title: TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice.
abstract: Although the transient receptor potential vanilloid type 1 (TRPV1)-containing afferent nerve fibers are widely distributed in the heart, the relationship between TRPV1 function and cardiac ischemic preconditioning (PC) has not been well defined. Using TRPV1 knockout mice (TRPV1(-/-)), we studied the role of TRPV1 in PC-induced myocardial protection. Hearts of gene-targeted TRPV1-null mutant (TRPV1(-/-)) or wild-type (WT) mice were Langendorffly perfused in the presence or absence of CGRP(8-37), a selective calcitonin gene-related peptide (CGRP) receptor antagonist; or RP-67580, a selective neurokinin-1 receptor antagonist when hearts were subjected to three 5-min periods of ischemia PC followed by 30 min of global ischemia and 40 min of reperfusion (I/R). PC before I/R decreased left ventricular (LV) end-diastolic pressure and increased LV developed pressure, coronary flow (CF), peak-positive maximum rate of rise of LV pressure in WT mice (PC-WT) compared with PC-TRPV1(-/-), TRPV1(-/-), or WT hearts (P < 0.05), and PC also decreased LV end-diastolic pressure in PC-TRPV1(-/-) compared with TRPV1(-/-). CGRP(8-37) or RP-67580 abolished PC-induced protection in WT but not TRPV1(-/-) hearts (P < 0.05). Moreover, PC decreased lactate dehydrogenase release and infarct size in PC-WT compared with PC-TRPV1(-/-), TRPV1(-/-), or WT hearts, and it also lowered these parameters in PC-TRPV1(-/-) compared with TRPV1(-/-) hearts (P < 0.05). Radioimmunoassay showed that the release of substance P and CGRP after PC was higher in WT hearts than in TRPV1(-/-) hearts (P < 0.05), which was attenuated by capsazepine in WT but not TRPV1(-/-) hearts. Thus PC-induced protection of the heart was impaired in TRPV1(-/-) hearts, indicating that TRPV1 contributes to the beneficial effects of preconditioning against I/R injury through release substance P and CGRP.
authors.affiliation: Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Beihua
authors.initials: B
authors.lastname: Zhong
authors.forename: Donna H
authors.initials: DH
authors.lastname: Wang
mesh_terms: D000818:Animals; D007211:Indoles / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D054833:Isoindoles; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D064729:Neurokinin-1 Receptor Antagonists; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000187:drug effects; D013373:Substance P / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000378:metabolism
chemical_list: D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D018015:Receptors, Calcitonin Gene-Related Peptide; D018040:Receptors, Neurokinin-1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D013373:Substance P; D007770:L-Lactate Dehydrogenase