Substance P (SP), a member of the tachykinin group of peptides, has been shown to augment the sensory discharge of the carotid body, an oxygen sensing chemoreceptor. In this study we present evidence that the excitatory effect of SP, in part, could arise from a direct effect of the peptide on mitochondrial oxidative phosphorylation. Measurement of the partition coefficient of SP showed that the peptide has a relatively high apolar partition, which could be consistent with its distribution across lipid bilayers and in intracellular organelles. In addition, the effects of three concentrations of SP were tested on oxygen consumption of mitochondria isolated from rat hearts. The results showed that while the lower concentration of the peptide (0.5 microM) did not affect O2 consumption, higher concentrations, i.e., 1 and 2 microM, enhanced the rate of state 4 respiration by 52 and 64%, respectively. The rate of state 3 respiration, on the other hand, was unaltered with 0.5 and 1 microM, and was only slightly decreased with 2 microM of the peptide. The ADP:O ratio was unaffected by any concentrations of SP tested. The peptide-induced effect on state 4 respiration was even more pronounced with glutamate as a respiratory substrate and in presence of K+ in the medium. These results indicate that SP, in addition to its more accepted role as a neurotransmitter or modulator in the carotid body, may elicit intracellular response by interfering directly with oxidative phosphorylation.