1. Low pH and lactic acid perfusion evoke a reproducible, and concentration-dependent outflow of CGRP from the isolated heart. 2. PGI2 causes outflow of CGRP from the isolated heart. Furthermore, low pH perfusion causes release of PGI2, and cyclo-oxygenase inhibition attenuates not only this release of PGI2, but also the outflow of CGRP that is evoked by low pH perfusion, indicating that a portion of the C-fibre activation exerted by low pH is mediated by PGI2. 3. The outflow of CGRP that is caused by low pH but not that evoked by capsaicin or PGI2 is dependent on the endothelium, whereas the vasodilating effect of CGRP is preserved after removal of the endothelium. 4. TTX attenuates release of CGRP caused by low concentrations of capsaicin, indicating that an axon reflex mechanism in the peripheral endings of C-fibre afferents can augment local outflow of CGRP. 5. Outflow of CGRP evoked by low pH and capsaicin have common features, such as sensitivity to RR and CPZ. N-type calcium channels are involved in release of CGRP by both stimuli. 6. In the coronary vasculature, exogenous CGRP augmented post-occlusive hyperaemia. 7. In the pig in vivo, CGRP causes marked dose-dependent reduction of systemic vascular resistance. This effect of CGRP was partly reduced by CGRP(8-37). 8. Capsaicin pretreatment resulted in lower myocardial levels of CGRP, and ischaemic myocardium had lower content of CGRP than non-ischaemic areas. Capsaicin-treated animals had larger myocardial infarctions, possibly due to depletion of CGRP. When endogenous stores of CGRP were intact, administration of additional CGRP to the ischaemic myocardium had no cardioprotective effect. 9. In patients undergoing CABG without CPB, 10-20 minutes of local ischaemia (as evidenced by a net production of lactate) was associated with increased levels of CGRP in coronary sinus blood. 10. Based on the present findings it may therefore be suggested that local cardiac CGRP-release from capsaicin-sensitive C-fibre afferents during myocardial ischaemia functions as an endogenous physiological protective response. The possibility thus exists that effects of CGRP observed in animal studies may play a role in human myocardial ischaemia.