Role of different proton-sensitive channels in releasing calcitonin gene-related peptide from isolated hearts of mutant mice.
OBJECTIVE
Calcitonin gene-related peptide (CGRP), a potent vasodilator released from a subset of sensory Adelta- and C-fiber afferents, has been suggested to play a beneficial role in myocardial ischemia. The aim of the present study was to investigate some receptors possibly involved in the proton-mediated CGRP release from the heart.


METHODS
CGRP release from freshly isolated hearts of mice lacking the capsaicin receptor (TRPV1-/-), the bradykinin receptor type 2 (B2-/-), or the acid-sensing ion channel type 3 (ASIC3-/-) and their wild-type littermates (TRPV1+/+, B2+/+, ASIC3+/+) were compared. Hearts were passed through a series of solutions based on oxygenated synthetic interstitial fluid (SIF). SIF buffered to pH 5.7 or 5.2 was used as an acidic test stimulus, and capsaicin (5x10(-7) M) was finally applied as a positive control. All eluates were processed using an enzyme immunoassay (EIA) for measurement of CGRP concentrations.


RESULTS
SIF at pH 5.7 and 5.2 caused significant increases in CGRP release in TRPV1+/+ but not in mice lacking the TRPV1 receptor. The same acid stimuli caused no significant differences in CGRP release between ASIC3+/+ and ASIC3-/- or between B2+/+ and B2-/-, respectively. Capsaicin caused massive CGRP release in all mouse genotypes with the exception of TRPV1-/-.


CONCLUSIONS
We conclude that cardiac acidosis is a strong stimulus to release CGRP from the mouse heart. This effect seems to be primarily mediated through activation of TRPV1 receptors that are known to be expressed by slowly conducting nociceptive primary afferent nerve fibers.
Strecker
Thomas
T
Department of Physiology and Experimental Pathophysiology, Friedrich-Alexander-University of Erlangen-Nuremberg, Universitätsstr. 17, D-91054 Erlangen, Germany.
Messlinger
Karl
K
Weyand
Michael
M
Reeh
Peter W
PW
D062565:Acid Sensing Ion Channels; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis / Q000378:metabolism*; D005260:Female; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010477:Perfusion; D017494:Proton Pumps / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels
D062565:Acid Sensing Ion Channels; D007473:Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D017494:Proton Pumps; D043782:Receptor, Bradykinin B2; D015222:Sodium Channels; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D015740:Calcitonin Gene-Related Peptide