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Biomedical subjects

Meghan M Taylor

Publications and source records attributed to Meghan M Taylor.

At least 19 recordsLinked to original sources
PubMed2006

Intermedin (adrenomedullin-2) enhances cardiac contractile function via a protein kinase C- and protein kinase A-dependent pathway in murine ventricular myocytes.

Intermedin (IMD), also called adrenomedullin-2, is a 47-amino acid peptide from the calcitonin gene-related peptide (CGRP)/adrenomedullin family of peptides. Recent studies suggest that IMD may participate in the regulation of cardiovascular function and fluid and electrolyte homeostasis. To evaluate the role of IMD on cardiomyocyte contractile function, electrically paced murine ventricular myocytes were acutely exposed to IMD, and the following indexes were determined: peak shortening (PS), time to PS, time-to-90% relengthening, and maximal velocity of shortening and relengthening. Intracellular Ca(2+) was assessed using fura 2-AM fluorescent microscopy. Our results revealed that IMD (10 pM to 10 nM) significantly increased PS and maximal velocity of shortening and relengthening in ventricular myocytes, the maximal effect of which (approximately 46%) was somewhat comparable to those elicited by CGRP (1 nM) and adrenomedullin (100 nM). Exposure of IMD significantly shortened time-to-90% relengthening without affecting time to PS, similar to CGRP and adrenomedullin. IMD also enhanced intracellular Ca(2+) release, with a maximal increase of approximately 50%, and facilitated the intracellular Ca(2+) decay rate. The IMD-induced effects were abolished by the protein kinase C inhibitor chelerythrine (1 microM), downregulation of protein kinase C using phorbol 12-myristate 13-acetate (1 microM), and the protein kinase A inhibitor H89 (1 microM). Our data suggest that IMD acutely augments cardiomyocyte contractile function through, at least in part, a protein kinase C- and protein kinase A-dependent mechanism.

Animals↗
PubMed2006

Prolactin releasing peptide (PrRP): an endogenous regulator of cell growth.

Prolactin releasing peptide (PrRP) was originally reported to act in the anterior lobe of the pituitary gland to stimulate prolactin (PRL) release; however, numerous other pharmacologic actions of PrRP have been described. In the central nervous system PrRP inhibits food intake, stimulates sympathetic tone, and activates stress hormone secretion. Here, we confirm the presence of immunoreactive PrRP in a pheochromocytoma-derived cell line (PC-12) and the ability of exogenous PrRP to stimulate adenylyl cyclase activity in these cultures. Our novel findings are that PrRP stimulated PC-12 cell growth. Furthermore, a role for endogenous PrRP in PC-12 cell growth is suggested by our observations that antisense oligonucleotides and small interfering RNA molecules, which decrease peptide content in these cells, also decrease thymidine incorporation, suggesting an autocrine action of the peptide.

Adenylyl Cyclases↗
PubMed2005

Intermedin/Adrenomedullin-2 inhibits growth hormone release from cultured, primary anterior pituitary cells.

Intermedin (IMD), a novel member of the adrenomedullin (AM), calcitonin gene-related peptide (CGRP), amylin (AMY) peptide family, has been reported to act promiscuously at all the known receptors for these peptides. Like AM and CGRP, IMD acts in the circulation to decrease blood pressure and in the brain to inhibit food intake, effects that could be explained by activation of the known CGRP, AM, or AMY receptors. Because AM, CGRP, and AMY have been reported to affect hormone secretion from the anterior pituitary gland, we examined the effects of IMD on GH, ACTH, and prolactin secretion from dispersed anterior pituitary cells harvested from adult male rats. IMD, in log molar concentrations ranging from 1.0 pm to 100 nm, failed to significantly alter basal release of the three hormones. Similarly, IMD failed to significantly alter CRH-stimulated ACTH or TRH-stimulated prolactin secretion in vitro. However, IMD concentration-dependently inhibited GHRH-stimulated GH release from these cell cultures. The effects of IMD, although requiring higher concentrations, were as efficacious as those of somatostatin and, like somatostatin, may be mediated, at least in part, by decreasing cAMP accumulation. These actions of IMD were not shared by other members of the AM-CGRP-AMY family of peptides, suggesting the presence of a novel, unique IMD receptor in the anterior pituitary gland and a potential neuroendocrine action of IMD to interact with the hypothalamic mechanisms controlling growth and metabolism.

Adrenocorticotropic Hormone↗
PubMed2005

Non-sleep effects of hypocretin/orexin.

Although a role for hypocretin/orexin (HCT/ORX) in sleep/wakefulness and arousal is widely recognized, other actions, not necessarily related to sleep, have been identified. Neurons producing the peptides project to brain sites known to be important in neuroendocrine and autonomic function, as well as appetite regulation. There is consensus that HCT/ORX plays a role in the regulation of cardiovascular function via its effects on sympathetic nervous activity, and the reported pharmacologic effects have been demonstrated to be physiologically relevant. Equally provocative are the actions of these peptides in the hypothalamus and pituitary gland to regulate reproductive and stress hormone secretion. While HCT/ORX are less potent stimulators of food intake than other hypothalamic peptides, HCT/ORX may play an integral role in the organization of hunger and satiation behaviors because of their interaction with those other peptides. In fact recent discoveries of interactions of HCT/ORX with peptides such as corticotropin releasing hormone and neuropeptide Y, as well as with aminergic neurotransmitter systems, are now defining the cellular and molecular mechanisms by which these potent neuropeptides act and promise insight into their physiologic relevance in a variety of non-sleep related behaviors and other homeostatic mechanisms.

Adrenocorticotropic Hormone↗
PubMed2005

Stress hormone secretion is altered by central administration of intermedin/adrenomedullin-2.

Intermedin/Adrenomedullin-2 (IMD), a newly described peptide with structural homology to adrenomedullin (AM), is present in brain and pituitary gland and binds to the same receptors as AM and calcitonin gene-related peptide (CGRP). We hypothesized that IMD would exert actions similar to AM and CGRP and previously have demonstrated that indeed IMD, like AM and CGRP, increases sympathetic tone and inhibits feeding and drinking when administered centrally. Here, we extend those observations by demonstrating that like AM, IMD acts in brain to stimulate the secretions of prolactin (PRL) and adrenocorticotropin (ACTH) and to inhibit the secretion of growth hormone (GH) in conscious rats. In addition, in conscious rats, central administration of IMD results in increased plasma levels of oxytocin (OT) and vasopressin (AVP). The ability of IMD to activate the hypothalamo-pituitary-adrenal (HPA) axis can be blocked by intravenous pretreatment with the corticotropin releasing factor (CRF) antagonist, astressin. These results suggest that multiple members of the AM family of peptides may be involved in the cardiovascular, behavioral and neuroendocrine responses to stress.

Adrenocorticotropic Hormone↗
PubMed2005

Brain-derived adrenomedullin controls blood volume through the regulation of arginine vasopressin production and release.

Central nervous system-derived adrenomedullin (AM) has been shown to be a physiological regulator of thirst. Administration of AM into the lateral ventricle of the brain attenuated water intake, whereas a decrease in endogenous AM, induced by an AM-specific ribozyme, led to exaggerated water intake. We hypothesized that central AM may control fluid homeostasis, in part by regulating plasma arginine vasopressin (AVP) levels. To test this hypothesis, AM or a ribozyme specific to AM was administered intracerebroventricularly, and alterations in plasma AVP concentrations were examined under basal and stimulated (hypovolemic) conditions. Additionally, we examined changes in blood volume, kidney function, and plasma electrolyte and protein levels, as well as changes in plasma aldosterone concentrations. Intracerebroventricular administration of AM increased plasma AVP levels, whereas AM ribozyme treatment led to decreased plasma AVP levels under stimulated conditions. During hypovolemic challenges, AM ribozyme treatment led to an increased loss of plasma volume compared with control animals. Although overall plasma osmolality did not differ between treatment groups during hypovolemia, aldosterone levels were significantly higher and, consequently, plasma potassium concentrations were lower in AM ribozyme-treated rats than in controls. These data suggest that brain-derived AM is a physiological regulator of vasopressin secretion and, thereby, fluid homeostasis.

Adrenomedullin↗
PubMed2004

Intermedin/adrenomedullin-2 acts within central nervous system to elevate blood pressure and inhibit food and water intake.

Intermedin (IMD)/adrenomedullin-2 (AM2) is a novel peptide that was independently discovered by two groups. The 47-amino acid peptide is homologous to adrenomedullin (AM) and can activate both the AM and calcitonin gene-related peptide (CGRP) receptors. IMD should therefore have actions similar to those of AM and CGRP. Indeed, like AM and CGRP, intravenous administration of IMD decreased blood pressure in rats and mice. We demonstrate here that immunoreactive IMD is present in plasma as well as heart, lung, stomach, kidney, pituitary, and brain. Because IMD is present in brain and both AM and CGRP have potent central nervous system (CNS) effects, we examined the ability of IMD within brain to regulate blood pressure and ingestive behaviors. Administration of IMD into the lateral cerebroventricle of rats caused significant, long-lasting elevations in mean arterial pressure and heart rate. These elevations are similar to the effects of CGRP and significantly greater than the effects of AM. IMD-induced elevations in mean arterial pressure were inhibited by intravenous administration of phentolamine, indicating that IMD activates the sympathetic nervous system. Intracerebroventricular administration of IMD also inhibited food and water intake in sated and in food- and water-restricted animals. The effects on feeding are likely related to activation of the CGRP receptor and are independent of the effects on water intake, which are likely through the AM receptor. Our data indicate that IMD has potent actions within the CNS that may be a result of the combined activation of both AM and CGRP receptors.

Adrenomedullin↗
PubMed2004

Actions of neuropeptide W in paraventricular hypothalamus: implications for the control of stress hormone secretion.

Neuropeptide W (NPW) is produced in neurons located in hypothalamus and brain stem, and its receptors are present in the hypothalamus, in particular in the paraventricular nucleus (PVN). Intracerebroventricular (ICV) administration of NPW activated, in a dose-related fashion, the hypothalamic-pituitary-adrenal axis, as determined by plasma corticosterone levels in conscious rats but, at those same doses, did not stimulate the release of oxytocin or vasopressin into the peripheral circulation or alter blood pressure or heart rate. The ability of ICV-administered NPW to stimulate the hypothalamic-pituitary-adrenal axis in conscious male rats was blocked by intravenous pretreatment with a corticotropin-releasing hormone antagonist. This suggested an action of NPW in the parvocellular division of the PVN. Indeed, in hypothalamic slice preparations (whole cell patch recording), bath application of NPW depolarized and increased the spike frequency of the majority of electrophysiologically identified putative neuroendocrine PVN neurons. Effects on membrane potential were maintained in the presence of TTX, suggesting them to be direct postsynaptic actions on these neuroendocrine cells. Our data suggest that endogenous NPW, produced in brain, may play a physiologically relevant role in the neuroendocrine response to stress.

Animals↗
PubMed2004

A possible mechanism for the action of adrenomedullin in brain to stimulate stress hormone secretion.

Adrenomedullin (AM) has been reported to have actions at each level of the hypothalamo-pituitary-adrenal (HPA) axis, suggesting that the peptide plays a role in the organization of the neuroendocrine responses to stress. We examined the mechanism by which AM regulates the central nervous system branch of the HPA axis as well as the possible role of AM in the modulation of the releases of two other hormones, prolactin and GH, whose secretions also are altered by stress. Intracerebroventricular administration of AM led to elevated plasma corticosterone levels in unrestrained, conscious male rats. This effect was abrogated by pretreatment with a CRH antagonist, suggesting that AM activates the HPA axis by causing the release of CRH into hypophyseal portal vessels. In addition, AM given intracerebroventricularly stimulated the release of prolactin but did not alter the secretion of GH. We propose that AM produced in the brain may be an important neuromodulator of the hormonal stress response.

Adrenomedullin↗
PubMed2003

Prolactin-releasing peptides.

Physiologic control of prolactin (PRL) secretion is largely dependent upon levels of dopamine accessing the adenohypophysis via the hypophysial portal vessels. However, it is clear that other factors of hypothalamic origin can modulate hormone secretion in the absence or presence of dopamine. Several neuropeptides have been identified as PRL releasing factors (PRFs) but none of these peptides appears to be a major determinant of PRL secretion in vivo. There remain uncharacterized activities in hypothalamic extracts that can alter secretion and production of the hormone. In addition, there exist a wide variety of substances (neurotransmitters, neuromodulators, neuropeptides) that can act within the hypothalamus to modify the neuroendocrine regulation of PRL secretion. These factors may not be considered true PRFs because their actions are not exerted directly at the level of the lactotroph; however, they can act in brain to stimulate PRL release in vivo and therefore might be considered PRL releasing peptides (PRPs).

Animals↗
PubMed2003

Involvement of the central adrenomedullin peptides in the baroreflex.

The peptides derived from post-translational processing of preproadrenomedullin are produced in and act on areas of the autonomic nervous system important for blood pressure regulation. We examined the role of endogenous, brain-derived adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in the central nervous system arm of the baroreflex by using passive immunoneutralization to block the actions of the endogenous peptides. Our results indicate that the preproadrenomedullin-derived peptides do not play a role in sensing changes in blood pressure (baroreflex sensitivity), but the adrenomedullin peptides do regulate the speed with which an animal returns to a normal, stable blood pressure. These findings suggest that endogenous, brain-derived AM and PAMP participate in the regulation of autonomic activity in response to baroreceptor activation and inactivation.

Adrenomedullin↗
PubMed2003

The other side of the orexins: endocrine and metabolic actions.

Although it is clear that the orexin/hypocretin peptides have a significant, physiologically relevant role in sleep/wakefulness, a broader picture has emerged indicating metabolic actions that may depend upon both neural and endocrine mechanisms for their manifestation. The ability of exogenous peptide to activate sympathetic tone, increase locomotor activity, and alter feeding behavior, together with the observed alterations in those functions in knockout animals, strongly suggests important neural actions of the endogenous orexins/hypocretins. Likewise, the action of exogenously administered peptides to alter endocrine function, in particular corticotropin release, has now been mirrored by potential endocrinopathies in knockout animals. Thus these pluripotent peptides hold great potential not only for the treatment of human narcolepsy but also to provide insight into the coordinated regulation of multiple physiological systems.

Animals↗
PubMed2003

Neuropeptide W acts in brain to control prolactin, corticosterone, and growth hormone release.

The endogenous, peptide ligand for the orphan receptors GPR7 and GPR8 was identified to be neuropeptide W (NPW). Because these receptors are expressed in brain and in particular in hypothalamus, we hypothesized that NPW might interact with neuroendocrine systems that control hormone release from the anterior pituitary gland. No significant effects of NPW were observed on the in vitro releases of prolactin (PRL), ACTH, or GH when log molar concentrations ranging from 1 pM to 100 nM NPW were incubated with dispersed anterior pituitary cells. However, NPW, when injected into the lateral cerebroventricle of conscious, unrestrained male rats, in a dose-related fashion elevated PRL and corticosterone and lowered GH levels in circulation. The threshold dose for all three effects was 1.0 nmol. We conclude that endogenous NPW may play a regulatory role in the organization of neuroendocrine signals accessing the anterior pituitary gland but does not itself act as a true releasing or inhibiting factor in the gland. Central administration of NPW23 also stimulated water drinking and food intake. The ability of exogenous peptide to decrease GH but stimulate PRL secretion and activate the hypothalamo-pituitary adrenal axis, together with the observed behavioral effects, suggests that endogenous NPW may play a role in the hypothalamic response to stress.

Adrenocorticotropic Hormone↗
PubMed2002

Adrenomedullin and the integrative physiology of fluid and electrolyte balance.

Adrenomedullin (AM) is hypothesized to be a physiologically relevant regulator in fluid and electrolyte homeostasis. AM acts within the central nervous system to inhibit both water and salt intake. The peptide has direct actions in the hypothalamus to decrease vasopressin secretion and in the pituitary gland to inhibit ACTH release. AM decreases production and release of aldosterone from the adrenal glands and acts directly in the kidneys to increase renal blood flow and cause diuresis and natriuresis. Whether or not these complementary actions in brain, pituitary, adrenal gland, and kidney reflect coordinated regulatory mechanisms is currently unknown. Development of molecular tools to determine the physiologic role of endogenous AM will greatly enhance our understanding of AM and its regulation of fluid and electrolyte homeostasis.

Adrenal Glands↗
PubMed2002

Orexin actions in hypothalamic paraventricular nucleus: physiological consequences and cellular correlates.

Orexinergic neurons originating in the perifornical, lateral hypothalamus project to numerous brain sites including neuroendocrine centers known to be important in the physiologic response to stress. Those projections suggest an action of endogenous orexin on adrenocorticotropin (ACTH) release, either by neuromodulatory effects in the paraventricular nucleus (PVN), or by neuroendocrine actions in the pituitary gland following release into the median eminence. We sought to determine if exogenously applied orexin A might act in the brain to alter ACTH release and to determine if a site of action in the hypothalamic paraventricular nucleus could be identified. Cerebroventricular administration of orexin A in conscious male rats resulted in a dose-related elevation in circulating ACTH levels. At 30 min post-infusion, ACTH levels were elevated 2.5-fold by the low dose of orexin A (0.3 nmol), 5.7-fold by the middle dose tested (1.0 nmol), and 7.5-fold by the highest dose tested (3.0 nmol). Pretreatment with a CRH-antagonist (i.v.) blocked the ability of i.c.v. administered orexin A to activate the hypothalamo-pituitary-adrenal (HPA) axis. Bath application of orexin A in hypothalamic slice preparations resulted in depolarizations (8.0+/-0.6 mV), accompanied by increases in spike frequency in identified magno- and parvocellular neurons in the PVN. Our data suggest a potential role for endogenous orexin in the hypothalamic regulation of stress hormone secretion.

Adrenocorticotropic Hormone↗
PubMed2002

Ribozyme compromise of adrenomedullin mRNA reveals a physiological role in the regulation of water intake.

The adrenomedullin (AM) preprohormone is posttranslationally processed to result in two biologically active fragments, AM and proadrenomedullin NH(2)-terminal 20 peptide (PAMP). AM is thought to play a role in fluid and electrolyte balance by acting in brain to inhibit salt and water appetite and in the kidney to cause diuresis and natriuresis. We previously have shown that AM is necessary for the short-term regulation of salt intake. In this paper, we have designed a ribozyme, a catalytic RNA molecule, which specifically recognizes and cleaves the AM transcript. In cultured vascular smooth muscle cells, ribozyme treatment lowered AM mRNA and reduced peptide content. Intracerebroventricular administration of the ribozyme lowered hypothalamic AM content and led to an exaggerated drinking response in rats, demonstrating that endogenous, brain-derived AM is physiologically relevant and necessary for short-term control of water intake.

Adrenomedullin↗
PubMedDate not supplied

Knockout knockouts.

Deletion of the genes for a variety of neuropeptides or their receptors has provided great insight into the physiological roles played by those peptides. Strikingly, several of these knockout models mature into very similar metabolic phenotypes, providing clues to the mechanisms underlying the regulation of glucose homeostasis, cardiovascular regulation and the hormonal response to stress.

Animals↗