1. The possible influence of ruthenium-red (RR) on contractility and outflow of calcitonin gene-related peptide (CGRP)-like and neuropeptide Y (NPY)-like immunoreactivity (LI) from the heart of the guinea-pig induced by capsaicin, resiniferatoxin, nicotine, ouabain or bradykinin was studied in vitro. 2. In the isolated right atrium, exposure to capsaicin evoked an increase in contractile rate and tension simultaneously with an enhanced outflow of CGRP-LI, indicating release from the atria. Repeated administration of capsaicin induced tachyphylaxis. Incubation with RR markedly attenuated the capsaicin-evoked release of CGRP-LI while no clear-cut effects were seen on contractile tension or rate. 3. In the isolated whole heart, perfusion with capsaicin induced an increased outflow of CGRP-LI and stimulated heart rate, while a negative inotropic effect was observed. A second administration of capsaicin to the same preparations failed to influence the CGRP-LI outflow and in these experiments the positive chronotropic effect was absent while the negative inotropic action remained unchanged. Capsaicin-perfusion in the presence of RR failed to induce any increased outflow of CGRP-LI from the hearts or changes in contractile activity. However, after 1 h of rinsing with Tyrode solution repeated capsaicin perfusion in the absence of RR caused a clear-cut (60% of control) release of CGRP-LI and contractile responses were restored. 4. Perfusion with resiniferatoxin evoked a RR-sensitive, clear-cut increased CGRP-LI output without any effects on contractile force or heart rate. Repeated administration of resiniferatoxin induced tachyphylaxis with respect to outflow. Capsaicin perfusion after resiniferatoxin did not influence cardiac rate, force or CGRP-LI outflow suggesting development of cross-tachyphylaxis. 5. Perfusion with RR did not influence the outflow of CGRP-LI or contractility changes evoked by perfusion with nicotine, ouabain or bradykinin. In addition, the release of NPY-LI by nicotine remained unchanged in the presence of RR. Furthermore, the positive chronotropic effect of human CGRP alpha remained intact in the presence of RR. 6. It is concluded that RR selectively inhibits capsaicin- and resiniferatoxin-induced excitation of cardiac sensory nerves as revealed by inhibition of both CGRP-LI release and the cardiostimulatory action of capsaicin. RR also seems to protect the cardiac capsaicin-sensitive fibres from the development of tachyphylaxis to capsaicin. Finally, RR prevents the capsaicin-evoked negative inotropic effect which is not related to activation of sensory nerves.