Abstract
Severe ketoacidosis induces heart failure and cardiac arrest, but its mechanism is unknown. Recently, hydroxy-carboxylic acid receptor 2 (HCA2) was found to be a receptor for a ketone body, β-hydroxybutyric acid (BHB), and is coupled with Gi-GTP binding protein. HCA2 expression was reported in the guinea pig heart. Therefore, using guinea pig cardiac myocytes, we investigated effects of BHB on L-type Ca2+ current pre-augmented with β-adrenoceptor agonist, isoproterenol under the whole-cell voltage clamp. BHB significantly reduced the Ca2+ current pre-augmented with isoproterenol. The effect of BHB was concentration dependent with IC50 of 1.1 mM. Nicotinic acid (NA), another ligand for HCA2, also exerted an effect on the Ca2+ current similar to that of BHB. The effects of BHB and NA were reduced by a specific Gi inhibitor, pertussis toxin in the pipette solution. Our results suggest that BHB activates Gi-coupled signal transduction pathway via HCA2 in guinea pig cardiac myocytes. The HCA2-mediated signal transduction may be associated with ketoacidosis-induced cardiac suppression.
