Dual capsaicin effects on ureteric motility: low dose inhibition mediated by calcitonin gene-related peptide and high dose stimulation by tachykinins?

The effects of capsaicin, in relation to substance P (SP), neurokinin A (NKA), neuropeptide K (NPK) and calcitonin gene-related peptide (CGRP) which coexist in local sensory nerves, on the motility of the guinea-pig ureter were studied in vivo and in vitro. Capsaicin in a low dose (10 nmol kg-1) given i.v. inhibited spontaneous, peristaltic contractions, as revealed by perfusion-pressure changes of the constantly perfused ureter in vivo. This action was independent of autonomic reflexes and prostaglandin formation. Capsaicin stimulated ureteric motility at higher doses (100 and 500 nmol kg-1). The dual effects of capsaicin on the ureteric contractility were absent 2 weeks after systemic capsaicin treatment, which depletes sensory neuropeptides. Both NKA and NPK initiated, as well as increased, the magnitude of the peristaltic contractions of the ureter, while SP only caused a minor excitatory effect. The CGRP inhibited spontaneous, as well as NKA- and NPK-induced ureteric peristaltic contractions. In vitro experiments on the ureter revealed that capsaicin (10(-6) M) induced phasic circular muscle contractions in 60% of the experiments. Neurokinin A, NPK and SP consistently increased the contractile activity. The NKA tachyphylaxis inhibited the contractile response to other tachykinins and capsaicin. The SP analogue Spantide (/D-Arg1, D-Trp7,9, Leu11/-SP) inhibited the contractile responses to SP, NKA and NPK. The CGRP also inhibited the NKA- and NPK-induced contractions of the ureter in vitro. In conclusion, capsaicin, which induces the release of mediators from sensory nerves within the ureter, has either stimulatory or inhibitory effects on ureteric smooth muscle, depending on the in vivo dose administered. The inhibitory response at a low capsaicin dose is similar to the effect of CGRP, while the contractile effects at higher doses resemble the response to tachykinins.