Hormones of the Cardiovascular System

For the past few decades, several hormones secreted by myocardium and blood vessel walls and regulate various physiological functions have been identified. They include natriuretic hormones, endothelins, proteins related to the parathyroid hormone, adrenomedullin and others. Therefore, the heart and blood vessels, apart from their main function, blood circulation, also perform important endocrine function, i.e., they are an organ controlling various physiological processes including hemodynamics, skeletal growth, reproductive function, immunity, etc.     

Responses of vasoactive hormones in congestive cardiac failure

Congestive cardiac failure causes activation of various neurohumoral responses that increase total peripheral resistance and promote salt and water retention. These effects increase blood pressure and organ perfusion in the short term, but ultimately cause further cardiac decompensation by increasing ventricular afterload and cardiac work. The role of the renin-angiotensin-aldosterone system and the catecholamines is partially understood, and blockade of these systems as a treatment of heart failure is now established. The role of vasopressin in heart failure is more controversial, but there is now compelling evidence that vasopressin may have important vasoconstrictor actions in addition to its fluid retaining properties. Atrial natriuretic factor is a newly described cardiac hormone released from the atrium. Atrial natriuretic factor causes natriuresis, diuresis, vasodilatation, suppression of thirst, and suppression of both renin and aldosterone. These actions largely counteract the effects of the renin-angiotensin system and vasopressin. Plasma atrial natriuretic factor has been reported to be markedly elevated in human and experimental heart failure, and may act to limit the neurohumoral response to reduced cardiac output. This review summarizes our understanding of the vasoactive hormones and reports experimental evidence supporting a pathophysiological role for vasopressin and atrial natriuretic factor in congestive cardiac failure.     

Leptin,NPY, Melatonin and Zinc Levels in Experimental Hypothyroidism and Hyperthyroidism: The Relation to Zinc

Since zinc mediates the effects of many hormones or is found in the structure of numerous hormone receptors, zinc deficiency leads to various functional impairments in the hormone balance. And also thyroid hormones have important activity on metabolism and feeding. NPY and leptin are affective on food intake and regulation of appetite. The present study is conducted to determine how zinc supplementation and deficiency affect thyroid hormones (free and total T3 and T4), melatonin, leptin, and NPY levels in thyroid dysfunction in rats. The experiment groups in the study were formed as follows: Control (C); Hypothyroidism (PTU); Hypothyroidism+Zinc (PTU+Zn); Hypothyroidism+Zinc deficient; Hyperthyroidism (H); Hyperthyroidism+Zinc (H+Zn); and Hyperthyroidism+Zinc deficient. Thyroid hormone parameters (FT₃, FT₄, TT₃, and TT₄) were found to be reduced in hypothyroidism groups and elevated in the hyperthyroidism groups. Melatonin values increased in hyperthyroidism and decreased in hypothyroidism. Leptin and NPY levels both increased in hypo- and hyperthyroidism. Zinc levels, on the other hand, decreased in hypothyroidism and increased in hyperthyroidism. Zinc supplementation, particularly when thyroid function is impaired, has been demonstrated to markedly prevent these changes.     

Human skin: an independent peripheral endocrine organ

The historical picture of the endocrine system as a set of discrete hormone-producing organs has been substituted by organs regarded as organized communities in which the cells emit, receive and coordinate molecular signals from established endocrine organs, other distant sources, their neighbors, and themselves. In this wide sense, the human skin and its tissues are targets as well as producers of hormones. Although the role of hormones in the development of human skin and its capacity to produce and release hormones are well established, little attention has been drawn to the ability of human skin to fulfil the requirements of a classic endocrine organ. Indeed, human skin cells produce insulin-like growth factors and -binding proteins, propiomelanocortin derivatives, catecholamines, steroid hormones and vitamin D from cholesterol, retinoids from diet carotenoids, and eicosanoids from fatty acids. Hormones exert their biological effects on the skin through interaction with high-affinity receptors, such as receptors for peptide hormones, neurotransmitters, steroid hormones and thyroid hormones. In addition, the human skin is able to metabolize hormones and to activate and inactivate them. These steps are overtaken in most cases by different skin cell populations in a coordinated way indicating the endocrine autonomy of the skin. Characteristic examples are the metabolic pathways of the corticotropin-releasing hormone/propiomelanocortin axis, steroidogenesis, vitamin D, and retinoids. Hormones exhibit a wide range of biological activities on the skin, with major effects caused by growth hormone/insulin-like growth factor-1, neuropeptides, sex steroids, glucocorticoids, retinoids, vitamin D, peroxisome proliferator-activated receptor ligands, and eicosanoids. At last, human skin produces hormones which are released in the circulation and are important for functions of the entire organism, such as sex hormones, especially in aged individuals, and insulin-like growth factor-binding proteins. Therefore, the human skin fulfils all requirements for being the largest, independent peripheral endocrine organ.     

Modulation of spermatozoon acrosome reaction

Spermatozoon acrosome reaction is an exocytotic event of the utmost importance for the development of mammalian fertilisation. Current evidence shows that the triggering of the acrosome reaction (AR) could be regulated by the action of diverse compounds, namely, metabolites, neurotransmitters and hormones. The aim of the present review is to describe the modulating effects of several compounds that have been classified as inductors or inhibitors of acrosome reaction. Among AR inductors, it is necessary to mention progesterone, angiotensin II, atrial natriuretic peptide, cathecolamines, insulin, leptin, relaxin and other hormones. Regarding the inhibitors, oestradiol and epidermal growth factor are among the substances that retard AR. It is worth mentioning that gamma-aminobutyric acid, a neurotransmitter known to be an inhibitor in the central nervous system, has been shown to induce AR. The multiple hormones located in the fluids of the female reproductive tract are also likely to act as subtle regulators of AR, constituting a fundamental aspect for the development of successful fertilisation. Finally, it is necessary to emphasise that the study of regulation exerted by hormones and other compounds on AR is essential for further understanding of mammalian reproductive biology, especially spermatozoon physiology.     

Is there a hormonal network in Tetrahymena? A systematic investigation of hormonal effects on the hormone content

The effect of six hormones (histamine, serotonin, insulin, epidermal growth factor (EGF), oxytocin and gonadotropin) was studied on the hormone (histamine, serotonin, adrenocorticotropic hormone [ACTH], endorphin and triiodothyronine [T(3)]) content of Tetrahymena. The hormones were given in 10(-9) or 10(-12) M concentrations or as 0.1 and 0.001 I.U. ml(-1) (in the case of oxytocin and gonadotropin) for 1 h. The hormones in picomolar concentration, i.e. at levels which can be present also in natural conditions, influence the amount of other hormones inside the cell. Their effect is not a general one: it is individual, the level of one of the hormones was elevated, while that of the others diminished under the effect of the same hormonal stimulus. Insulin was the only hormone, which influenced the concentration of other hormones in one direction, elevating them. This effect could have a role in the life-saving property of this hormone in Tetrahymena, but the hormones were not studied from this point of view. Usually there is no difference between the effect of the two concentrations used, but there are situations when the effect of the two concentrations is opposite. This means that there is a possible concentration dependence and this could influence differently the cells which are far from or near to the secretor cell. Considering earlier observations, the duration of the treatment can also influence the result. The results give new data to the hormonal regulation at unicellular level (which can be the base of regulation at higher evolutionary levels) and point to the possibility of a hormonal network.     

Phospholipid metabolism in rat kidney cortical tubules. II. Effects of hormones on 32P incorporation

To evaluate the effect of hormones on renal phospholipid metabolism and turnover, we studied the changes in 32P-labeling of phospholipids in rat cortical tubule suspension. Angiotensin II, phenylephrine and parathyroid hormone (PTH) stimulate 32P incorporation into PC by 25, 29 and 26% and into PI by 189, 328 and 33% above control rates, respectively, whereas phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate labeling was not affected. However, when phospholipids were prelabeled with [32P]Pi, addition of angiotensin II led to a significant decrease in phosphatidylinositol 4,5-bisphosphate labeling in the first 2 min with no effect on the other phospholipid fractions. The phenylephrine effect on phospholipid labeling was blocked by prazosin but not by yohimbine, indicating an alpha 1-mediated action. In contrast, the effect of angiotensin II was not inhibited by either antagonist. The stimulating effect of substrates on 32P incorporation reported in the preceding paper was additive to that of hormones. Our results confirm previous studies on renal gluconeogenesis that catecholamines act by an alpha 1-type receptor on proximal tubules, and indicate that phenylephrine and angiotensin II act by different receptor sites exerting the same metabolic effect. The additivity of hormone effects with that of renal substrates indicates that the former are not secondary to release of precursors for phospholipid biosynthesis. The rapid decrease in phosphatidylinositol 4,5-bisphosphate labeling after angiotensin II suggests that the polyphosphoinositide is degraded after hormone binding to the receptor and that PI labeling is a secondary event.     

Role of carbohydrates in glycoprotein hormone signal transduction

The structure of the polypeptide chains and oligosaccharide moieties of the alpha and beta subunits of pituitary and placental glycoprotein hormones are known. The dimeric polypeptide structure (but not the carbohydrate) is important for binding of the hormone to specific receptors. The N-linked but not O-linked carbohydrates, on the other hand, are required in some manner to activate the effector system. Hormones with depleted carbohydrate content (deglycosylated hormones) interact with receptor but are unable to activate intracellular events. Because of such discordant properties, these forms act as competitive inhibitors of hormone action. Through a combination of chemical deglycosylation procedures and site-directed mutagenesis, the first site of N-glycosylation from the NH2 terminus of the common alpha subunit has been identified to be more critical for glycoprotein hormone signal transduction. Control of glycosylation by the endocrine milieu could contribute to regulation of hormone function by secreting variable forms of agonist/antagonist.     

The role of leptin in human physiology and pathophysiology.

This review focuses on current knowledge of leptin biology and the role of leptin in various physiological and pathophysiological states. Leptin is involved in the regulation of body weight. Serum leptin can probably be considered as one of the best biological markers reflecting total body fat in both animals and humans. Obesity in man is accompanied by increased circulating leptin concentrations. Gender differences clearly exist. Leptin is not only correlated to a series of endocrine parameters such as insulin, glucocorticoids, thyroid hormones, testosterone, but it also seems to be involved in mediating some endocrine mechanisms (onset of puberty, insulin secretion) and diseases (obesity, polycystic ovary syndrome). It has also been suggested that leptin can act as a growth factor in the fetus and the neonate.     

Atrial natriuretic peptide prohormone gene expression: hormones and diseases that upregulate its expression

Atrial natriuretic peptides consist of a family of peptide hormones that are synthesized by three separate genes and then stored as three different prohormones (i.e., 126-amino acid [a.a.]) atrial natriuretic peptide (ANP), 108-a.a. brain natriuretic peptide (BNP), and 126-aa. C-natriuretic peptide (CNP) prohormones. The gene encoding for the synthesis of the atrial natriuretic peptide prohormone (proANP) consists of three exons and two introns. Exon 1 encodes the signal peptide and the first 16 aa. of the ANP prohormone. These 16 a.a. form the N-terminus of a peptide hormone named long-acting natriuretic hormone (LANH). A valine-to-methionine substitution in LANH results in a 2-fold increased incidence of strokes in humans. Exon 2 of the proANP gene encodes for three peptide hormones, i.e., vessel dilator, kaliuretic hormone, and ANP. Each of the proANP gene products have vasodilatory, diuretic, natriuretic, and/or kaliuretic properties. Stretch, glucocorticoids, thyroid hormone(s), mineralocorticoids, and calcium enhance proANP gene expression. Enhanced proANP gene expression is found in congestive heart failure, hypertension, and cirrhosis with ascites. The proANP gene is present with invertebrates and plants as well as in humans and other vertebrates.     

Natriuretic peptides in fish physiology

Natriuretic peptides exist in the fishes as a family of structurally-related isohormones including atrial natriuretic peptide (ANP), C-type natriuretic peptide (CNP) and ventricular natriuretic peptide (VNP); to date, brain natriuretic peptide (or B-type natriuretic peptide, BNP) has not been definitively identified in the fishes. Based on nucleotide and amino acid sequence similarity, the natriuretic peptide family of isohormones may have evolved from a neuromodulatory, CNP-like brain peptide. The primary sites of synthesis for the circulating hormones are the heart and brain; additional extracardiac and extracranial sites, including the intestine, synthesize and release natriuretic peptides locally for paracrine regulation of various physiological functions. Membrane-bound, guanylyl cyclase-coupled natriuretic peptide receptors (A- and B-types) are generally implicated in mediating natriuretic peptide effects via the production of cyclic GMP as the intracellular messenger. C- and D-type natriuretic peptide receptors lacking the guanylyl cyclase domain may influence target cell function through G(i) protein-coupled inhibition of membrane adenylyl cyclase activity, and they likely also act as clearance receptors for circulating hormone. In the few systems examined using homologous or piscine reagents, differential receptor binding and tissue responsiveness to specific natriuretic peptide isohormones is demonstrated. Similar to their acute physiological effects in mammals, natriuretic peptides are vasorelaxant in all fishes examined. In contrast to mammals, where natriuretic peptides act through natriuresis and diuresis to bring about long-term reductions in blood volume and blood pressure, in fishes the primary action appears to be the extrusion of excess salt at the gills and rectal gland, and the limiting of drinking-coupled salt uptake by the alimentary system. In teleosts, both hypernatremia and hypervolemia are effective stimuli for cardiac secretion of natriuretic peptides; in the elasmobranchs, hypervolemia is the predominant physiological stimulus for secretion. Natriuretic peptides may be seawater-adapting hormones with appropriate target organs including the gills, rectal gland, kidney, and intestine, with each regulated via, predominantly, either A- or B-type (or C- or D-type?) natriuretic peptide receptors. Natriuretic peptides act both directly on ion-transporting cells of osmoregulatory tissues, and indirectly through increased vascular flow to osmoregulatory tissues, through inhibition of drinking, and through effects on other endocrine systems.     

Parathyroid hormone-related protein treatment of pregnant rats delays the increase in connexin 43 and oxytocin receptor expression in the myometrium

Myometrial quiescence during pregnancy is maintained by progesterone, which suppresses the expression of labor-associated genes such as connexin 43 (Cx43) and the oxytocin receptor (OTR). Parathyroid hormone-related protein (PTHrP) is a smooth muscle relaxant that inhibits myometrial contractions and therefore may act in synergy with progesterone to maintain myometrial quiescence during late pregnancy. We investigated the possibility that PTHrP, like progesterone, could act to suppress the expression of labor-associated genes. Pregnant rats were treated starting on Day 19 with daily i.p. injections of 100 microg/kg PTHrP (human synthetic fragment 1-34). On Day 22 of gestation, there was a significant reduction in the expression of Cx43 (mRNA and protein) and OTR (mRNA) in the myometrium of PTHrP-treated animals, whereas on Day 23 (labor) the expression of both Cx43 and OTR was unchanged by PTHrP treatment. Treatment of pregnant rats with PTHrP did not affect the time of delivery, concentrations of progesterone in maternal plasma, or levels of c-fos, fra-2, or parathyroid hormone/PTHrP receptor mRNA on any gestational day. Because PTHrP treatment delayed the dramatic increase in the expression of Cx43 and OTR, it may be an important factor in the maintenance of the quiescent state of the myometrium at a time when the concentrations of progesterone in maternal circulation decrease. PTHrP treatment did not prevent the increase in Cx43 and OTR gene expression on Day 23 or the timing of labor, suggesting that the effects of PTHrP signaling are overridden with the onset of labor.     

Thirty years of the heart as an endocrine organ: physiological role and clinical utility of cardiac natriuretic hormones

Thirty years ago, De Bold et al. (20) reported that atrial extracts contain some biologically active peptides, which promote a rapid and massive diuresis and natriuresis when injected in rats. It is now clear that the heart also exerts an endocrine function and in this way plays a key role in the regulation of cardiovascular and renal systems. The aim of this review is to discuss some recent insights and still-debated findings regarding the cardiac natriuretic hormones (CNHs) produced and secreted by cardiomyocytes (i.e., atrial natriuretic peptide and B-type natriuretic peptide). The functional status of the CNH system depends not only on the production/secretion of CNHs by cardiomyocytes but also on both the peripheral activation of circulating inactive precursor of natriuretic hormones and the transduction of the hormone signal by specific receptors. In this review, we will discuss the data supporting the hypothesis that the production and secretion of CNHs is the result of a complex integration among mechanical, chemical, hemodynamic, humoral, ischemic, and inflammatory inputs. The cross talk among endocrine function, adipose tissue, and sex steroid hormones will be discussed more in detail, considering the clinically relevant relationships linking together cardiovascular risk, sex, and body fat development and distribution. Finally, we will review the pathophysiological role and the clinical relevance of both peripheral maturation of the precursor of B-type natriuretic peptides and hormone signal transduction.     

Role of adipose tissue for cardiovascular-renal regulation in health and disease.

Obesity is associated with profound alterations of the cardiovascular system including an increase in systemic blood pressure. Several vasoactive factors, including non-esterified fatty acids, angiotensin II, prostaglandins, and nitric oxide are known to be produced by adipose tissue, and are therefore of particular interest regarding their potential role for the regulation of vascular tone and structure. In addition, central nervous system actions of the adipose tissue-derived hormone leptin may contribute to increased sympathetic nervous system activity that is typically found in obesity. Enhanced leptin-driven renal sympathetic out-flow, in combination with low atrial natriuretic peptide plasma levels possibly due to over-expression of the natriuretic peptide clearance receptor in adipocytes, may enhance sodium retention and volume expansion, both key features in the pathophysiology of obesity-associated hypertension. In this review, we discuss these and other possible contributions of adipose tissue to the regulation of cardiovascular-renal function and speculate on the role of adipose tissue for the development of obesity-associated hypertension.     

The atrial natriuretic peptide- and catecholamine-induced lipolysis and expression of related genes in adipose tissue in hypothyroid and hyperthyroid patients

Thyroid dysfunction is associated with several abnormalities in intermediary metabolism, including impairment of lipolytic response to catecholamines in subcutaneous abdominal adipose tissue (SCAAT). Atrial natriuretic peptide (ANP) is a powerful lipolytic peptide; however, the role of ANP-mediated lipolysis in thyroid disease has not been elucidated. The aim of this study was to investigate the role of thyroid hormones in the regulation of ANP-induced lipolysis as well as in the gene expression of hormone-sensitive lipase, phosphodiesterase 3B (PDE3B), uncoupling protein-2 (UCP2), natriuretic peptide receptor type A, and beta(2)-adrenergic receptor in SCAAT of hyperthyroid and hypothyroid patients. Gene expression in SCAAT was studied in 13 hypothyroid and 11 hyperthyroid age-matched women before and 2-4 mo after the normalization of their thyroid status. A microdialysis study was performed on a subset of nine hyperthyroid and 10 hypothyroid subjects. ANP- and isoprenaline-induced lipolyses were higher in hyperthyroid subjects, with no differences between the groups following treatment. Hormone-sensitive lipase gene expression was higher in hyperthyroid compared with hypothyroid subjects before treatment, whereas no difference was observed following treatment. No differences in gene expression of other genes were observed between the two groups. Following treatment, the gene expression of UCP2 decreased in hyperthyroid, whereas the expression of PDE3B decreased in hypothyroid subjects. We conclude that thyroid hormones regulate ANP- and isoprenaline-mediated lipolysis in human SCAAT in vivo. Increased lipolytic subcutaneous adipose tissue response in hyperthyroid patients may involve postreceptor signaling mechanisms.     

Effects of hydrosaline treatments on prolyl endopeptidase activity in rat tissues

Enzymatic cleavage of some peptide hormones, neurotransmitters and neuromodulators could be implicated in the regulation of extra- and intracellular fluid volume and osmolality. Prolyl endopeptidase is known to hydrolyze several peptides, which act on hydromineral balance, such as angiotensins, bradykinin, vasopressin, oxytocin, thyrotropin-releasing hormone, neurotensin and opioids. In this work, we analyzed the effects of certain volume and/or osmotic changes in the activity of the soluble and membrane-bound prolyl endopeptidase in several brain areas, heart, lungs, kidney and adrenal and pituitary glands of the rat. Soluble prolyl endopeptidase activity was higher in the renal cortex of the chronic salt-loaded rats than in the control rats. In the water-deprived and polyethylene glycol-treated rats, heart particulate prolyl endopeptidase was lower than in the control rats. Particulate prolyl endopeptidase was also lower in the adrenal gland of the acute salt-loaded rats and in the brain cortex of the water-loaded rats than in the control rats. Data suggest that tissue-dependent peptide hydrolysis evoked by prolyl endopeptidase activity is involved in the water-electrolyte homeostasis.     

Human osteoclasts express oxytocin receptor

Increasing evidences demonstrated many new targets for the hypothalamic hormone oxytocin, as the regulation of food balance and in some cases of leptin secretion. Considering that leptin is a potent inhibitor of bone formation and that oxytocin receptors (OTR) were detected in normal human osteoblasts, we investigated if OTR was expressed by human osteoclasts (hOCs) and the effect of the hormone on these cells. Here, we demonstrate by immunofluorescence and by Western blot analysis the expression of OTR by fully differentiated hOCs and by their precursors (pOCs). We also show that the receptor is functional, as OT treatment induces an increase of [Ca(2+)](i), and that the hormone may affect osteoclastogenesis, since it increases the number of pre-osteoclasts.     

beta-Adrenergic receptors in rat skeletal muscle. Effects of thyroidectomy.

Thyroid hormones may participate in the regulation of beta-adrenergic receptors in skeletal muscle sarcolemmal membrane. Since skeletal muscles are not innervated by sympathetic nerve endings, the biochemical mechanism involved in the control of beta-adrenergic receptors by thyroid hormones appears to be mediated by thyroid-induced regulation of serum levels of catecholamines.     

Influence of thyroid dysfunction on serum concentrations of adipocytokines

Thyroid hormones act on several aspects of metabolic and energy homeostasis influencing body weight, thermogenesis, and lipolysis in adipose tissue. Adipocytokines are biologically active substances produced by adipocyte with different physiological functions. These substances have multiple effects on several tissues acting on the intermediate and energy metabolism. For these reasons, attention has recently been focused on the possible relationship between adipocytokines, thyroid status, and thyroid dysfunction. Leptin, a signal of satiety to the brain and regulator of insulin and glucose metabolism, reflects the amount of fat storage and is considered as a pro-inflammatory adipocytokine. Adiponectin is inversely related to the degree of adiposity, increases insulin sensitivity, and may have antiatherogenic and anti-inflammatory properties. Resistin impairs glucose homeostasis and insulin action in mice but not in humans. Resistin might be considered a pro-inflammatory adipocytokine and participate in obesity-associated inflammation. Several reports indicate that leptin regulates thyroid function at hypothalamic-hypophyseal level and, conversely, thyroid hormones might control leptin metabolism at least in some animals studies. Both adiponectin and thyroid hormones share some physiological actions as reduction of body fat by increasing thermogenesis and lipid oxidation. Resistin also seems to be regulated by thyroid hormones, at least in rats. Thyroid dysfunction does not significantly affect serum leptin concentrations. Serum levels of adiponectin are no influenced by thyroid hypofunction; however, hyperthyroidism is associated with normal or elevated adiponectin levels. Finally, discordant results in resistin levels in thyroid dysfunction have been reported in humans.     

Localization and role of leptin in the thyroid gland of the lizard Podarcis sicula (Reptilia, Lacertidae)

Leptin, the product of the ob gene, is a hormone secreted by adipocytes that regulates food intake and energy expenditure. The hypothalamus-pituitary-thyroid axis is markedly influenced by the metabolism status, being suppressed during food deprivation. The present study was designed to ascertain whether (1) lizard thyroid gland expresses the long form of leptin receptor (Ob-Rb) and (2) the leptin administration affects the thyroid gland activity in this species (and to verify whether leptin plays a similar role in reptiles as observed in the other vertebrates). The presence of leptin receptor in the thyroid gland of Podarcis sicula was demonstrated by immunohistochemical technique (avidin-biotin-peroxidase complex--ABC method). The role of leptin in the control of thyroid gland activity was studied in vivo using light microscopy (LM) technique coupled to a specific radioimmunoassay for thyroid-stimulating hormone (TSH) and thyroid hormones (T4 and T3). Leptin (0.1 mg/100 g body wt)/day increased T4 and T3 release for 3 days but decreased the plasma concentration of TSH; using LM clear signs of stimulation in the thyroid gland were observed. These findings suggest that systemic administration of leptin stimulates the morphophysiology of the thyroid gland in the lizard through a direct mechanism involving Ob-Rb.