ARACHIDONIC-ACID AND BRADYKININ SHARE A COMMON PATHWAY TO RELEASE NEUROPEPTIDE FROM CAPSAICIN-SENSITIVE SENSORY NERVE-FIBERS OF THE GUINEA-PIG HEART

The ability of arachidonic acid (AA) and bradykinin to release caicitonin gene-related peptide-like immunoreactivity (CGRP-LI) from capsaicin-sensitive primary afferents was studied in guinea pig isolated and perfused heart. Infusion of AA (50-mu-M to 5 mM, 0.5 ml/min over 2 min) produced a remarkable and dose-dependent CGRP-LI release that was abolished by in vitro capsaicin (10-mu-M) pretreatment or in the presence of indomethacin (10-mu-M). The capsaicin antagonist ruthernium red (10-mu-M) did not affect the CGRP-LI release produced by AA, whereas it blocked that produced by capsaicin (10-mu-M). In vitro capsaicin pretreatment reduced the increase in heart rate evoked by AA, whereas it did not affect the increase in coronary flow and decrease in contractility. Bradykinin (10-mu-M, 0.5 ml/min over 2 min) induced CGRP-LI release in a similar manner to that produced by AA, with the only difference being that in the presence of indomethacin, a residual increase in CGRP-LI outflow was still observed. AA increased the outflow of 6-keto-prostaglandin (PG)F1-alpha, PGE2 and leukotriene B4, whereas bradykinin enhanced only the release of 6-keto-PGF1-alpha. Infusion of either PGl2 or PGE2 (1-100-mu-M) released CGRP-LI in a dose-dependent manner and with a similar potency. PGl2 (100-mu-M)- or PGE2 (100-mu-M, 0.5 ml/min over 2 min)-evoked release was abolished by previous exposure to capsaicin and not affected by indomethacin. It is proposed that both AA and bradykinin promote release of CGRP from cardiac capsaicin-sensitive afferents of the guinea pig by a common pathway (e.g., by prostanoid production), and that this mechanism is distinct from that activated by capsaicin.