CYCLOOXYGENASE PRODUCTS RELEASED BY LOW PH HAVE CAPSAICIN-LIKE ACTIONS ON SENSORY NERVES IN THE ISOLATED GUINEA-PIG HEART

Objective: Previous work has shown that ischaemia releases calcitonin gene related peptide (CGRP) from capsaicin sensitive nerve terminals in the perfused heart. Prostacyclin (PGI(2)) is also released during ischaemia. The aim of this study was to investigate whether the release of CGRP by low pH and lactic acid was associated with PGI(2) formation and if PGI(2) mediated its effect through capsaicin receptors which could be inhibited by capsazepine. Methods: The isolated Langendorff perfused guinea pig heart was used with a constant perfusion pressure of 70 cm H2O. Low pH was accomplished by changing the Tyrode solution to buffers with pH 7, 6, and 5, or lactic acid (5 mM with pH 6.9). The outflow of CGRP and the stable PGI(2) metabolite 6-keto-PGF(1 alpha) was measured by radioimmunoassay. Results: Low pH (pH 7, 6, 5) and lactic acid evoked release of CGRP. At moderate acidosis (pH 7 and 6) the CGRP release was dependent on extracellular Ca2+, while at pH 5 approximately half of the peptide release persisted in the absence of extracellular Ca2+. This release was attenuated by diclophenac or indomethacin, two inhibitors of prostaglandin formation, as well as by the capsaicin receptor antagonist capsazepine. Both arachidonic acid and PGI(2), the predominant cyclo-oxygenase product formed during myocardial ischaemia, evoked a capsazepine sensitive release of CGRP, while capsazepine did not influence the formation of PGI(2) evoked by low pH or arachidonic acid. Conclusions: In the isolated guinea pig heart, moderate acidosis is associated with CGRP release dependent on influx of extracellular Ca2+ and formation of PGI(2), with subsequent stimulation of capsazepine sensitive receptors. With more severe acidosis there is an additional non-PGI(2)-linked CGRP release. Capsazepine represents a novel pharmacological principle for inhibiting the effects of prostanoids on sensory nerves without influencing their formation.