Laurel A. Fisher

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.

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.

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.

Comparison of the biologic actions of corticotropin-releasing factor and sauvagine

Corticotropin-releasing factor (CRF), a peptide isolated from ovine hypothalamus, and sauvagine, a peptide isolated from frog skin, share significant structural homology and elicit a number of similar biological responses. CRF is more potent than sauvagine in stimulating pituitary ACTH secretion. Sauvagine, however, is 5-10 times more potent than CRF to act within the brain to increase plasma levels of catecholamines and glucose and to elevate mean arterial pressure. Sauvagine is likewise more potent than CRF to act outside the brain to increase superior mesenteric artery flow and plasma glucose concentrations and to decrease mean arterial pressure. CRF and sauvagine produce important effects representative of biologically active peptides.

Glucocorticoid suppression of the sympathetic nervous system and adrenal medulla.

Studies were performed to evaluate the effects of glucocorticoids on the activity of the sympathetic nervous system and adrenal medulla. Plasma concentrations of norepinephrine and epinephrine were measured in rats in which endogenous glucocorticoids were removed by bilateral adrenalectomy and in rats to which exogenous glucocorticoids were administered. In intact rats, dexamethasone (2.5, 25 or 250 micrograms) pretreatment suppressed ether vapor-induced elevations of norepinephrine and epinephrine concentrations in plasma. Corticosterone (3 mg/kg), similar to dexamethasone, attenuated the elevation of plasma concentrations of norepinephrine and epinephrine in rats exposed to ether vapor. Glucocorticoids did not alter the elevation of plasma catecholamines stimulated by intracerebroventricular injections of corticotropin-releasing factor or calcitonin gene-related peptide, thus demonstrating functional integrity of the sympathetic nervous system and adrenal medulla. Adrenalectomy resulted in elevation of basal plasma norepinephrine levels and accentuation of ether vapor-induced elevations of plasma norepinephrine concentrations in rats. Dexamethasone (25 ug) administration blunted the effects of adrenalectomy on both basal and ether vapor-stimulated levels of plasma norepinephrine. It is concluded that glucocorticoids acting at as yet undefined sites may be involved in the regulation of sympathetic nervous system and adrenal medullary function.

Corticotropin-releasing factor receptor antagonist: effects on the autonomic nervous system and cardiovascular function

The corticotropin-releasing factor (CRF) receptor antagonist, alpha-helical [Glu27]-corticotropin-releasing factor 9-41 (CRF 9-41) has been assessed for its ability to modify plasma concentrations of epinephrine and norepinephrine, mean arterial pressure (MAP) and heart rate (HR). Basal concentrations of epinephrine and norepinephrine were not altered by lateral ventricular (icv) administration of CRF 9-41. However, this CRF antagonist, given icv, attenuated the rise of plasma epinephrine following 30% hemorrhage and insulin-induced hypoglycemia. CRF 9-41 did not alter the increased plasma concentrations of epinephrine or norepinephrine following icv administration of bombesin. Icv administration of CRF 9-41 blunted CRF-induced elevation of MAP and HR in normal animals. However, this CRF antagonist did not modify the MAP or HR in spontaneously hypertensive rats. Similarly, this CRF antagonist administered to Sprague-Dawley rats neither prevented the rise of MAP or HR following electrical stimulation of the central nucleus of the amygdala, nor did it affect nitroprusside-induced hypotension and tachycardia.

Central nervous system effects of corticotropin releasing factor in the dog

UNLABELLEDnCorticotropin releasing factor (CRF) given intracerebroventricularly (i.c.v.) increases mean arterial pressure (MAP) and heart rate (HR), while CRF given intravenously decreases MAP and increases HR. CRF given i.c.v. elevates plasma concentrations of vasopressin and catecholamines. Ganglionic blockade with chlorisondamine prevents CRF-induced increases in MAP; the vasopressin antagonist, [1-deaminopenicillamine,2-(O-methyl)tyrosine]-vasopressin does not alter CRF-induced increases in MAP. In contrast to CRF, angiotensin II (A-II) given i.c.v. increases MAP but decreases HR.nnnIN CONCLUSIONn(1) CRF elevation of MAP and HR in dogs is dependent on an intact sympathetic nervous system, and (2) CRF and A-II have different CNS effects on cardiovascular function.

Corticotropin-releasing factor and angiotensin II: comparison of CNS actions to influence neuroendocrine and cardiovascular function.

The cardiovascular and hormonal responses to intracerebroventricular administration of corticotropin-releasing factor (CRF) and angiotensin II (AII) were compared in conscious, freely moving rats. CRF elevated mean arterial pressure (MAP) and heart rate (HR), increased plasma catecholamine levels and had no effect on plasma vasopressin levels. AII increased MAP and decreased HR, had no effect on plasma catecholamine levels and elevated plasma vasopressin levels. Ganglionic blockade with chlorisondamine blocked the cardiovascular effects of CRF but failed to antagonize the pressor response to AII. The vasopressin antagonist, [1-deaminopenicillamine, 2-(0-methyl)tyrosine]-AVP, did not modify CRF-induced cardiovascular changes but greatly attenuated AIIs effects on blood pressure. These results suggest that CRF and AII have different central actions on hormonal and cardiovascular systems.

Biological effects of cysteamine: relationship to somatostatin depletion

Cysteamine given subcutaneously to rats decreases brain concentrations of somatostatin-like immunoactivity (SLI) but does not affect vasopressin-like immunoactivity as determined by radioimmunoassay and immunocytochemistry. Since somatostatin-related peptides act within the central nervous system (CNS) to increase body temperature and decrease adrenal epinephrine secretion, changes in these parameters were assessed following cysteamine administration. Cysteamine administration lowers oxygen consumption and body temperature, and elevates plasma concentrations of epinephrine, glucose, insulin and glucagon. The lowering of body temperature and elevation of plasma epinephrine is prevented by CNS administration of the CNS-selective somatostatin analog desAA1,2,4,5,12,13[D-Trp8 ))somatostatin. The CNS actions of somatostatin-related peptides are opposite to the effects of cysteamine. The observations are consistent with the possibility that brain somatostatin-related peptides are involved in regulation of body temperature and adrenal epinephrine secretion.

3 Central regulation of stress responses: regulation of the autonomic nervous system and visceral function by corticotrophin releasing factor-41

Our understanding of the role of CRF in mediating integrated endocrine, autonomic and visceral stress responses is rudimentary at best. Delineating the large number of neurochemical factors that influence the activity of CRF-containing hypophyseotrophic neurones offers one direction for future research in this area. Another approach might be to examine the neuropharmacological actions of transmitters which are co-localized within CRF-containing neurones. For example, CRF and dynorphin-related peptides coexist within a subpopulation of paraventricular neurones (Roth et al, 1983), suggesting the potential for their simultaneous release and possible functional interactions between them. Interestingly, CRF and dynorphin-related peptides exhibit reciprocal actions on the release of each other in vitro and in vivo. CRF stimulates the release of immunoreactive dynorphin from rat hypothalamic slices (Nikolarakis et al, 1986) while dynorphin A1-17 inhibits the basal secretion of immunoreactive CRF from rat hypothalami (Yajima et al, 1986). In vivo experiments demonstrate that i.c.v. administration of dynorphin A1-13 reduces basal and hypotension-induced secretion of CRF into hypophyseal portal blood (Plotsky, 1986). Recent studies suggest that, in addition to their interactions at the level of release, these peptides may also modify the CNS actions of each other on autonomic and cardiovascular function (Overton and Fisher, 1989b). Thus, CRF-induced elevations of arterial pressure, heart rate and plasma catecholamine levels are attenuated by co-administration of low doses of dynorphin A1-17. The reciprocal release actions and neuropharmacological interactions between CRF and dynorphin A1-17 suggest that local integration or perhaps feedback regulation of stress-induced autonomic and cardiovascular responses may be achieved by the co-release of multiple neurotransmitters from a single source. In summary, the combined anatomical, pharmacological and physiological data provide support for the involvement of CRF neuronal systems in mediating the integration of endocrine, autonomic, and visceral functions, particularly in response to stress. Future research in this area may contribute to our understanding of the neurobiology of CRF as well as the CNS mechanisms governing homeostasis.