The role of the alpha 2-adrenergic system in regulating prolactin release has been studied in vivo in male rats. Yohimbine administration alone, at doses ranging from 0.2 to 5.0 mg/kg, resulted in a dose-related elevation of plasma prolactin levels from a basal level of 8 +/- 2 to 65 +/- 6 ng/ml at the highest dose. In the same experiment clonidine, 0.2 mg/kg, suppressed basal prolactin levels to 4 +/- 1 ng/ml and returned prolactin levels of all animals receiving 0.2-5.0 mg/kg yohimbine to basal levels. Rats were treated with increasing doses of clonidine (0.05-1.0 mg/kg) in the presence or absence of a constant dose (1.0 mg/kg) of yohimbine. Clonidine alone at doses of 0.05 and 0.2 mg/kg again significantly suppressed prolactin levels, while a dose of 1.0 mg/kg did not (failure of high dose clonidine to suppress prolactin levels suggests an additional effect of clonidine on prolactin secretion unrelated to alpha 2-adrenergic agonist action). All three doses of clonidine completely reversed yohimbine-induced prolactin release. Basal prolactin levels were also significantly reduced by the selective alpha 2-adrenergic agonist UK-14,304 at a dose of 0.2 mg/kg. Yohimbine-induced prolactin release was reversed by UK-14,304 at doses of 0.2 and 1.0 mg/kg, but not at the lowest dose studied, 0.05 mg/kg. The lower potency of UK-14,304 than clonidine in this assay is consistent with the lower potency of UK-14,304 as an alpha 2-adrenergic-agonist antihypertensive agent. Several alpha 2-antagonists in addition to yohimbine were studied.(ABSTRACT TRUNCATED AT 250 WORDS)

The method of administration of [D-Ala5,D-Trp8] somatostatin is of central importance in determining the degree and duration of suppression of insulin and glucagon release. The analog decreased insulin levels in rats when injected by s.c. or i.v. routes, with a nadir 15 minutes following injection. After i.v. injection, insulin levels rapidly returned to basal values while s.c. injection produced significant suppression for 60 minutes. Neither type of injection altered glucagon levels. Intravenous infusion resulted in inhibition of both insulin and glucagon release, with rebound hyperglucagonemia, but not hyperinsulinemia in the post-infusion period. Plasma glucose levels reflected these hormonal changes. Thus, dramatic alterations in the specificity of this somatostatin analog may be achieved by employing different methods of administration.

A long-acting somatostatin analog, Wy-41,747, improved glucose homeostasis in steptozotocin-diabetic dogs. In insulin-withdrawn, fasted dogs, a single 100 μg/kg s.c. injection of Wy-41,747 significantly suppressed plasma glucagon levels for 2 h (a nadir of 53 ± 8% of basal being reached at 1 h) and plasma glucose for 3 h (77 ± 5% of basal); even more potent suppression of glucagon and glucose levels was observed during experiments with 500 μ/kg of Wy-41,747. During meal studies, the combined administration of Wy-41,747 (100 μ/kg) and insulin resulted in lower postprandial glucagon and glucose levels than did the administration of insulin alone. When the somatostatin analog was given alone to fed animals, a rise in glucose occurred 4-5 h after the meal, suggesting the possibility of delayed absorption under these conditions. Improved glucose tolerance profiles followed oral administration of glucose or 14C-3-O-methyl glucose; a normal or near-normal time course of absorption was observed with diminished peak plasma glucose or 14C levels. No major malabsorption of carbohydrate occurred in the 14C-3-O-methyl glucose study, since only low levels of 14C were found in the feces of peptide-treated dogs. No undesirable gastrointestinal effects were noted during these studies. In conclusion, administration of a singlesubcutaneous dose of the long-acting somatostatin analog Wy-41,747 to streptozotocin-diabetic dogs lowered fasting plasma glucose levels and augmented insulin action in lowering postprandial glucose levels.

A somatostatin analog, [D-Ala5, D-Trp8]-somatostatin, has been found to selectively inhibit insulin and GH release in rats. The release of these hormones is inhibited by an analog dose of 5 microgram/kg in short term experiments (15 min from analog administration to blood sampling), while glucagon levels are not lowered by analog doses as high as 500 microgram/kg. The lowered insulin to glucagon ratio results in hyperglycemia. [D-Ala5, D-Trp8]Somatostatin is also long acting; a 1 mg/kg dose results in hypoinsulinemia for 2 h and hyperglycemia for 3 h.

FEBS LettersVolume 88, Issue 2 p. 208-210 Full-length articleFree Access Stimulation of growth hormone and prolactin release by a potent enkephalin analog E.L. Lien, E.L. Lien Biochemistry Section, Wyeth Laboratories, Philadelphia, PA 19101, USASearch for more papers by this authorD.E. Clark, D.E. Clark Biochemistry Section, Wyeth Laboratories, Philadelphia, PA 19101, USASearch for more papers by this authorW.H. McGregor, W.H. McGregor Biochemistry Section, Wyeth Laboratories, Philadelphia, PA 19101, USASearch for more papers by this author E.L. Lien, E.L. Lien Biochemistry Section, Wyeth Laboratories, Philadelphia, PA 19101, USASearch for more papers by this authorD.E. Clark, D.E. Clark Biochemistry Section, Wyeth Laboratories, Philadelphia, PA 19101, USASearch for more papers by this authorW.H. McGregor, W.H. McGregor Biochemistry Section, Wyeth Laboratories, Philadelphia, PA 19101, USASearch for more papers by this author First published: April 15, 1978 https://doi.org/10.1016/0014-5793(78)80175-6Citations: 9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 J. Hughes, T.W. Smith, H.W. Kosterlitz, L.A. Fothergill, B.A. Morgan, R.H. Morris, Nature, 258, (1975), 577– 579. 2 R. Simantov, S.H. Snyder, Mol. Pharmacol., 12, (1976), 987– 998. 3 J.D. Belluzzi, N. Grant, V. Garsky, D. Sarantakis, C.D. Wise, L. Stein, Nature, 260, (1976), 625– 626. 4 S. Bajusa, A.Z. Ronai, J.I. Szekely, L. Graf, Z. Dunai-Kovacs, I. Berzetei, FEBS Lett., 76, (1977), 91– 92. 5 McGregor, W. H., Dvonch, W., Dheer, S., Belluzzi, J. D., Stein, L. and Gluckman, M. I. (1978) submitted. 6 C. Rivier, W. Vale, N. Ling, M. Brown, R. Guillemin, Endocrinology, 100, (1977), 238– 241. 7 C. Rivier, M. Brown, W. Vale, Endocrinology, 100, (1977), 751– 754. 8 E.L. Lien, R.L. Fenichel, V. Garsky, D. Sarantakis, N.H. Grant, Life Sci., 19, (1976), 837– 840. 9 C.J. Shaar, R.C.A. Frederickson, N.B. Dininger, J.A. Clemens, R.N. Hull, Fed. Proc. Fed. Am. Soc. Exp. Biol., 36, (1977), 311– 10 J.D. Neill, J.E. Reichert Jr., Endocrinology, 88, (1971), 548– 555. 11 Y.N. Sinha, F.W. Selby, U.J. Lewis, W.P. Vanderlaan, Endocrinology, 91, (1972), 784– 792. 12 P. Brazeau, J. Rivier, W. Vale, R. Guillemin, Endocrinology, 94, (1974), 184– 187. 13 L. Ferland, F. Labrie, D.H. Coy, A. Arimura, A.V. Schally, Mol. Cell. Endocrinol., 4, (1976), 79– 88. 14 J.B. Martin, J. Audet, R. Saunders, Endocrinology, 96, (1975), 839– 847. 15 A. Dupont, L. Cusan, M. Garon, D. Coy, C. Li, F. Labrie, Fed. Proc. Fed. Am. Soc. Exp. Biol., 36, (1977), 311– Citing Literature Volume88, Issue2April 15, 1978Pages 208-210 ReferencesRelatedInformation

A potent analog of somatostatin has been synthesized which suppresses plasma levels of growth hormone, insulin and glucagon in short term experiments in rats (15 minutes from analog administration to blood sampling). This analog lowers plasma growth hormone in rats and plasma glucose and glucagon in streptozotocin diabetic dogs for prolonged periods of time.

The tetradecapeptide somatostatin was cyclized by a combination of conventional and solid phase peptide synthesis methods, to a homodetic cyclic disulfide tetradecapeptide, Wy-40,391: The analog inhibits the release of growth hormone (GH) in vivo without affecting either insulin or glucagon secretion. A correlation between binding affinity to the receptors and specificity is suggested.

The effect of methionine- and leucine-enkephalinaa on prolactin secretion was studied in vivo and in vitro. Administration of methionine-enkephalin to rats (5 mg/kg) resulted in a consistent increase in plasma prolactin. In monolayer cultures of rat pituitaries both enkephalins released prolactin at concentrations as low as 5 ng/ml.

A cyclic undecapeptide, Wy-40,770, has been synthesized by a combination of solid phase and conventional peptide synthesis methodology. The compound inhibits the release of growth hormone without significantly affecting glucagon levels in rats. Wy-40,770 shows growth hormone release inhibiting activity for four hours after s.c. injection.