Preconditioning induced by brief ischemia or hyperthermia or some drugs shows two phases, early and delayed protection. The cardioprotection afforded by preconditioning is related to stimulation of endogenous mediators release. Calcitonin gene-related peptide (CGRP), a major transmitter of capsaicin-sensitive sensory nerves, has recently been shown to play an important role in mediation of the preconditioning induced by brief ischemia or hyperthermia or by some drugs, and alpha-CGRP seems to play a major role in the mediation of delayed preconditioning. It has been shown that the cardioprotection afforded by CGRP-mediated preconditioning is due to inhibition of cardiac tumor necrosis factor-alpha (TNF-alpha) production, but not to the activation of the K(ATP) channel.