname: Mazón
authors.forename: R
authors.initials: R
authors.lastname: Coronel
authors.forename: T
authors.initials: T
authors.lastname: Opthof
authors.forename: M J
authors.initials: MJ
authors.lastname: Janse
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D052160:Benzothiazoles; D002118:Calcium / Q000378:metabolism; D006329:Heart Conduction System / Q000187:drug effects; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000188:drug therapy*; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D052160:Benzothiazoles; D010880:Piperidines; D013844:Thiazoles; C054551:R 56865; D002118:Calcium