Impact of imidapril on cardiac mitochondrial function in an ex-vivo animal model of global myocardial ischemia.
Imidapril is an angiotensin I converting enzyme inhibitor, a class of drugs with known cardioprotective activity. It is now known that this is due not only to their antihypertensive activity, but also to the fact that they decrease cellular and tissue levels of angiotensin II, a potent vasoconstrictor and inducer of myocardial fibrosis. These mechanisms may explain the good clinical results of this class of drugs in the treatment of coronary artery disease and heart failure, two diseases whose etiopathogenesis is closely related to the activation of the renin-angiotensin-aldosterone system. However, the impact of this class of drugs on cardiac mitochondrial function during acute myocardial ischemia is still largely unknown. With the aim of studying the effect of imidapril on cardiac mitochondrial function during acute ischemia, we used an ex-vivo animal model, perfused in a Langerdorff system and then subjected to ischemia in the presence or absence of imidapril. We evaluated mitochondrial membrane electrical potential, respiratory chain O2 consumption, and rate and amplitude of mitochondrial swelling. We conclude that imidapril did not significantly change oxygen consumption by cardiac mitochondria, as assessed by the rate of respiratory state 3 (the state that corresponds to the active phosphorylation phase). However, imidapril significantly increased transmembrane electrical potential and, in ischemic cardiac mitochondria, was able to prevent the calcium-induced increase in the rate and amplitude of mitochondrial swelling, thus enabling better preservation of mitochondrial membrane structure, with consequent improvement of electrical potential after the phosphorylation cycle. These findings enabled a better understanding of the mechanisms behind the cytoprotection provided by imidapril during ischemic cardiomyopathy, clearly highlighting, at a cellular biology level, the importance of pharmacological modulation of cardiac mitochondrial function during acute ischemia.
Monteiro
Pedro
P
Unidade de Investigação Básica em Cardiologia-Serviço de Cardiologia, Hospitais da Universidade de Coimbra, Coimbra, Portugal.
Gala
Sónia
S
Nobre
Susana
S
Carreira
Raquel
R
Gonçalves
Lino M
LM
Providência
Luís A
LA
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D048289:Imidazolidines / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar
D000806:Angiotensin-Converting Enzyme Inhibitors; D048289:Imidazolidines; C065166:imidapril