Mechanism underlying the negative inotropic effect in rat left ventricle in hyperthermia: the role of TRPV1

We have previously reported that the negative inotropic effects of hyperthermia (42 °C) on left ventricular (LV) mechanoenergetics using the excised, cross-circulated rat heart model. Here, we investigated the role of TRPV1 on LV mechanoenergetics in hyperthermia. We analyzed the LV end-systolic pressure–volume relation (ESPVR) and the linear relation between the myocardial oxygen consumption per beat (VO2) and the systolic pressure–volume area (PVA; a total mechanical energy per beat) during infusion of capsazepine (CPZ) in hyperthermia, or capsaicin (Cap) under 300 bpm pacing. LV ESP decreased in each LV volume and the resultant downward-shift of LV ESPVR was suppressed by CPZ infusion in hyperthermia-hearts. In Cap-treated hearts, LV ESPVR shifted downward from the control ESPVR, similar to hyperthermia-hearts. The slopes of VO2–PVA relationship were unchanged. The VO2 intercepts in hyperthermia-hearts did not decrease because of decreased E–C coupling VO2, and inversely increased basal metabolic VO2, which was suppressed by CPZ, though the VO2 intercepts in Cap-treated hearts significantly decreased. The levels of phosphorylated phospholamban at serine 16 decreased significantly in hyperthermia-hearts, as well as Cap-treated hearts. These results indicate that a Cap-induced decrease in the LV contractility, like in cases of hyperthermia, are due to the down-regulation of the total calcium handling in E–C coupling, suggesting that negative inotropic effect in hyperthermia-heart is, at least in part, mediated through TRPV1 signaling pathway.