The contractile effect of the analogue 1 \ x = r e q -\ deamino-1-carba-2-tyrosine(O-methyl)-oxytocin (carbetocin) on isolated myometrial strips from rats was compared with that of oxytocin. The uterotonic activity of the analogue was 15 \m=+-\3 IU/mg as compared with 438 \ m=+-\ 41 for oxytocin, however, the response was more prolonged and could not be abolished by washing of the preparation. Despite the low biological activity of carbetocin, its binding affinity to receptors of isolated myometrial plasma membranes was of the same order of magnitude as that of oxytocin. On the basis of the present results it is concluded that a longer half-life of the analogue at the receptor compartment may be a contributing factor to the prolonged uterotonic effect observed in vivo.

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Ahsrrocr:The results of the present study describe the course of reaction and the products following chymotrypsin treatment of the oxytocin analogue carbetocin ([l-deamino-l-monocarha-2-0-methyltyrosinel-oxytocin). The metabolites were analyzed and identified through TLC, HPLC and mass spectrometry. The main product emerging after treatment of carbetocin with chymotrypsin is 9-desglycineamide carbetocin indicating preferential hydrolysis of the peptide bond between leucine at position 8 and carboxyterminal glycineamide. At the same time the stability of the bond between tyrosine at position 2 and isoleucine at position 3 appears significantly enhanced through the alkylation of the hydroxyl group of tyrosine.

The in vitro contractile effect of neuropeptide Y (NPY) on rat myometrial strips was for the first time demonstrated and characterised, and the EC50 value estimated to be 267 +/- 87 nM. This effect is presumably mediated by the NPY1 receptor being responsible for postsynaptic effects throughout the peripherial nervous system, thus indicating a direct uterotonic effect of NPY. Further, the effect was demonstrated to the dependent on extracellular Ca2+. Short-term exposures to NPY markedly desensitized the tissue affecting subsequent responses to NPY as well as to oxytocin (OT). This desensitization was time and concentration-dependent, but lasted less than three hours. However, long-term infusions of NPY for 5 days increased to response to both NPY and OT. Long-term infusions of OT caused a marked decrease of the NPY response, and it is concluded that common pathways for up and down regulation of the myometrial responsiveness to several peptide hormones may exist.