The molecular structures of several polypeptides isolated from hypothalamic tissue have been established and the synthesis of these compounds has been achieved. These polypeptides selectively stimulate or inhibit the release of anterior pituitary hormones and melanocyte-stimulating hormone. Various studies indicate their important physiological role and support the concept that some of these polypeptides are hormones. Some synthetic hypothalamic hormones and their derivatives may find important clinical and veterinary applications.

http://science.sciencemag.org/content/sci/179/4071/341.full.pdf

Hypothalamic Regulatory Hormones

WE have found that when rats are treated with the prostaglandin PGE1 adjuvant arthritis is prevented and suppressed. Although the treatment had no effect on delayed hypersensitivity to PPD, it reduced the immune response to sheep red blood cells (SRBC). Our findings support earlier indications that PGE1 might modify the inflammatory response1,2.

Effect of prostaglandin E 1 on adjuvant arthritis.

1. Lysine vasopressin induces resistance to extinction of active avoidance behaviour (De Wied, 1971).

2. Digestion of lysine vasopressin with trypsin almost completely destroys the pressor-, antidiuretic-, oxytocic- and corticotrophin-releasing factor activities of lysine vasopressin, but does not materially influence its effect on the maintenance of an avoidance response.

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Dissociation of the behavioural and endocrine effects of lysine vasopressin by tryptic digestion.

ANGIOTENSIN II, a circulating peptide which regulates electrolyte balance by controlling the adrenal release of aldosterone, may also act on the central nervous system. The reported central effects include elevations of blood pressure1–6, drinking behaviour7–11, adrenocorticotrophic hormone release12,13 and antidiuretic hormone (ADH) release5,14,15. The evidence for ADH release from the supraoptico-neurohypophysial system is based on studies involving the parenteral and intraventricular administration of angiotensin II. These routes of administration make an exact localization of the releasing action impossible and therefore we have attempted to locate the site by applying angiotensin II directly to individual supraoptic neurosecretory cells. We now report that angiotensin II increases the discharge rate of these and other neurones in the supraoptic nucleus.

Excitation of supraoptic neurosecretory cells by angiotensin II.

PIP: Some aspects of prostaglandin (PG) functions are reviewed including: 1) the role of PGs in the hypothalamic and pituitary control of gonadotropin secretions; and 2) their roles in ovulation, 3) in luteinization, and 4) in corpus luteum regression. PGE1 is known for its role in stimulation of increased cyclic adenosine 3',5' monophosphate (cAMP) and hormone secretion in the anterior pituitary. Direct effects of PGs on the secretion of luteinizing hormone, follicle stimulating hormone, and adrenal cortex hormones are not clearly known, but surmised. Such actions may not be the direct effects of PGs on pituitary action. Instead, more studies on receptor functions for PGs in pituitary cells are needed. Systemic administration of PGs has been shown to increase circulating levels of gonadotropins, adrenal cortex hormones, prolactin, follicle stimulating hormone, and luteinizing hormone; and in general, PGs of the E series are more potent than those of the F series. This response to systemic administration seems to be caused by an hypothalamic site of action, a conclusion based on several observations, including the observation that direct application of PGs to brain tissue causes a mimicking of endogenous PG effects of gonadotropin secretion. PGs also play a role in ovulation. Elevated PG levels in follicular tissues are induced by gonadotropins; cyclic nucleotides may be involved in mediating the action of gonadotropins on follicular PG production; a recognized time lag after exposure of the follicle to gonadotropin or cyclic nucleotides indicates that macromolecular synthesis may be involved in follicular PG production; and plasminogen activator may play a role in the process of follicular rupture that leads ot ovulation. The role of PGs in luteinization has been suggested by experiments which showed that granulosa cells cultured with PGE1 and PGE2 luteinized. PGs, particularly PGF2 alpha, cause luteal regression in many species, except perhaps in humans. And PGF2 alpha may be an antagonist of gonadotropin action in the corpus luteum. A proposed mechanism of PGF2 alpha-induced luteolysis in rats is also presented.

Prostaglandins in hypothalamo- pituitary and ovarian function

The ACTH-releasing activity of some substances of low molecular weight was tested in several assay systems in the rat, in which attempts were made to block the nonspecific release of ACTH. The rate of corticosteroid production in vitro and corticosterone content of plasma were used as parameters of pituitary ACTH release. In the rat pretreated with sodium pentobarbital and chlorpromazine, none of the amino acids, amino acid mixtures, various di- and tripeptides, or biogenic amines exhibited a significant effect on pituitary-addrenal activity. However, prostaglandin E1 and E2, in contrast to F1α and F2α, stimulated pituitary ACTH release in rats blocked with sodium pentobarbital and chlorpromazine. Angiotensin II, arginine vasopressin, carbachol and a crude CRF from calf brain also activated the pituitary-adrenal system of similarly blocked rats. The corticotrophic effect of these “active agents” was further studied in rats pretreated with sodium pentobarbital, atropine and chlorpromazine; sodium pentobarb...

Release of ACTH by substances of central nervous system origin.

Rat median eminence homogenates were fractionated by differential and density gradient centrifugations. The CRF activity was assayed in pentobarbital-chlorpromazine pretreated rats. The peptide character of the CRF activity in the rat ME was apparent from its complete destruction by the proteolytic enzyme pronase. Furthermore, the CRF activity was partially destroyed by treatment with thioglycollate. The crude mitochondrial fraction (10,000×20 gmin) was separated into 5 subfractions (P1–P5) on a discontinuous gradient ranging from 1.0 to 1.5M sucrose. From the 10,000×20 gmin supernatant 3 subfractions (M1–M3) were obtained after centrifugation on a similar type of gradient. Electron microscopic examination revealed the presence of synaptosomes in the subfractions P2 to P5. Small membrane fragments and different types of granules were mainly concentrated in the subfractions Ml, M2 and M3. About half of the total CRF activity was associated with the subfractions containing the synaptosomes and part of the r...

A. H. Mulder

Papers

Release of ACTH by substances of central nervous system origin.

Studies on the subcellular localization of corticotrophin releasing factor (CRF) and vasopressin in the median eminence of the rat.