Cardiovascular Profile of Oligomycin, a Mitochondial Complex‐V inhibitor, in Anesthetized Dogs

Abstract

Oligomycin A (oligo) is an antibiotic that inhibits mitochondrial complex‐V, leading to impaired energy formation in cells. Cells that have high energy demands, such as cardiac myocytes, may be sensitive to mitochondrial toxins, like oligo. Our goal was to determine the effect of oligo on hemodynamics and heart rate in the anesthetized dog preparation. Oligo was infused at 0, 0.01, 0.1 and 1 mg/kg IV (30 min/dose) and caused a dose‐related tachycardia (39–176%) and hypotension (19–36%). An increase in cardiac contractility (18–39%) was secondary to the heart rate increase (Bowditch phenomena). ATP depletion can stimulate norepinephrine release from sympathetic neurons, therefore, a follow‐up study evaluated whether atenolol could block oligo‐induced tachycardia. Atenolol (5 mg/kg, IV) demonstrated that the tachycardia induced by 1 mg/kg oligo was sensitive to cardiac b1‐blockade, but negative inotropy was not observed. These findings show that acute administration of oligo in this model elicits a profound sympathomimetic response, including an increase in cardiac contractility. Since energy depletion would be expected to reduce cardiac contractility, it is plausible that an acute cardiac sympathomimetic response masks negative inotropy. Evaluation of oligo in isolated heart preparations, are needed to address whether complex‐V inhibition has a direct negative inotropic effect on cardiac myocytes.