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Tripeptide aldehyde protease inhibitors may depress in vitro prolactin and growth hormone release
Abstract:
The effects of novel nontoxic tripeptide aldehyde inhibitors of proteolytic enzymes were examined in order to investigate the possibility that serine-thiol protease(s) may be involved in PRL and GH secretion. Rat anterior pituitary cells maintained in culture for 7-8 days or freshly taken pituitary quarters were treated with BOC-DPhe-Pro-Arg-H (BOC-dPPA), DPhe-Pro-Arg-H (dPPA), BOC-DPhe-Leu-Lys-H (BOC-dPLL), or BOC-DPhe-Phe-Lys (BOC-dPPL). Newly synthetized [3H]PRL and [3H]GH as well as immunoreactive (i) hormones (iPRL, iGH) were measured in the incubation media and cell homogenates. Four hours of incubation in the presence of 0.1 mM dPPA resulted in a 30% decrease of [3H]PRL and iPRL release by cell cultures; the inhibition by BOC-dPPA was 60% and 48%, respectively. [3H]PRL biosynthesis was unchanged or slightly decreased. The effect of these tripeptide aldehydes on [3H]GH and iGH release was less pronounced but statistically significant. Pituitary quarters treated with 1.0 or 3.0 mM BOC-dPPA release 20% and 57% less [3H]PRL than the controls. In the same system BOC-dPPA in a 1.0 mM concentration did not effect GH secretion, and 3.0 mM BOC-dPPA inhibited [3H]GH output by 27%. Forty micromolars of BOC-dPPL decreased by 47%, 0.2 mM by 79%, and 1.0 mM by 94% [3H]PRL release from pituitary quarters. GH secretion was not influenced. A similar selectivity was observed when BOC-dPLL was used. It is clear that by serine-thiol protease inhibitors whose effects are sequence and dose dependent, PRL and GH release are decreased. The relative inhibiting potency on PRL release was BOC-dPPL greater than BOC-dPLL greater than BOC-dPPA greater than dPPA. The biosynthesis of [3H]PRL was reduced only in the presence of the highest tripeptide aldehyde concentrations or long (8 h) exposure, and only 1.0 mM Boc-dPPL reduced [3H]GH biosynthesis by 30%. The data suggest that proteolysis may be involved in the process of PRL and GH release and the enzyme(s) in question may be serine-thiol protease(s).