Aldosterone secretion: a molecular perspective.

The major mineralocorticoid hormone aldosterone is secreted from the zona glomerulosa of the adrenal cortex. Aldosterone is synthesized from cholesterol via a series of hydroxylations and oxidations. The enzymes involved in these reactions are mostly members of the cytochrome P450 superfamily.

The brain as an endocrine target for Peptide hormones.

Unlike circulating steroid hormones, which have a relatively unhindered passage into the central nervous system, blood-borne peptides are usually restricted by the blood-brain barrier. Some circulating peptides, such as angiotensin II, atrial natriuretic peptide and relaxin, influence central neural pathways subserving cardiovascular and body fluid homeostasis by acting on neurons in the subfornical organ, organum vasculosum of the lamina terminalis and area postrema, all of which lack a blood-brain barrier. There are some circulating peptides such as insulin and leptin that are transported from the bloodstream across cerebral blood vessel walls into sites in the hypothalamus that have appropriate neural connections to influence food intake and sympathetic control of brown fat.

Therapeutic targeting of insulin-regulated aminopeptidase: heads and tails?

Insulin-regulated aminopeptidase, IRAP, is an abundant protein that was initially cloned from a rat epididymal fat pad cDNA library as a marker protein for specialized vesicles containing the insulin-responsive glucose transporter GLUT4, wherein it is thought to participate in the tethering and trafficking of GLUT4 vesicles. The same protein was independently cloned from human placental cDNA library as oxytocinase and is proposed to have a primary role in the regulation of circulating oxytocin (OXY) during the later stages of pregnancy. More recently, IRAP was identified as the specific binding site for angiotensin IV, and we propose that it mediates the memory-enhancing effects of the peptide.

Relaxin plays an important role in the regulation of airway structure and function.

Relaxin is a reproductive hormone with pleiotropic actions. In addition to airway fibrosis, relaxin deficiency results in airway structural changes (epithelial thickening) and increased lung recoil, suggesting that relaxin may impact other aspects of airway/lung structure and function beyond its ability to regulate collagen turnover. Furthermore, these structural changes associated with relaxin deficiency show marked similarity to the structural changes seen in asthma.

Independent vasomotor control of rat tail and proximal hairy skin.

Quantitative differences are known to exist between the vasomotor control of hairy and hairless skin, but it is unknown whether they are regulated by common central mechanisms. We made simultaneous recordings from sympathetic cutaneous vasoconstrictor (CVC-type) fibres supplying back skin (hairy) and tail (hairless) in urethane-anaesthetized, artificially ventilated rats. The animal's trunk was shaved and encased in a water-perfused jacket.

Comparison of airway remodeling in acute, subacute, and chronic models of allergic airways disease.

The relationship between airway inflammation and structural changes of airway remodeling, and their relative effects on airway function, are poorly understood. Remodeling is thought to result from chronic repetitive injury to the airway wall caused by airway inflammation; however, the mechanisms regulating remodeling changes have not been clearly defined. We examined the sequence of events in remodeling using three commonly used mouse models of allergic airways disease in which mice are exposed to nebulized ovalbumin for four consecutive days (acute), seven consecutive days (subacute), or three times a week for 6 wk (chronic).

Human epilepsies: interaction of genetic and acquired factors.

Epilepsies, once regarded as due to demoniacal possession, can have both genetic and acquired causes, with interaction of these factors in many cases. To date, nearly all the genes discovered to be involved in human epilepsies encode subunits of ion channels, both voltage-gated and ligand-gated. Established acquired causes include serious brain trauma, stroke, tumours and infective lesions.

Water intake and the neural correlates of the consciousness of thirst.

Thirst and resultant water drinking can arise in response to deficits in both the intracellular and extracellular fluid compartments. Inhibitory influences mediating the satiation of thirst also are necessary to prevent overhydration. The brain regions that underpin the generation or inhibition of thirst in these circumstances can be categorized as sensory, integrative, or cortical effector sites.

Differential regional haemodynamic changes during mineralocorticoid hypertension.

Background: Primary aldosteronism is a cause of hypertension in up to 10% of hypertensive patients, but the mechanisms by which excess aldosterone raises arterial pressure remain unclear.

Objective: To investigate the systemic and regional haemodynamic changes during the development and maintenance of aldosterone-induced hypertension and the effect of sympathetic and vasopressin blockade.

Methods: Responses to intravenous infusion of aldosterone (10 microg/h) for 4 weeks were determined in five conscious sheep.

Relaxin in cardiovascular and renal disease.

Fibrosis (organ scarring) is a hallmark of many forms of cardiovascular and renal disease, and causes organ dysfunction and structural changes when normal tissue is replaced with scar tissue; the accumulation of scar tissue being a leading cause of death around the world. Despite deep organ scarring potentially existing in many forms (including myocardial and vascular sclerosis, renal interstitial fibrosis, and glomerulosclerosis), current therapies have only had limited success in delaying end-stage disease. The peptide hormone relaxin is emerging as a potent antifibrotic therapy with rapid-occurring efficacy.

Murine embryonic EGF-responsive ventral mesencephalic neurospheres display distinct regional specification and promote survival of dopaminergic neurons.

Similar to embryonic forebrain, the embryonic mesencephalon contains Fibroblast Growth Factor 2 (FGF2)- and Epidermal Growth Factor (EGF)-responsive progenitors that can be isolated as neurospheres. Developmentally, the FGF2-responsive population appears first and is thought to give rise to EGF-responsive neural stem cells. It is not known whether following this developmental switch of growth factor responsiveness ventral mesencephalic (VM)-derived neural stem cells display distinct region-specific properties.

Comparison between two rat sympathetic pathways activated in cold defense.

In cold defense and fever, activity increases in sympathetic nerves supplying both tail vessels and interscapular brown adipose tissue (iBAT). These mediate cutaneous vasoconstrictor and thermogenic responses, respectively, and both depend upon neurons in the rostral medullary raphé. To examine the commonality of brain circuits driving these two outflows, sympathetic nerve activity (SNA) was recorded simultaneously from sympathetic fibers in the ventral tail artery (tail SNA) and the nerve to iBAT (iBAT SNA) in urethane-anesthetized rats.

Differential effects of aging on fluid intake in response to hypovolemia, hypertonicity, and hormonal stimuli in Munich Wistar rats.

A significant proportion of aged humans may have impaired thirst and inadequate fluid intake after a period of fluid deprivation. We have studied the water drinking responses, relative to body weight, of Munich Wistar (MW) rats in response to osmotic, hypovolemic, dehydrational, and angiotensin (Ang)-related stimuli as they aged from 3 to 24 months. Young 3-months-old (m.

Reflex activation of rat fusimotor neurons by body surface cooling, and its dependence on the medullary raphe.

The nature of muscle efferent fibre activation during whole body cooling was investigated in urethane-anaesthetized rats. Multiunit efferent activity to the gastrocnemius muscle was detected when the trunk skin was cooled by a water-perfused jacket to below 36.0 +/- 0.

Human medullary responses to cooling and rewarming the skin: a functional MRI study.

A fall in skin temperature precipitates a repertoire of thermoregulatory responses that reduce the likelihood of a decrease in core temperature. Studies in animals suggest that medullary raphé neurons are essential for cold-defense, mediating both the cutaneous vasoconstrictor and thermogenic responses to ambient cooling; however, the involvement of raphé neurons in human thermoregulation has not been investigated. This study used functional MRI with an anatomically guided region of interest (ROI) approach to characterize changes in the blood oxygen level-dependent (BOLD) signal within the human medulla of nine normal subjects during non-noxious cooling and rewarming of the skin by a water-perfused body suit.

Relaxin receptor activation in the basolateral amygdala impairs memory consolidation.

The peptide-hormone relaxin has well-established actions in male and female reproductive tracts, and has functional effects in circumventricular regions of brain involved in neurohormonal secretion. In the current study, we initially mapped the distribution of mRNA encoding the relaxin receptor--leucine-rich repeat-containing G-protein-coupled receptor 7 (LGR7)- and [33P]-human relaxin-binding sites in extra-hypothalamic sites of male Sprague-Dawley rats. The basolateral amygdala (BLA) expressed high levels of LGR7 mRNA and relaxin-binding sites and, although relaxin peptide was not detected in the BLA, several brain regions that send projections to the BLA were found to contain relaxin-expressing neurons.

Endogenous relaxin regulates collagen deposition in an animal model of allergic airway disease.

We examined the relationship among relaxin (a peptide hormone that stimulates collagen degradation), airway fibrosis, other changes of airway remodeling, and airway hyperresponsiveness (AHR) in an animal model of allergic airway disease. Eight- to 10-wk-old relaxin gene-knockout (RLX(-/-)) and wild-type (RLX(+/+)) mice were sensitized with ovalbumin (OVA) or saline ip at d 0 and 14 and challenged three times per week for 6 wk with nebulized 2.5% OVA or saline.

Mice lacking the alpha4 nicotinic receptor subunit fail to modulate dopaminergic neuronal arbors and possess impaired dopamine transporter function.

Neuronal nicotinic acetylcholine receptors (nAChRs) at presynaptic sites can modulate dopaminergic synaptic transmission by regulating dopamine (DA) release and uptake. Dopaminergic transmission in nigrostriatal and mesolimbic pathways is vital for the coordination of movement and is associated with learning and behavioral reinforcement. We reported recently that the D2 DA receptor plays a central role in regulating the arbor size of substantia nigra dopaminergic neurons.

Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats.

The antifibrotic effects of the peptide hormone relaxin on cardiac and renal fibrosis were studied in 9- to 10-month-old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Rats (n=8 to 9 per group) were allocated into 3 groups: WKY controls, vehicle-treated SHR (SHR-V), and relaxin-treated SHR (SHR-R). Relaxin (0.

Insulin-relaxin family peptide signaling and receptors in mouse brain membranes and neuronal cells.

Several orphan G-protein-coupled receptors (GPCRs), LGR7 and LGR8, GPCR135 and GPCR142, were recently identified as putative, native receptors for different relaxin-family peptides, and their cell signaling mechanisms were elucidated in stably transfected cell lines. Anatomic studies have demonstrated that discrete populations of neurons in rat brain express relaxin and relaxin-3 mRNA/peptide, relaxin and relaxin-3 binding sites, and LGR7 and GPCR135 mRNAs. Thus, we began to assess the ability of relaxin-family peptides to alter cAMP production in brain and the involvement of the different native receptors.

Localization of LGR7 (relaxin receptor) mRNA and protein in rat forebrain: correlation with relaxin binding site distribution.

Discrete neuronal populations in brain express relaxin and relaxin-3, and molecular studies have identified former-orphan, G-protein-coupled receptors LGR7 and GPCR135 as their native receptors. To better understand the role of central relaxin systems, we began to assess the anatomic distribution of these receptors and ligands in brain. This study documents the widespread distribution of LGR7 mRNA and LGR7-like immunoreactivity (LI) throughout adult rat forebrain areas shown to contain specific [33P]-relaxin binding sites.

Localization of LGR7 gene expression in adult mouse brain using LGR7 knock-out/LacZ knock-in mice: correlation with LGR7 mRNA distribution.

Knowledge of the distribution of the relaxin receptor, LGR7, in the brain provides a basis for studies of the physiologic actions of relaxin. LGR7 knock-out (KO) mice were produced by the in-frame replacement of LGR7 exon 10 and 11 with a LacZ-reporter cassette (knock-in [KI]), and in this study we used LGR7-KO/LacZ-KI mice to determine the regional/cellular distribution of LGR7 gene expression in adult mouse brain by assessing beta-galactosidase activity in perfusion-fixed sections. High densities of beta-galactosidase-positive neurons were detected in anterior olfactory and claustrum/endopiriform nuclei, deep layers of cortex (particularly somatosensory), and the subiculum.

Investigating the role of relaxin in the regulation of airway fibrosis in animal models of acute and chronic allergic airway disease.

Airway remodeling is a characteristic feature of asthma that leads to chronic irreversible airway obstruction. Fibrosis in the basement membrane region is a hallmark of remodeling in asthma that is not found in other diseases. In the outlined studies, we investigated the relationship between relaxin and airway fibrosis in asthma using acute and chronic models of allergic airway disease.

Receptors for relaxin family peptides.

Recent studies have identified four receptors that are the physiological targets for relaxin family peptides. All are class I (rhodopsin like) G-protein-coupled receptors with LGR7 (RXFP1) and LGR8 (RXFP2) being type C leucine-rich repeat-containing receptors, whereas GPCR135 (RXFP3) and GPCR142 (RXFP4) resemble receptors that respond to small peptides such as somatostatin and angiotensin II. The cognate ligands for the receptors have been identified: relaxin for RXFP1; INSL3 for RXFP2; relaxin 3 for RXFP3 and INSL5 for RXFP4.

The chemistry and biology of human relaxin-3.

A novel member of the human relaxin subclass of the insulin superfamily was recently discovered during a genomics database search and named relaxin-3. Like human relaxin-1 and relaxin-2, relaxin-3 is predicted to consist of a two-chain structure and three disulfide bonds in a disposition identical to that of insulin. To undertake detailed biophysical and biological characterization of the peptide, its chemical synthesis was undertaken.