title: Verapamil attenuates calcium-induced mitochondrial swelling and respiratory dysfunction.
abstract: A protective effect of verapamil against hypoxic renal proximal tubule injury has been demonstrated in vitro. In contrast to other cytoprotective agents such as glycine or alanine, the protective effect of verapamil is associated with better maintenance of cellular ATP and potassium levels. These findings suggested a possible direct effect of verapamil on the mitochondria in addition to known effects of verapamil on membrane Ca channels. In the present study, the direct effects of verapamil on Ca-induced swelling, respiratory dysfunction, Ca uptake rate and phospholipase activity of renal cortical mitochondria were determined. Verapamil (100 microM) significantly inhibited Ca-induced mitochondrial swelling and partially prevented the associated reduction in respiratory control ratio (State 3/State 4: Ca + verapamil: 2.8 +/- 0.1 vs. Ca alone, 2.0 +/- 0.2; P < .01). A phospholipase A2 inhibitor, dibucaine (100 microM), significantly inhibited Ca-induced mitochondrial swelling and attenuated the decrease in respiratory control ratio (Ca + dibucaine: 2.9 +/- 0.1 vs. Ca alone, 2.0 +/- 0.2; P < .001). Neither agent, either alone or combined, completely prevented the respiratory dysfunction. Either verapamil or dibucaine attenuated the mitochondrial Ca uptake rate and reduced the rate of Ca-stimulated polyunsaturated free fatty acid accumulation; verapamil treatment also was associated with diminished net release of saturated and monounsaturated free fatty acids. These findings demonstrate that verapamil exerts a protective effect against Ca-induced mitochondrial damage which may be mediated in part by its effect to suppress mitochondrial Ca uptake and mitochondrial phospholipase activity.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Koo
authors.forename: P E
authors.initials: PE
authors.lastname: Gengaro
authors.forename: T J
authors.initials: TJ
authors.lastname: Burke
authors.forename: R W
authors.initials: RW
authors.lastname: Schrier
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008933:Mitochondrial Swelling / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects*; D010740:Phospholipases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D014700:Verapamil; D010740:Phospholipases; D002118:Calcium