Marvin R. Brown

Chemical and Biological Characterization of Corticotropin Releasing Factor

Publisher Summary Hypothalamus liberates a substance into the hypophysial portal blood that stimulates the adrenocorticotrophic hormone (ACTH) activity of the pituitary. This chapter discusses the chemical and biological characterization of this corticotropin releasing factor (CRF). Several known naturally occurring substances including vasopressin, oxytocin, norepinephrine, epinephrine, and angiotensin II are found to stimulate ACTH secretion. Partially purified preparations of CRF stimulates the secretion of a number of peptides derived from the proopiomelanocortin (POMC) precursor—including the opioid peptide, β-endorphin. The chapter explains that CRF is likely to be distributed outside of the hypothalamus and possess extra hypophysiotropic actions. In vitro systems are vulnerable to non specific secretagogs in extracts including myelin basic protein, histones, potassium ion, and the components of various buffers and solvents. Ovine CRF is homologous with several known peptides including sauvagine and urotensin I. CRF also shows some homology with calmodulin and with angiotensinogen. The tetrapeptide Phe-His-Leu-Leu is common to both angiotensinogen and CRF and is the site in angiotensinogen of renin and converting enzyme cleavage. The chapter concludes with the evidence that supports CRF or a closely related peptide in the neuroregulation of the pituitary corticotropic cells.

Corticotropin-releasing factor: Effects on the sympathetic nervous system and oxygen consumption

Corticotropin-releasing factor administered intracerebroventricularly produces prolonged elevation of plasma concentration of epinephrine, norepinephrine and glucose. These hormonal changes are associated with an increase in motor activity and oxygen consumption. No change in body temperature is observed. CRF produces changes in animal physiology that are similar to those observed in response to stress.

Bombesin affects the central nervous system to produce hyperglycemia in rats

Abstract Bombesin, a peptide isolated from frog skin, acts through the central nervous system to produce hyperglycemia in rats. Bombesin induced hyperglycemia may be mediated via adrenomedullary-catecholamine induced changes in insulin and glucagon secretion resulting in enhanced hepatic glucose output.

Bombesin-like activity: Radioimmunologic assessment in biological tissues

Abstract Highly specific sensitive radioimmunoassays (RIA) have been developed to quantitatively measure the anuran skin peptide, bombesin. These RIAs have been used to demonstrate a bombesin-like immunoactivity (BLI) within mammalian brain, gut, lung and plasma. BLI in rat brain is present in highest concentration in the hypothalamus, with lowest concentration in cerebellum. The highest concentrations of BLI outside the brain are found in the stomach, duodenum and jejunum, with lower levels in the lung. No BLI was detected in pineal, anterior pituitary, adrenal, liver, kidney or pancreas. While BLI was not detected in normal rat plasma, extraction of plasma with formic acid revealed the presence of significant amounts of BLI in normal rat plasma. Gel filtration of acidified rat plasma BLI produced a single peak of BLI, which appears to be of higher molecular weight than frog skin bombesin. Gel filtration of formic acid extracts of rat gastrointestinal tract demonstrated the presence of two forms of BLI; a large BLI and a smaller BLI similar in size to plasma BLI.

Biologic and immunologic activities and applications of somatostatin analogs.

Abstract With the realization of the numerous powerful effects of somatostatin (SS) on the adenohypophysis, pancreas, gastrointestinal tract, and central nervous system, 1,2 it was considered that analogs of this peptide might provide important investigational and, perhaps, therapeutic tools. Since the characterization of SS 5 yr ago, hundreds of analogs have been synthesized and biologically tested. These analogs have provided an appreciation of the structural requirements for somatostatins multiple biologic activities. It must be recognized, however, that the interpretation of structure/activity data is complicated by several factors; the biologic activity of an analog relative to SS can reflect variations in distribution and rates of metabolism, receptor affinity, or intrinsic activity (ability of the SS receptor complex to induce the appropriate intracellular mediatory signals). Furthermore, the observed biologic activities of an analog could reflect either an involvement of the altered regions in SS in the metabolism or action of the peptide, or might be secondary to changes in intramolecular associations and conformation. Somatostatin analogs are now available that are more potent, longer-acting, and possess a different spectrum of biologic activities. As will be described, such peptides have already been applied to several physiologic and clinical studies. Other SS analogs have been tailor-made for a variety of purposes, including their use as immunogens and receptor-binding assays.

Corticotropin-releasing factor: a physiologic regulator of adrenal epinephrine secretion.

Pituitary adrenocorticotropic hormone (ACTH) secretion following stress is mediated primarily by the release of corticotropin-releasing factor (CRF) from the brain. We have hypothesized that stress-induced alterations of autonomic nervous system activity also may be dependent on CRF release within the brain because administration of CRF into the brain produces changes in autonomic nervous system function that are similar to those observed following exposure to various types of stress. We now report confirmation of this hypothesis with studies using a CRF receptor antagonist. The CRF receptor antagonist, alpha-helical CRF9-41, placed into the brains of rats suppressed stress-induced elevations of plasma epinephrine levels. Thus, CRF appears to be physiologically involved in coordinating the pituitary and autonomic nervous system responses to stress.

Evidence for immunoreactive neurotensin in dog intestinal mucosa

Abstract Discrete cells containing neurotensin, as shown by immunofluorescence, have been observed in the lower portion of the dog ileum. This implies that neurotensin may be synthesized in the small intestine and may be involved in local regulation of intestinal functions. Neurotensin is a peptide characterized originally in the hypothalamus.

Corticotropin-releasing factor (CRF): mechanism to elevate mean arterial pressure and heart rate

The efferent mechanisms by which central administration of corticotropin-releasing factor (CRF) elevates mean arterial pressure and heart rate were assessed in unanesthetized, unrestrained rats. CRF increased blood pressure and heart rate by stimulating noradrenergic sympathetic nervous outflow. CRF-induced cardiovascular changes were not dependent on anterior pituitary hormone release, adrenomedullary epinephrine secretion, the renin-angiotensin system or circulating vasopressin.

Thyrotropin releasing factor: A putative CNS regulator of the automatic nervous system

Abstract Thyrotopin releasing factor (TRF) acts with the brain to elevate plasma levels of epinephrine and norepinephrine. In contrast to other CNS stimuli which increase plasma epinephrine levels, epinephrine secretion stimulated by TRF is not inhibited by peptides related to somatostatin. Associated with the TRF induced increase in plasma catecholamines is an elevation of plasma glucagon and glucose, effects which are prevented by adrenalectomy.

D-Trp8-somatostatin: An analog of somatostatin more potent than the native molecule

Summary D-Trp8-somatostatin (Ala-Gly- Cys-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-Cys -OH) was synthesized by solid phase methodology. This tetradecapeptide was found to be 8 times more potent than somatostatin under different assay conditions. This finding is interpreted in terms of conformational aspects of somatostatin or of enzymic resistance to degradation.