Published online before print November 28, 2005, doi: 10.1161/CIRCULATIONAHA.105.556274
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(Circulation. 2005;112:3617-3623.)
© 2005 American Heart Association, Inc.
Heart Failure |
TRPV1 Gene Knockout Impairs Postischemic Recovery in Isolated Perfused Heart in Mice
From the Department of Medicine, Michigan State University, East Lansing (D.H.W.), and Department of Cardiovascular Sciences, First Affiliated Hospital, College of Medicine, Zhejiang University, China (L.W.).
Correspondence to Donna H. Wang, MD, Department of Medicine, B316 Clinical Center, Michigan State University, East Lansing, MI 48824. E-mail donna.wang{at}ht.msu.edu
Received April 15, 2005; revision received July 22, 2005; accepted August 8, 2005.
Background— Although pharmacological studies suggest that the transient receptor potential vanilloid type 1 (TRPV1) channels expressed in sensory nerve fibers innervating the heart may exert a cardioprotective effect, definitive evidence supporting such a notion is lacking. In addition, function and regulation of sensory neuropeptides, namely, calcitonin gene–related peptide (CGRP) and substance P (SP), in the face of challenges induced by cardiac injury in the presence or absence of the TRPV1 are largely unknown.
Methods and Results— The hearts of gene-targeted TRPV1-null mutant (TRPV1–/–) mice or wild-type (WT) mice were perfused in a Langendorff apparatus in the presence or absence of capsazepine (a TRPV1 receptor antagonist), CGRP, CGRP8–37 (a CGRP receptor antagonist), SP, or RP67580 (a neurokinin-1 [NK1] receptor antagonist) when hearts were subjected to 40 minutes of ischemia and 30 minutes of reperfusion. Hemodynamic alterations and SP release measured by radioimmunoassay were assessed before and after ischemia/reperfusion injury of the heart. Expression of the NK1 receptor in the hearts of TRPV1–/– and WT mice were determined with the use of Western blot analyses. Impairment of postischemic recovery, defined by increased left ventricular end-diastolic pressure (LVEDP) and decreased left ventricular developed pressure (LVDP) and coronary flow (CF), was more severe in TRPV1–/– hearts than in WT hearts. Although it had no effect on postischemic recovery of TRPV1–/– hearts, blockade of the TRPV1 with capsazepine caused a most severe impairment of postischemic recovery in WT hearts compared with untreated WT and TRPV1–/– hearts. Exogenous CGRP and SP produced a significant improvement in postischemic recovery in both TRPV1–/– and WT hearts, and the maximal functional improvement in TRPV1–/– hearts was not different from that of WT hearts except that SP-induced increases in LVDP were larger in the former than in the latter. Blockade of the NK1 receptor with RP67580, but not blockade of the CGRP receptor with CGRP8–37, caused more severe impairment in postischemic recovery in both TRPV1–/– and WT hearts than in untreated hearts in both genotypes. The release of SP after ischemia/reperfusion injury was increased in both WT and TRPV1–/– hearts, albeit with a smaller magnitude of the increase in the latter. Capsazepine attenuated injury-induced SP release in WT but not TRPV1–/– hearts. There was no difference in the expression of the NK1 receptor between the 2 genotype hearts.
Conclusions— Thus, our data show that (1) TRPV1 gene deletion decreases injury-induced SP release and impairs cardiac recovery function after ischemia/reperfusion injury; (2) TRPV1 gene deletion leads to reconditioning of the heart with improved postischemic recovery compared with that induced by acute TRPV1 blockade and in terms of cardiac response to exogenous SP; and (3) blockade of the NK1 but not CGRP receptors worsens postischemic recovery of hearts in both genotypes. Taken together, these data indicate that TRPV1 plays a role in protecting the heart from injury possibly via increasing SP release and that deletion of this receptor reconditions the heart for escaping, at least in part, from injury possibly via enhancing NK1 receptor function.
CLINICAL PERSPECTIVE
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