MSH-release inhibiting factors: recent studies.

The evidence which has finally resulted in the general acceptance of the concept that there are substances present in hypothalamic tissue which inhibit the release of melanocyte-stimulating hormone (MSH) from the pituitary glands of mammals as well as amphibians has been summarized in several recent reviews (1-3). Although the chemical structures of several compounds with such activity are known, it is still uncertain which one of these, if not a different one, is the actual hormone. Both a tripeptide, Pro-Leu-Gly-NH2, and a pentapeptide, Pro-His-Phe-Arg-GlyNH2, have been isolated from bovine hypothalamic tissue and structurally identified (4, 5). Since purification of the bovine extract involved heating to boiling in dilute acetic acid followed by rapid cooling (6), the recent suggestion by Hadley, Bower, and Hruby (7) that hypothalamic extracts heated to boiling under undefined conditions lose their ability to inhibit MSH release probably can be dismissed as a technical problem. The assay used for following the isolation of the two peptides is based on the lightening of the skin of a frog which has been previously darkened by destruction of the hypothalamus (8, 9). Pro-Leu-Gly-NH2 can be formed by incubating oxytocin with an enzyme found in hypothalamic tissue and has been reported previously to inhibit MSH release in the rat also (10). However, Bower et al. (11) did not find any MSH-release inhibiting factor (MIF) activity of ProLeu-Gly-NH2 (MIF-I) in the frog or rat. Why they failed to find activity in the frog, Rana pipiens, is easy to understand: they injected MIF-I into the dorsal lymph sac, a procedure already shown to be ineffective, and they also incubated MIF-I with pituitaries for 4 hr, a time which results in essentially complete inactivation of the material (9). It is also possible that an inactive (12) batch of MIF-I was tested. The reason for the inability of Bower et al. to find the activity of MIF-I which had been reported by Celis et al. (10) for rats is not known. Alternatively, Bower et al. proposed that tocinoic acid, Cys-Tyr-Ile-Gln-Asn-CysOH, the cyclic pentapeptide ring of oxytocin, or its amide, tocinamide, is more likely to be MIF (11). Interestingly, Celis et al. (13) have suggested that if the