An administration of 3 hydroxy-butyrate (3-OHB) in experimental animals or humans is associated with an increase of cardiac output (CO), but whether this hemodynamic benefit reflects direct myocardial inotropy or heart unloading due to peripheral vasodilation remains unclear. It is also unknown if myocardial effects are due to engagement of receptor-mediated inotropic response, or due to improvement of myocardial bioenergetics. To address these questions, we studied integrated cardiovascular response (pressure-volume analysis of the left ventricle) and isolated left ventricular (LV) trabeculae from normotensive male HanSD rats (age 20-30 weeks) after administration of 3-OHB (1 mmol/l) and drugs targeting adrenergic and cAMP-dependent signaling - metoprolol, adenylyl cyclase inhibitor 2,5-dideoxyadenosine and isoprenaline, during Tyrode solution perfusion and 1 Hz pacing. Pressure-volume analysis demonstrated increased left ventricular end-systolic elastance (+34%), improved ventriculo-arterial coupling (+65%) and increased LV efficiency (+28%), indicating direct inotropic effect of 3OHB. In isolated LV trabeculae, 3-OHB increased twitch force in both groups, but increase was greater in healthy hearts (+55.8%) than in the HF group (+35.6%) (p = 0.014). The inotropic effect of 3-OHB was not further augmented by coadministration of isoprenaline and was not attenuated by beta-1 adrenergic blockade or cAMP inhibition. Results suggest that 3-OHB directly improves LV inotropy and by a mechanism that is independent of receptor-mediated beta-adrenergic signaling, most consistent with a direct bioenergetic pathway. These findings support 3-OHB as a candidate inotropic agent with a mechanistic profile distinct from conventional cAMP-dependent inotropes.
Kropacek, J., Nguyen, T. T., Hajkova, E., Molnar, M., Monzo, L., Miklovic, M., Melenovsky, V.
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