Protective effects of amiloride on the ischemic reperfused rat heart. Relation to mitochondrial function.
We examined the effect of amiloride on mechanical, electrical and mitochondrial function as well as ultrastructural integrity, in isolated rat hearts subjected to 30 min low-flow ischemia and 30 min reperfusion. In control hearts, ischemia produced a rapid loss of contractility and a concomitant elevation in resting tension which were associated with a 100% incidence in arrhythmic activity. Reperfusion produced a 22 and 54% recovery in force and rate of force (dF/dt) development, respectively. In control hearts the incidence of arrhythmias was 100% within 5 min of reperfusion which then declined to 50% by 30 min. Ultrastructural defects in these hearts were restricted primarily to mitochondrial damage. Amiloride significantly attenuated the elevation in resting tension at the end of ischemia. Postischemic recovery was significantly increased to 38 and 86% for force and dF/dt, respectively and the incidence of arrhythmias was reduced to 30%. No ultrastructural defects were ever observed in amiloride-treated reperfused hearts. Both interfibrillar and subsarcolemmal mitochondria exhibited depressed respiratory function and adenine nucleotide translocase activity. Although virtually all parameters tended to be elevated in mitochondria isolated from amiloride-treated hearts, a significant increase was seen in only one case. Our results therefore demonstrate an ability of amiloride to enhance postischemic contractile recovery and reduce the incidence of arrhythmias, particularly during reperfusion, an effect associated with virtual total prevention of ultrastructural defects. Although the salutary effect was not significantly correlated to improved mitochondrial function, this dissociation may have been due to removal of damaged mitochondria during the isolation process, in view of diminished mitochondrial damage as viewed by transmission electron microscopy.(ABSTRACT TRUNCATED AT 250 WORDS)
Duan
J
J
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
Karmazyn
M
M
D000584:Amiloride / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D001696:Biomechanical Phenomena; D066298:In Vitro Techniques; D008297:Male; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000187:drug effects*; D000226:Mitochondrial ADP, ATP Translocases / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D000584:Amiloride; D000226:Mitochondrial ADP, ATP Translocases