N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1

N-oleoyldopamine (OLDA), a bioactive lipid originally found in the mammalian brain, is an endo-vanilloid that selectively activates the transient receptor potential vanilloid type 1 (TRPV1) channel. This study tests the hypothesis that OLDA protects the heart against ischemia and reperfusion (I/R) injury via activation of the TRPV1 in wild-type (WT) but not in genetargeted TRPV1-null mutant ([TRPV1.sup.-/-]) mice. Hearts of WT or [TRPV1.sup.-/-] mice were Langendorffly perfused with OLDA (2 X [10.sup.-9] M) in the presence or absence of CGRP8-37 (1 x [10.sup.-6] M), a selective calcitonin gene-related peptide (CGRP) receptor antagonist; RP-67580 (1 X [10.sup.-6] M), a selective neurokinin-1 receptor antagonist; chelerythrine (5 X [10.sup.-6] M), a selective protein kinase C (PKC) antagonist; or tetrabutylammonium (TBA, 5 x [10.sup.-4] M), a nonselective [K.sup.+] channel antagonist, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), coronary flow (CF), and left ventricular peak positive dP/dt (+dP/dt) were evaluated after I/R. OLDA improved recovery of cardiac function after I/R in WT but not [TRPV1.sup.-/-] hearts by increasing LVDP, CF, and +dP/dt and by decreasing LVEDP. CGRP8-37, RP-67580, chelerythrine, or TBA abolished the protective effect of OLDA in WT hearts. Radioirmnunoassay showed that the release of substance P (SP) and CGRP after OLDA treatment was higher in WT than in [TRPV1.sup.-/-] hearts, which was blocked by chelerythrine or TBA. Thus OLDA exerts a cardiac protective effect during I/R injury in WT hearts via CGRP and SP release, which is abolished by PKC or [K.sup.+] channel antagonists. The protective effect of OLDA is void in [TRPV1.sup.-/-] hearts, supporting the notion that TRPV1 mediates OLDA-induced protection against cardiac I/R injury. N-oleoyldopamine; transient receptor potential vanilloid 1; ischemia-reperfusion; substance P; calcitonin gene-related peptide; protein kinase C antagonist; potassium ion channel antagonist; gene knockout