Two androstenedione derivatives, 10-propargylestr-4-ene-3,17-dione and its 17-propionated form, were administered to normal cycling rats, and both compounds led to an inhibition of ovarian aromatase. Under in vitro conditions, only the former compound exhibited high potency as an inhibitor of rat ovarian and human placental microsomal aromatase. At 1 mg/kg/day both compounds were effective in promoting regression of 9,10-dimethyl-1,2-benzanthracene-induced mammary tumors in rats without terminating their estrous cycle. PED also inhibited growth of a human ovarian carcinoma in athymic mice. The results with the 17-propionated compound testify to the necessity of in vivo assays in screening antitumor agents. In summary, PED and its propionated derivative inhibited ovarian aromatase in vivo and inhibited the growth of hormone-responsive tumors.

Androstenedione↗

PubMedDate not supplied

Contribution of the amino terminal tyrosine to the interaction of gamma-endorphin with opiate receptors.

The putative behavioral hexadecapeptide, des-Tyr1-gamma-endorphin, has been compared with gamma-endorphin in an in vitro radioreceptor assay utilizing [3H] beta-endorphin as the labeled ligand and rat brain membranes as a source of opiate receptors. Under the conditions used, beta-endorphin and gamma-endorphin exhibit Kd's of 0.4 nM and 58 nM, respectively. The Kd of des-Tyr1-gamma-endorphin was estimated to be 42 micro M indicating that the amino terminal tyrosine in gamma-endorphin contributes about -4 kcal/mol at 30 degrees C to free energy of binding associated with the peptide-opiate receptor interaction. Circular dichroic spectra were obtained, and the only structural element discernible was a possible beta-turn. Thus, at physiological levels it seems unlikely that the des-Tyr1 fragment of gamma-endorphin will exhibit any significant interaction with the opiate receptor.

Animals↗

PubMedDate not supplied

des-(1-13) human beta-endorphin interacts with calmodulin.

It is known that the 31-residue neuropeptide beta-endorphin inhibits the calcium-dependent, calmodulin-mediated stimulation of cyclic nucleotide phosphodiesterase activity. The results of this study demonstrate that a non-opiate, synthetic amino terminal deletion peptide, des-(1-13), of human beta-endorphin is also capable of inhibiting the stimulated enzymic activity, but not the basal activity. This inhibition occurs with the same efficacy as the intact 31-residue peptide. Thus, the amino terminal region of beta-endorphin, which is responsible for opiate activity, does not appear to contribute to the calmodulin interaction. Circular dichroic spectroscopy of des-(1-13) beta-endorphin, calmodulin, and mixtures of the two shows that the ellipticity at 221 nm was more negative in the peptide-protein mixture than could be accounted for on the basis of simple additivity of the peptide and calmodulin. This spectral change implies enhanced alpha-helicity concomitant with the peptide-protein association. Helix formation may occur in the peptide since this sequence has the potential to form an amphipathic helix.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMedDate not supplied

Thromboxane synthetase inhibitor UK38,485 lowers blood pressure in the adult spontaneously hypertensive rat.

Treatment of young spontaneously hypertensive rats (SHR) with a thromboxane synthetase inhibitor (TSI) attenuates their subsequent development of hypertension. In this study, treatment of adult SHR during the established phase of hypertension with the TSI UK38,485 (100 mg/kg daily) lowered systolic blood pressure from baseline after 4 days of treatment to a maximum depression of 25 mm Hg on day 10 of the study. Additional confirmation of the fact that this TSI does not lower blood pressure acutely was made via continuous intraarterial recordings in SHR administered their first dose of UK38,485. Urinary dinor-6-keto-PGF1 alpha excretion was measured by a highly specific chemical-ionization, negative-ion GC/MS assay in the selective ion monitoring mode. This metabolite of PGI2 was not significantly affected by 6 days of daily administration of UK38,485 to adult SHR and implies that there was not sufficient endoperoxide shunting to affect total body PGI2 production. The finding that UK38,485 exhibited antihypertensive activity during established SHR hypertension was unexpected and has considerable practical and theoretical significance.

Animals↗

PubMedDate not supplied

Characterization of endothelin receptor subtypes on airway smooth muscle cells.

Endothelin-1 (ET-1) has constrictor and mitogenic effects on airway smooth muscle strips and cultured cells, respectively. This study addresses the type of the ET receptor subtype(s) present on ovine airway smooth muscle cells and the possibility of autocrine effects. The expression of the preproendothelin-1 gene was demonstrated by Northern analysis, and the medium obtained from these cells contained immunoreactive-ET-1. Competitive binding experiments between [125I]ET-1 and ET-1, ET-3, and two ET-receptor subtype selective-ligands, BQ-123 (ETA) and sarafotoxin S6c (ETB), yielded IC50 values of 1.1 +/- 0.1, 227 +/- 13, 12 +/- 1, and 194 +/- 21 nM, respectively. ET-3 also gave a limited number of higher affinity sites. In the presence of BQ-123 (1 microM), the binding of [125I]ET-1 was decreased by 80-85%, and the IC50 values with ET-1, ET-3, and S6c were 2.0 +/- 0.4, 3.6 +/- 0.6, and 1.1 +/- 0.9 nM, respectively. In similar experiments with 0.1 microM sarafotoxin S6c, the respective IC50 values for ET-1 and ET-3 were 2.4 +/- 0.4 and 300 +/- 20 nM. These results demonstrate that about 85 +/- 5% of ET-1 binding to airway smooth muscle cells is to ETA receptors and that these cells produce ET-1 in vitro.

Animals↗