Showing papers in "Annual Review of Physiology in 1988"

Regulation of the Synthesis of Steroidogenic Enzymes in Adrenal Cortical Cells by ACTH

Abstract: The mechanism of steroid hormone regulation of specific gene expression in target cells has provided a major focus of interest for investigators concerned with molecular mechanisms involved in cell regulation. This work has been given renewed impetus by the recent cloning and characterization of several steroid hormone receptors (1-6), the trans-acting elements which, upon binding specific ligands, namely the steroid hormones, interact with specific regions of many eukaryotic genes to alter their expression. In contrast, there has been considerably less interest in the mechanisms of regulation of steroid hormone biosynthesis. Yet this is also a topic of great importance, not only because these reactions provide the ligands that interact with the steroid hormone receptors, but also because the steroidogenic enzymes provide excellent model systems for studying the regulation of gene expression by cAMP-dependent mechanisms and by mechanisms involving protein kinase C and tyrosine kinase activity. A variety of mechanisms appear to regulate steroid hydroxylase gene expression in a given cell, and tissue-specific as well as developmental factors play important roles also. In this review, we focus primarily on the regulation of steroid hydroxylase gene expression by cAMP­ dependent mechanisms and, in particular, the mechanisms of ACTH regula­ tion of the synthesis of the steroidogenic enzymes present in the adrenal cortex.

Regulation of Aldosterone Secretion

Abstract: Regulation of aldosterone secretion is complex both in terms of the number of secretagogues that can influence its biosynthesis and the number of second messengers utilized by these secretagogues (Table 1, Figure 1). ACTH primarily acts via the adenylate cyclase system through a stimulatory G protein; however, there is evidence that at low concentration it may also activate calcium influx and phospholipase C in some species. The primary effect of AII is activation of phospholipase C, which increases both calcium release from intracellular stores and calcium flux across the cell membrane and activates protein kinase C. Potassium depolarizes the membrane, thereby activating calcium flow through voltage-dependent calcium channels. It also directly or indirectly causes release of calcium from intracellular binding sites. A small change in cAMP levels may also be involved in the sustained secretory response to potassium. Species variation in the regulation of aldosterone secretion probably exists; the control mechanisms in the human appear to be closer to those in the rat than to those in cow and sheep. How changes in dietary sodium and potassium modify aldosterone secretion and the adrenal's responsiveness to secretagogues remains unclear. Yet these effects may be of considerable importance, both in terms of understanding the overall regulation of aldosterone secretion and in resolving the discrepancies in the results obtained under different experimental conditions.

Peripheral Sympathetic Neural Activity in Conscious Humans

Abstract: Hagbarth & Vallbo made the first direct microneurographic recordings of postganglionic sympathetic nerve discharges in man (32). Since then per­ cutaneously inserted microelectrodes have been used extensively for the study of human sympathetic function. Apart from a recent study of sympathetic activity in trigeminal nerve branches (44), the microneurographic exploration of sympathetic mechanisms has bcen confined to nerves of the extremities. Two different types of sympathetic outflow have been recognized in multifi­ ber recordings: muscle nerve sympathetic activity (MSA) and skin nerve sympathetic activity (SSA). The former is dominated by vasoconstrictor signals; the latter is a mixture of sudomotor and vasoconstrictor and probably sometimes includes pilomotor and vasodilator impulses. Thus only two sub­ divisions of the anatomically multifaceted sympathetic nervous system are accessible to study. Despite this limitation, the results have allowed a number of conclusions, not only about peripheral sympathetic function but also about reflex patterns and hence general principles of sympathetic regulation.

Endocrine regulation and communicating functions of the Leydig cell.

Abstract: Activation and regulation of Leydig cell function is exerted primarily by LH, which is secreted in pulses of high biological activity and interacts with membrane receptors. Other hormones and factors secreted by the Leydig cell or from the tubular compartment can influence Leydig cell differentiation and acute or chronic actions of LH on steroidogenesis. Conversely, hormones produced in the Leydig cell could modulate tubular function (e.g. beta-endorphin, oxcytocin). The LH receptor has been purified to homogeneity in sufficient quantities to allow its peptide sequence to be determined and its gene structure to be elucidated as well as functional reconstitution studies to be performed. The LH receptor subunit of Mr 90,000 can be phosphorylated by cAMP-dependent protein kinase. The native receptor appears to exist in the membrane as a dimer of identical subunits associated by noncovalent interactions. It is likely that receptor dimerization and further aggregation are necessary for signal transduction to occur, and receptor phosphorylation by one or more kinases may be involved in regulating gonadotropin action. Stimulation of the androgen pathway occurs mainly through a cAMP-mediated mechanism. The stimulatory event can be negatively influenced by the action of certain peptide hormones through the guanyl nucleotide inhibitory subunit of adenylate cyclase. Such an inhibitory action of angiotensin has further emphasized the importance of the cAMP pathway in the Leydig cell. The hormone also appears to facilitate androgen production by a cAMP-independent mechanism located at the plasma membrane or intracellular sites. A Ca2+ sensitive kinase system is present in the Leydig cell membranes. The presence of nM amounts of Ca2+ induces membrane phosphorylation of a protein Mr 45,000. Adenylate cyclase activation also is affected by Ca2+. Membrane phosphorylation may be a modifier of LH-stimulated adenylate cyclase activity and possibly other LH-induced actions in the activated Leydig cell membrane. In the adult rat testis, the ability of Leydig cells to respond to sustained gonadotropic stimulation with increased androgen production is limited by the development of a refractory state associated with loss of LH receptors and steroidogenic enzymes. Gonadotropin-induced steroidogenic lesions in adult rat testes include a late steroidogenic lesion at the site of conversion of progesterone to androgen and an early lesion before pregnenolone formation that leads to a decreased in vitro pregnenolone and testosterone response to hCG.

Molecular Aspects of Hormone Action in Ovarian Follicular Development, Ovulation, and Luteinization

Abstract: As stated earlier, the mammalian ovary maintains the continuous development of follicles, but only a few are selected to ovulate and form corpora lutea. These processes are regulated primarily by the gonadotropins and involve specific, sequential changes in the function of theca cells and granulosa cells. Data from recent studies (summarized in Figure 3) show that specific genes are turned on or off at different stages of follicular growth in response to estradiol and different amounts of gonadotropins and cAMP. For example, mRNA for RII51 in granulosa cells and theca cells increases in association with small increased in cAMP but is markedly reduced by the LH surge and high cAMP. The content of mRNA for other kinase subunits, RI and C alpha, show little or no change during similar hormonal changes. In theca cells, mRNA for 17 alpha-hydroxylase increased and decreased in a manner similar to that for RII51. In contrast, levels of mRNA for P450scc increased only gradually in follicles but were markedly increased by the LH surge and high concentrations of cAMP and then appeared to be constitutively expressed in rat corpora lutea in a cAMP-independent manner. PGS and t-PA appear to follow yet another pattern: rapid induction by the LH surge followed by a rapid decline in association with ovulation. One major task for reproductive endocrinologists and molecular biologists now is to determine how low and high concentrations of cAMP act to turn on and turn off the expression of these specific genes at specific times during follicular maturation. A working model of the molecular events occurring in theca and granulosa cells of PO follicles is shown in Figure 4. LH acts on theca cells via cAMP ro regulate both P450scc and P450(17) alpha mRNA levels, leading to increased biosynthesis of androstenedione. The mechanisms by which cAMP acts in theca cells remain to be determined but appear to involve an increase in the content of RII51, P450scc, and P450(17) alpha. In granulosa cells, androstenedione is converted to estradiol by the aromatase P450 enzyme system. Estradiol, in turn, binds to estradiol receptors present in these cells and may thereby regulate gene expression. However, despite the presence of estradiol and estradiol receptors, little or no effect of estradiol is observed unless FSH acts via the FSH receptor to increase intracellular concentrations of cAMP. In a manner not yet understood, cAMP appears to enhance the actions of estradiol.(ABSTRACT TRUNCATED AT 400 WORDS)

Tyrosine Sulfation and the Secretory Pathway

Abstract: Tyrosine sulfation is a widespread posttranslational modification. Most tyrosine-sulfated proteins identified so far are secretory, including several neuropeptides. Tyrosine sulfation occurs in the trans Golgi and is one of the last processing steps before proteins exit from the Golgi complex. The sulfation reaction is catalyzed by tyrosylprotein sulfotransferase, an integral membrane protein that recognizes tyrosine residues in exposed protein domains containing acidic amino acids. In the cases studied to date, tyrosine sulfation has been found to be irreversible, resulting in a life-long alteration in the phenotype of the secretory proteins. The biological role of tyrosine sulfation has so far been elucidated in only a few cases. The intracellular transport kinetics of a secretory protein and the biological activity of certain neuropeptides have been found to be affected by this modification. Future functional studies will be greatly facilitated by the use of chlorate, a sulfate analogue that has recently been found to be a potent and nontoxic inhibitor of sulfation in intact cells.

VOLTAGE DEPENDENCE OF THE Na-K PUMP

Abstract: Present evidence demonstrates that the Na-K pump rate is voltage dependent, whereas early work was largely inconclusive. The I-V relationship has a positive slope over a wide voltage range, and the existence of a negative slope region is now doubtful. Monotonic voltage dependence is consistent with the reaction cycle containing a single voltage-dependent step. Recent measurements suggest that this voltage-dependent step occurs during Na translocation and may be deocclusion of Na+. In addition, two results suggest that K translocation is voltage insensitive: (a) large positive potentials appear to have no influence on Rb-Rb exchange or associated conformational transitions; and (b) transient currents associated with Na translocation appear to involve movement of a single charge, which is sufficient for a 3Na-2K cycle. The simplest interpretation is that the pump's cation binding sites supply two negative charges. Pre-steady-state measurements demonstrate that Na translocation precedes the pump cycle's rate-limiting step, presumably K translocation. But, because K translocation seems voltage insensitive, the voltage dependence of the steady-state pump rate probably reflects that of the concentration of the intermediate entering this slow step. Further pump current and flux data (both transient and steady-state), carefully determined over a range of conditions, should increase our understanding of the voltage-dependent step(s) in the Na-K pump cycle.

The Bohr Effect

Abstract: The control of oxygen binding by hemoglobin (Hb) with pH is of profound importance in facilitating gas exchange in blood. This modulation, known as the Bohr effect, reflects the fact that protons are released upon Hb oxygena­ tion at physiological pH (the alkaline Bohr effect), and protons are taken up upon oxygenation at low pH (the acid or reversed Bohr effect). Reciprocally, changes in pH modulate oxygen affinity. These proton exchanges arise because conformational changes in the Hb associated with ligand binding at the heme result in pK changes in certain acid groups that are distant from the heme. Changes in proton binding also result from differential interaction of buffer ions with oxyand deoxy-Hb (3, 18). The binding of salt ions can be considered a special kind of Bohr effect (3). Resonance Raman spectroscopy shows that the iron-proximal histidine stretching motion is exquisitely sensi­ tive to amino acid substitutions distant from the heme (34). This review examines recent experiments to determine which groups are responsible for the Bohr effect and how these ligand-linked processes are modulated by other allosteric factors, e.g. buffer ions, organic phosphates, CO2, and chloride, all of which lower the oxygen affinity of Hb by preferential binding to deoxy-Hb. A central problem has been to determine the relative quantitative roles of different ionizable groups responsible for in the Bohr effect. What kinds and numbers of groups are involved? Attempts have been made to calculate pK values by using electrostatic theory. How do such electrostatic calculations compare with other methods for estimating the contributions of different groups?

Functional Adaptations in Hemoglobins from Ectothermic Vertebrates

Abstract: Hemoglobin (Hb) increases the O2 carrying capacity of the blood of ectothermic vertebrates by about twenty times compared to physically dis­ solved O2. This drastically raises the blood O2 capacitance coefficient ({30,= .leo /.lpo) and permits corresponding reductions in the cardiac output (Qh) 2 2 • required for a given convective O2 transfer (V 0) as predicted by the Fick • • 2 equation (V 0, = Qh . (30, . .lp 0,). The O2 transporting role of Hb, however, also depends on its qualitative properties, namely (a) its intrinsic O2 binding properties and (b) its interaction with factors that modulate these properties inside the red cells. Ectotherm erythrocytes contain a full complement of cellular apparatus (including nucleus, mitochondria, and endoplasmic reticu­ lum), exhibit high metabolic activity compared to mammalian erythrocytes, and greater potential for feedback regulation of tissue O2 supply via cellular metabolites that affect Hb-02 affinity. The molecular properties of Hb have been dealt with in recent treatises (1, 77, 84, lO7). This review focuses on the physiological function of ectotherm Hb in the red blood cells, particularly the interand intraspecific adaptations to exogenous and endogenous factors like ambient hypoxia (low O2 tension), temperature, activity, and dormancy, and illustrates these with representative examples.

Central Coordination of Respiratory and Cardiovascular Control in Mammals

Abstract: Cardiorespiratory homeostasis in mammals requires the regulation of O2, CO2, and pH and is accomplished via central nervous system (CNS) control of two exquisite, constantly active pumping systems. The bidirectional res­ piratory pump (lung and associated skeletal musculature) moves air in and out of the alveoli, where gas exchange takes place. The unidirectional cardiovas­ cular pump (heart and vasculature) moves 02-enriched blood from the pul­ monary circulation to the systemic capillaries, where O2 diffuses into tissue and CO2 moves into blood; the systemic venous blood returns to the heart, then is pumped through the pulmonary circulation for gas exchange. The CNS controls all aspects of the respiratory pump, since skeletal muscle contracts only in response to motoneuronal activity, whereas the eNS controls the cardiovascular pump by modulating the pattern of cardiac and vascular smooth muscle contraction. The CNS also coordinates these pumps and participates in the optimization, adaptation, and adjustment of their perform­ ance. Understanding the CNS role in cardiorespiratory homeostasis requires knowledge of how (i) respiratory rhythm and sympathetic and parasympathet­ ic tone are generated; (ii) the spatiotemporal patterns of motor outflow are determined; (iii) these systems are coordinated, and; (iv) responses to changes in behavioral state or afferent signals are mediated. We focus on point (iii) and concentrate on brain stem and spinal mechanisms (for discussion of other points see 11,21,32,39,69).

Electroconformational coupling: how membrane-bound ATPase transduces energy from dynamic electric fields.

Abstract: Cells are constantly exposed to or surrounded by electric fields either from self-generating or from external sources. Proteins of cell membranes are thus subjected to influences by these electric fields; two of the most prominent electric fields are the in vivo surface and transmembrane potentials, which have magnitudes of 100-500 kV cm-I (see below). A protein molecule under such an intense electric field will behave quite differently than it would in an homogeneous aqueous solution. It is interesting to compare these values with the dielectric breakdown point of pure water, which is approximately 100 kV cm-I, Why a cell should actively maintain such large electric fields across its membranes is a theoretically interesting question since this requires sustained input of free energy. We propose that these fields serve many essential functions. Starting from the principles of thermodynamics, we summarize how an electric field can interact with a cell membrane and membrane proteins and 'The U.S, Government has the right to retain a nonexclusive royalty-free license in and to any copyright covering this paper,

Modulation of the Na,K-ATPase by Ca and intracellular proteins.

Abstract: The activity of the Na,K-ATPase can be sensitive to physiological changes in Cai. Intracellular proteins such as calnaktin, calmodulin, and protein kinase C could regulate the pump during transient changes in Cai. The mechanisms by which these proteins interact with the Na,K-ATPase, their distribution in different kinds of cells, and their role in regulating the Na,K-ATPase are not yet determined. Preliminary data indicate that an increase in Cai within the physiological range could be associated with either a stimulation or an inhibition of enzyme activity or a change in the affinity of the Na,K-ATPase for ouabain. The type of response probably depends on the kind of cell, its associated intracellular proteins, and its physiological state. Ca and intracellular proteins could play a key role in the regulation of the Na,K-ATPase by hormones.

Cardiovascular Control in Spinal Man

Abstract: The sympathetic outflow emerges from the thoracic and upper lumbar seg­ ments of the spinal cord and in patients with high spinal cord lesions is dissociated from cerebral regulation. This results in disordered cardiovascular control that is influenced by the level and completeness of the lesion, in addition to other factors such as hormones that directly alter cardiovascular function or indirectly influence it by changing renal function or intravascular volume. In this review emphasis is placed on patients with complete cervical spinal cord transection above the sympathetic outflow; they form a human physiological model, in whom the afferent, central, and vagal efferent com­ ponents of the baroreflex arc are intact, but where the spinal and peripheral sympathetic nervous system is isolated (Figure 1). Other than a section on recently injured tetraplegics in spinal shock, all descriptions refer to chroni­ cally injured tetraplegics (synonomous with quadriplegics).

Mitogens and Ion Fluxes

Abstract: The response of growth-arrested cells to a variety of growth factors and pharmacological mitogens involves a cascade of biochemical and ionic changes that occur within minutes and are believed to play critical roles in the initiation of cell proliferation. In general, investigations of these phenomena have used proliferating cells in culture that can be made to reversibly enter the nonproliferative Go/Gt state, usually by the withdrawal of serum. The bio­ chemical changes observed within the first few minutes of the addition of growth factors and mitogens include protein phosphorylation, an increased turnover of inositol lipids, and increased transcription of several proto­ oncogenes. The ionic alterations include rapid increases in the cytosolic free calcium concentration ([Ca2+l) from intracellular calcium stores andlor ,via influx through channels in the plasma membrane and the stimulation of the plasma membrane Na+ -H+ exchanger, which promotes an increase in sodium influx and cytoplasmic alkalinization. The relationship between these early changes and the increase in DNA synthesis that occurs many hours later is a key question in the understanding of mitogenesis. This article focuses on the alterations in ion fluxes that have been observed in response to mitogens in a variety of cells. In addition, the association of biochemical events with ion fluxes and the association of these eady events with the subsequent initiation of DNA synthesis are discussed. Important considerations that arc addressed are whether there are multiple pathways by which different mitogens induce proliferation and whether a single mitogen can induce proliferation by multi­ ple pathways.

The Kinetics of HCO3− Synthesis Related to Fluid Secretion, pH Control, and CO2 Elimination

Abstract: In 1928 Henriques (20) deduced from the rates of HC03 � CO2 reactions published by Faurholt (14), that the conversion process was too slow to account for the loss of respiratory CO2 across the lung. Henriques sought for an enzyme in blood to catalyze the process; for reasons I have reviewed elsewhere (32) he concluded that there was none, but that the rapid reaction was mediated by carbaminohemoglobin (20). Meldrum & Roughton, five years later, discovered carbonic anhydrase (CA) in red cells (38). It is now clear that the interconversion of CO2 � HC03 has physiological implications far greater than the carriage and excretion of metabolic CO2 in red cells. This process occurs in other sites, and the reaction is also central to the formation of H+ and HC03 in secretory organs (reviewed in 30). In the present chapter I consider anew HC03 formation in certain secre­ tory processes, in generation of an alkaline milieu, and in subserving the excretion or removal of CO2 from certain special tissues. Chemically, these are analogous to the interconversion in red cells; the latter is considered by Klocke elsewhere (this volume). An earlier review (34) covers other aspects of HC03 or COjsynthesis, i.e. in shell formation and salivary secretion. The purpose of this review is to try to coordinate this subject by weaving

Site-Directed Mutagenesis and ION-Gradient Driven Active Transport: On the Path of the Proton

Abstract: The lac permease of Escherichia coli is a hydrophobic transmembrane pro­ tein, encoded by the lac Y gene, that catalyzes the coupled translocation of (3-galactosides with H+ (i.e. H+ -substrate symport or cotransport) (see 12, 13, and 31 for recent reviews). Thus when a H+ electrochemical gradient (AjLw) is generated across the cytoplasmic membrane (interior becoming negative and/or alkaline), the permease utilizes free energy released from the downhill translocation of H+ in response to AjLw to drive uphill accumula­ tion of (3-galactosides against a concentration gradient (Figure 1A). Con­ versely, when a concentration gradient of substrate is created in the absence of AjLw, the permease utilizes free energy released from the downhill trans­ location of substrate to drive H+ uphill with generation of AjLw. The polar­ ity of this electrochemical gradient depends on the direction of the substrate concentration gradient: When [substrate]in AjLw is interior positive and acid (Figure 18); when [substrate]in > [substrate]out. AjLJI+ is interior negative and alkaline (Figure Ie)]. The lac permease is a model sys­ tem for a wide range of biological machines that transduce free energy

Velocity of CO2 exchange in muscle and liver.

Abstract: Until about ten years ago it had been generally believed (82, 108) that carbonic anhydrase is not present in muscle tissue. Although it is acknowl­ edged that exercising skeletal muscle is an organ with one of the highest rates of CO2 production and tissue Pco2, it was questioned whether fast kinetics of the CO2 reactions would be useful for the elimination of CO2• Roughton (108) argued that carbonic anhydrase in such a tissue would be "an enemy to the organism rather than a friend" because it would favour the conversion of CO2, which diffuses quickly and permeates cell membranes easily (41), to HC03 -, a form of CO2 whose diffusivity is somewhat smaller and whose permeability across the muscle cell membrane is extremely low (131). During the last decade not only have several forms of carbonic anhydrase been found in skeletal muscle, but it is also clear that the presence of carbonic anhydrase is in fact useful for the elimination of CO2 from muscle tissue. It has been shown by Gros et al (43) that very little carbamate is formed by the muscle proteins. The hydration-dehydration reaction thus appears to be the only reaction of CO2 that is important in muscle. This review will therefore entirely concentrate on the enzyme that determines its velocity, namely carbonic anhydrase.

Effects of Lipid Environment on Membrane Transport: The Human Erythrocyte Sugar Transport Protein/Lipid Bilayer System

Abstract: Membrane transport proteins (carriers) catalyze transmembrane movements of hydrophilic molecular species. To perform this function, carriers employ a variety of mechanisms for transmembrane solute flux that are distinct from and more rapid than leakage or non-Stokesian transbilayer diffusion of solutes (37). The low permeability of the membrane lipid bilayer to most hydrophilic species prevents the rapid dissipation of transbilayer solute gradients co­ established by membrane transport systems and intracellular metabolism and thus assists in the maintenance of a cytosolic environment favorable to cellular homeostasis. In addition to providing a permeability barrier, the membrane lipid bilayer provides a matrix for the attachment of membrane proteins. Most integral membrane proteins contain extensive, hydrophilic (extramembranous) and hydrophobic (membrane spanning) sequences. As a consequence, transverse protein reorientations (flip-flop) within the lipid bilayer arc highly improbable

Chloride transport in thick ascending limb, distal convolution, and collecting duct

Abstract: The traditional view in the field of epithelial transport has been to look upon the chloride ion as the obedient passive partner that follows the actively transported Na+ ion. This view has to be modified or even rejected for several epithelia, including different nephron segments. In this volume, Schild et al examine the mechanisms of proximal tubule chloride transport. My contribu­ tion briefly summarizes the mechanisms of chloride transport in distal nephron segments. In the reabsorptive processes the Clion generally takes the transcellular route rather than that between cell. To cross the cell, the Cl­ ion must penetrate the luminal and basolateral cell membranes. In different distal tubular segments various carrier systems and ion channels are responsi­ ble for chloride permeation. Much progress has been made recently in the understanding of the mech­ anism of NaCl reabsorption in the thick acending limb of the loop of Henle (13, 29). Our knowledge about the mechanisms responsible for NaCl reabsorption in the early distal tubule (19) is much less extensive. With respect to research on the collecting tubule, rapid progress has been made since intracellular microelectrode technology has been applied to the various segments and functionally heterogenous cell types (35, 45, 48). In the collect­ ing tubule, Cltransport is closely related to bicarbonate transport. This specific transport proc'ess is covered in this volume by Luke & Galla. The

Effects of Putative Neurotransmitters on Sympathetic Preganglionic Neurons

Abstract: Epinephrine, substance P, and glutamate have all been hypothesized as primary chemical mediators in the descending pathway from the brain stem "vasomotor center" to SPNs. Interestingly, lesions of or antagonists to epinephrine, substance P, glutamate, and 5-HT neurons all abolish sympathetic activity and reduce blood pressure to a level similar to that in a spinal-transected animal. However, it is unlikely that all these substances are primary mediators of sympathetic information carried from the brain stem to the spinal cord. How then do we resolve these findings? A plausible explanation is that monoamines and neuropeptides act in the IML, as in other areas of the central nervous system, as neuromodulators, setting the level of excitability of SPNs rather than relaying sympathetic information over a functionally specific pathway from brain stem sympathetic neurons to the IML. For example, the time course of the norepinephrine-mediated slow EPSPs and IPSPs in SPNs is consistent with a gain-setting function. Likewise, the depolarization of SPNs by 5-HT is similar to the depolarization elicited in myenteric and celiac ganglion cells. In these ganglia, 5-HT appears to mediate a slow excitatory potential that enhances incoming fast synaptic potentials. A similar gain-enhancing effect of 5-HT has been demonstrated in facial motoneurons. By analogy, epinephrine is likely to act as a neuromodulator in the IML rather than to serve as the primary mediator of sympathetic information descending from the brain stem. Similarly, it is difficult to imagine that an agent with such a long duration of excitatory action as substance P could serve as the primary descending transmitter in a system where moment to moment changes in activity are essential. It is more likely that substance P aids in setting the excitability of SPNs. Pharmacological antagonism of any of the excitatory neuromodulators (i.e. gain setters) might act to decrease, at least temporarily, the excitability of SPNs to the point where primary sympathetic activity from the brain stem could not excite SPNs. This accounts for the wide variety of pharmacological agents that act to eliminate sympathetic activity and drastically reduce blood pressure. On the basis of the above arguments, the most logical candidate for a transmitter mediating primary excitatory sympathetic information from brain stem "vasomotor centers" would be an excitatory amino acid. Fast EPSPs in SPNs appear to be mediated by glutamate and excitatory amino acid antagonists markedly inhibit sympathetic activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Peptides as Regulators of Gastric Acid Secretion

Abstract: Several peptides are important regulators of gastric acid secretion. The best characterized is gastrin. This circulating hormone is produced in the gastric antrum and mediates the gastric phase of acid secretion. Somatostatin is important as an inhibitory regulator of acid secretion, but the relative importance of paracrine versus endocrine delivery to its targets remains to be determined. The mammalian bombesin peptides, GRP27 and GRP10, probably are mediators of neural release of gastrin. Opioid peptides in the gastric wall appear to act as endogenous neurostimulants of gastric acid secretion under some conditions. Other neuropeptides in the gastric mucosa and submucosa, including sensory neuropeptides, may be important regulators of acid secretion. Hormones or nerves activated by fat and other substances in the lumen of the small intestine cause inhibition of acid secretion, but the specific peptides responsible for this effect have not yet been identified from a long list of candidates. The effects of peptides on the parietal cell and the gastrin and somatostatin cells are functionally linked with those of cholinergic and adrenergic nerves and with locally released histamine.

Structural and chemical organization of the myenteric plexus.

Abstract: The most striking characteristics of the myenteric plexus are the heterogeneity of its neuronal populations and the complexity of its organization. Myenteric neurons greatly differ in their morphological characteristics, projection patterns, and topographical arrangement within the ganglia. The discovery of histochemically distinct types of neurons together with the development of nerve-tracing techniques and specific lesions have allowed a better understanding of the relationships of enteric neurons to specific target tissues. Consequently, these techniques have contributed significantly to our knowledge of the highly ordered organization of the ENS, which represents the anatomical substrate for the neural coordination and integration of the complex functions it subserves. The existence of different types of neurons that probably use different substances as transmitters may reflect on the existence of defined functional roles for each type of neurons. To date, only ACh, NE, and probably 5-HT seem to satisfy all the criteria necessary for establishing a neurotransmitter, although there is increasing evidence that some of the other substances, such as GABA, SP, and VIP, are enteric transmitters or modulators. The functional roles of the different types of neurons in the neural circuitry that regulates gastrointestinal functions remain to be elucidated.

Endocrine regulation of the corpus luteum

Abstract: The corpus luteum is a small gland that develops rapidly from the ovulated follicle and performs a vital function in the reproductive process, namely, the secretion of progesterone, which is necessary for implantation of the blasto­ cyst. Following implantation, the continued secretion of progesterone is essential to maintain a quiescent uterus and an intrauterine environment that is conducive to continued development of the embryo (29). " If fertilization or implantation does not occur, the corpus luteum regresses, and the consequent withdrawal of progesterone leads to increased frequency of pulsatile luteiniz­ ing hormone (LH) secretion, increased follicular estrogen synthesis, and a new follicular phase (56). If implantation occurs, then the embryo signals the corpus luteum either directly or indirectly to continue to secrete progesterone and to prevent the corpus luteum from regressing (78). Thus, the corpus luteum can be viewed as the terminal stage of the ovarian follicle, which after shedding the oocyte, continues to nurture the (fertilized) egg indirectly by producing progesterone. The progestational changes in the uterus must pre­ cede the arrival of the preimplantation embryo and require the rapid conver­ sion of the predominantly estrogen-producing follicle to a predominantly progesterone-producing corpus luteum. This is accomplished by the pre­ ovulatory "surge" of luteinizing hormone, which serves the dual role of stimulating both ovulation and the conversion of the follicle into a corpus luteum, a process known as luteinization (57). This review COncentrates On certain aspects of the regulation of the corpus luteum that represent relatively new directions in research, and emerging concepts. For more information about the regulation of the corpus luteum in

Cns peptides and regulation of gastric acid secretion

Abstract: The influence of the central nervous system (eNS) on gastric secretory and motor function has been recognized for one and a half centuries, ever since William Beaumont's studies of his fistulous subject. In 1833 he reported that "fear, anger, whatever depresses or disturbs the nervous system" was accom­ panied by suppression of gastric secretion and by a marked delay in gastric digestion and emptying (4). A landmark in the establishment of a physiolog­ ical role for the brain in the regulation of gastric secretion was Pavlov's work at the beginning of this century. He discovered that sham feeding, anticipation of eating, and the sight or smell of food were powerful stimulants of hoth gastric acid and pepsin secretion in the dog (78). These studies were extended to humans in 1907 (40) and since then have been amply confinued (17). Brain pathways influencing gastric secretion were subsequently investigated via electrical stimulation or lesions of specific nuclei in various experimental animals (5, 25). More recently, advances in neurophysiological techniques, the development of sensitive anterograde and retrograde transport techniques and the discovery of a large number of peptides and their receptors in brain structures influencing gastric function have provided new tools and impetus to the investigation of the anatomical and chemical substrates mediating brain­ gut interactions.