Vessel dilator, long acting natriuretic peptide, and kaliuretic peptide increase circulating prostaglandin E2

Prostaglandin E2 (PGE2) increases in the circulation of persons with congestive heart failure (CHF), but the cause of this increase is unknown. Prostaglandins are not stored, therefore, they cannot be released in response to congestive heart failure itself but rather need to have their synthesis stimulated by a hormone or some other substance. Prostaglandin E2's biologic properties are nearly identical to four peptide hormones originating from amino acids 1-30 [long acting natriuretic peptide], 31-67 [vessel dilator], 79-98 [kaliuretic peptide] and 99-126 [atrial natriuretic peptide, ANP] of the 126 amino acid ANP prohormone. ANP previously has been found to have no effect on circulating PGE2 concentrations in persons with CHF. The present investigation was designed to determine if one or more of the other three atrial natriuretic peptides might increase PGE2 when infused at their respective 100 ng/kg body weight/minute concentrations for 60 minutes in persons with congestive heart failure. Vessel dilator increased PGE2 8-fold (P<0.001) in the first 20 minutes of its infusion with PGE2 remaining 2-3 fold increased (P<0.05) for 60 minutes after stopping its infusion. Long acting natriuretic peptide did not increase PGE2 until 40 minutes of its infusion but it caused the maximal increase (27-fold; P<0.001) of PGE2 of the three peptide hormones tested. Kaliuretic peptide's stimulated increase of PGE2 also began in a delayed fashion but its effects lasted the longest, with PGE2 being increased (P<0.05) for two hours after the cessation of kaliuretic peptide's infusion. This investigation demonstrates that 1) three endogenous peptide hormones increase PGE2 in the circulation and 2) suggests that the known increase in PGE2 in CHF may be in part secondary to these peptides.     

Cardiac natriuretic peptides: hormones with anticancer effects that localize to nucleus, cytoplasm, endothelium, and fibroblasts of human cancers

Four cardiac peptide hormones, i.e., vessel dilator, long acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP) synthesized by the same gene decrease within 24 hours up to 97% the number of human breast, colon, pancreatic, and prostate adenocarcinoma cells as well as human small-cell and squamous carcinomas of the lung cells. These peptide hormones completely inhibit the growth of human pancreatic adenocarcinomas growing in athymic mice. Immunocytochemical investigations have revealed that LANP, vessel dilator, kaliuretic peptide and ANP localize to the nucleus and cytoplasm of human pancreatic adenocarcinomas, which is consistent with their ability to decrease DNA synthesis in the nucleus of this cancer mediated by the intracellular messenger cyclic GMP. These peptide hormones also localize to the endothelium of capillaries and fibroblasts within these cancers. These are the first growth-inhibiting peptide hormones ever demonstrated to localize to the nucleus. Their ability to decrease the activation of growth promoting substances such as Extracellular Receptor Kinase (ERK)-1/2 and Nuclear Factor Kappa Beta (NFkappaB) suggests that in addition to inhibiting DNA synthesis their ability to decrease the activation of growth promoting substances helps to mediate their ability to inhibit the growth of human cancers.     

Atrial natriuretic hormone, vessel dilator, long acting natriuretic hormone, and kaliuretic hormone decrease circulating prolactin concentrations.

The present investigation was designed to test whether four cardiac hormones--long acting natriuretic hormone, vessel dilator, kaliuretic hormone and atrial natriuretic hormone--decrease the circulating concentration of prolactin in humans (n = 30). Vessel dilator, kaliuretic hormone, long acting natriuretic hormone and atrial natriuretic hormone decreased the circulating concentration of prolactin to 3 %, 31 %, 27 %, and 23 % of control values, respectively, at the end of their infusions when infused at concentrations of 100 ng/kg body weight per minute for 60 minutes (p < 0.001 for each). Vessel dilator, kaliuretic hormone, long acting natriuretic hormone and atrial natriuretic hormone had sustained effects on modulating prolactin's concentrations, with circulating concentrations of 1 %, 64 %, 28 %, and 2 % of control values (p < 0.001) 3 hours after stopping their respective infusions. These results suggest that there are four circulating prolactin-inhibitory hormones in addition to the hypothalamic mediators, dopamine and corticotropin-releasing hormone, which modulate prolactin release. These peptide hormones' ability to decrease circulating prolactin concentrations may be mediated in part by dopamine and in part by their demonstrated ability to decrease corticotropin-releasing hormone concentrations, which stimulate prolactin release.     

A gene located at 71F in Drosophila melanogaster encodes a novel zinc-finger protein that interacts with protein kinase CK2

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are two hormones produced and secreted by the heart to control blood pressure, body fluid homeostasis and electrolyte balance. Each peptide binds to a common family of 3 receptors (GC-A, GC-B and C-receptor) with varying degrees of affinity. The proANP gene disrupted mouse model provides an excellent opportunity to examine the regulation and expression of BNP in the absence of ANP. A new radioimmunoassay (RIA) was developed in order to measure mouse BNP peptide levels in the plasma, atrium and ventricle of the mouse. A detection limit of 3–6 pg/tube was achieved by this assay. Results show that plasma and ventricular level of BNP were unchanged among the three genotypes of mice. However, a significant decrease in the BNP level was noted in the atrium. The homozygous mutant (ANP–/–) had undetectable levels of BNP in the atrium, while the heterozygous (ANP+/–) and wild-type (ANP+/+) mice had 430 and 910 pg/mg in the atrium, respectively. Northern Blot analysis shows the ANP–/– mice has a 40% reduction of BNP mRNA level in the atrium and a 5-fold increase in the ventricle as compared with that of the ANP+/+ mouse. Our data suggest that there is a compensatory response of BNP expression to proANP gene disruption. Despite the changes in the atrial and ventricular tissue mRNA and peptide levels, the plasma BNP level remains unaltered in the ANP–/– mice. We conclude that the inability of BNP to completely compensate for the lack of ANP eventually leads to chronic hypertension in the proANP gene disrupted mice.     

心钠素前体分子内调控对心肌Na^＋—K^＋—ATP酶的作用

目的：研究利钾尿肽及心钠素前体分子内调控作用对心肌Ｎａ＋Ｋ＋ＡＴＰ酶的作用。方法：将大鼠心肌匀浆后,分别加入利钾尿肽、心钠素以及利钾尿肽＋心钠素,用比色法测定Ｎａ＋Ｋ＋ＡＴＰ酶活性。将大鼠心脏悬挂于Ｌａｎｇｅｎｄｏｒｆ灌流装置,分别以利钾尿肽、心钠素、利钾尿肽＋心钠素为灌流液,灌注心脏,用四道生理仪观测左心室内压、左心室收缩最大速率,左心室舒张最大速率,心率及冠脉流量。结果：心钠素虽然对Ｎａ＋Ｋ＋ＡＴＰ酶有抑制作用（抑制率２６．２％）,但是,与对照无显著性差异（Ｐ＞０．０５）。利钾尿肽显著抑制酶的活性（抑制率４６．５％,Ｐ＜０．０１）这种抑制作用可被心钠素抵消（抑制率１７．６％,Ｐ＞０．０５）。利钾尿肽可以增加左心室收缩和舒张最大速率以及左室内压,而这种强心作用可因心钠素的加入而消失或减弱。结论：利钾尿肽可以抑制心肌Ｎａ＋Ｋ＋ＡＴＰ酶的活性,产生强心作用,心钠素可以抵消以上作用。     

Combined treatment with vessel dilator and kaliuretic hormone in persons with congestive heart failure

Vessel dilator and kaliuretic hormone, two cardiovascular peptide hormones, enhance urine flow 2- to 13-fold and 4-fold, respectively, in persons with class III New York Heart Association congestive heart failure (CHF). The natriuresis and diuresis secondary to vessel dilator and kaliuretic hormone are not blunted as are atrial natriuretic peptide and brain natriuretic peptide effects in persons with CHF compared with healthy individuals. The present investigation determined if the two peptide hormones that do not have blunted effects in persons with CHF may have added beneficial effects when given simultaneously to individuals with class III CHF. Together with each at 100 ng/kg of body weight per minute, vessel dilator and kaliuretic hormone increased urine flow rate 3.5-fold (P < 0.05) compared with their 60-min baseline and control CHF subjects' urine flow rates. Combined, they enhanced the excretion rate of sodium a maximum of 3.6-fold (P < 0.05) with 2.5- and 2-fold enhancement 2 and 3 hrs after infusion. These data indicate that vessel dilator and kaliuretic hormone have diuretic and natriuretic effects when used in combination, but these effects are not additive over their individual effects in persons with CHF.     

Estradiol, progesterone and testosterone exposures affect the atrial natriuretic peptide gene expression in vivo in rats.

To clarify the effects of sex hormones on the expression of atrial natriuretic peptide (ANP), ovariectomized and intact female rats were subcutaneously injected with estradiol, progesterone, a mixture of them or olive oil solvent; castrated and untouched male rats were subcutaneously injected with estradiol, testosterone or olive oil, once a day for 7 days. The relative rANP-mRNA contents of rat atrial were measured by molecular hybridization. rANP-cDNA was labeled with 32P as a probe. The results revealed that estradiol and progesterone increased ANP gene expression. Furthermore their effects were associated with administration dose of these hormones and it was shown that they are probably coordinated. The physiological amounts of estradiol and progesterone may maintain suitable levels of rANP-mRNA and androgen may also increase the ANP gene expression in vivo. These experiments suggested that female sex hormone may have a dual purpose in fluid balance.     

Circadian Rhythm of Prohormone Atrial Natriuretic Peptides 1-30, 31-67 and 99-126 in Man

Two peptides consisting of amino acids 1-30 and 31-67 of the N-terminal end of the prohormone of the atrial natriuretic factor (pro ANF), vasodilate aortas in vitro, lower blood pressure in vivo, and have natriuretic properties similar to the atrial natriuretic factor (ANF, amino acids 99-126 of the prohormone). It has been recently discovered that pro ANF 1-30 and pro ANF 31-67 as well as ANF circulate in man. To determine if these three peptide hormones have a circadian variation in their circulating plasma concentrations, eight housestaff volunteers were studied on a day when they were in the hospital for 24 hr. These 5 men and 3 women, ages 25 to 39 had blood samples taken at 0800, 1200, 1600, 2000, 0000, 0400 and 0800 on the following day. One-half of these house officers were up all night while the other half went to sleep from midnight to 0800 and had their 0400 plasma samples drawn while in a supine position. The peak level for all three peptide hormones was at 0400 for both supine and upright subjects. It was concluded that there are circadian rhythms in normal, active people of these three peptide hormones, whose peak levels are at 0400 irrespective of posture.     

The natriuretic peptide system in eels: a key endocrine system for euryhalinity?

The natriuretic peptide system of a euryhaline teleost, the Japanese eel (Anguilla japonica), consists of three types of hormones [atrial natriuretic peptide (ANP), ventricular natriuretic peptide (VNP), and C-type natriuretic peptide (CNP)] and four types of receptors [natriuretic peptide receptors (NPR)-A, -B, -C, and -D]. Although ANP is recognized as a volume-regulating hormone that extrudes both Na(+) and water in mammals, ANP more specifically extrudes Na(+) in eels. Accumulating evidence shows that ANP is secreted in response to hypernatremia and acts to inhibit the uptake and to stimulate the excretion of Na(+) but not water, thereby promoting seawater (SW) adaptation. In fact, ANP is secreted immediately after transfer of eels to SW and ameliorates sudden increases in plasma Na(+) concentration through inhibition of drinking and intestinal absorption of NaCl. ANP also stimulates the secretion of cortisol, a long-acting hormone for SW adaptation, whereas ANP itself disappears quickly from the circulation. Thus ANP is a primary hormone responsible for the initial phase of SW adaptation. By contrast, CNP appears to be a hormone involved in freshwater (FW) adaptation. Recent data show that the gene expression of CNP and its specific receptor, NPR-B, is much enhanced in FW eels. In fact, CNP infusion increases (22)Na uptake from the environment in FW eels. These results show that ANP and CNP, despite high sequence identity, have opposite effects on salinity adaptation in eels. This difference apparently originates from the difference in their specific receptors, ANP for NPR-A and CNP for NPR-B. VNP may compensate the effects of ANP and CNP for adaptation to respective media, because it has high affinity to both receptors. On the basis of these data, the authors suggest that the natriuretic peptide system is a key endocrine system that allows this euryhaline fish to adapt to diverse osmotic environments, particularly in the initial phase of adaptation.     

Atrial natriuretic-like peptide and its prohormone within metasequoia.

Metasequoia glyptostroboides was one of the dominant conifers in North America, Asia, and Europe for more than 100 million years since the late Cretaceous Albian Age, but Quaternary glaciations drove the Metasequoia population to apparent extinction. A small pocket of Metasequoia, however, was found in central China in the 1940s representing the only surviving population of this "living fossil" species. Atrial natriuretic peptide, a 28-amino-acid peptide hormone that causes sodium and water excretion in animals, has been found to be part of the first peptide hormonal system in lower plants. The existence of this hormonal system has never been examined within trees of any genus. High-performance gel permeation chromatography of the leaves and stems (i.e., branches) of Metasequoia followed by atrial natriuretic peptide radioimmunoassay revealed an ANP-like peptide and its prohormone (i.e., approximately 13,000 mol wt) were present in both leaves and stems of this conifer. The elution profile of ANP-like peptide in stems of Metasequoia had a shoulder to the left of where pure synthetic ANP elutes suggesting the possibility of a slightly larger peptide eluting within this shoulder secondary to alternate processing of the ANP-like prohormone and similar to what occurs with the kidney of animals. The elution profile of ANP-like peptide in the leaves of Metasequoia revealed two peaks; one where ANP elutes and a second peak suggesting a smaller peptide that has been metabolically processed. The presence of the ANP-like prohormone strongly suggests that ANP-like gene expression is occurring in both leaves and stems of Metasequoia since this prohormone is the gene product of this hormonal system. The presence of the ANP-like hormonal system in trees implies that this hormonal system may have been present early in land plant evolution to allow trees to reach heights of greater than 30 feet where a water flow-enhancing substance is absolutely necessary for water flow to occur to these heights.     

Structural determinants of natriuretic peptide receptor specificity and degeneracy

Cardiovascular homeostasis and blood pressure regulation are reliant, in part, on interactions between natriuretic peptide (NP) hormones and natriuretic peptide receptors (NPR). The C-type NPR (NPR-C) is responsible for clearance of NP hormones from the circulation, and displays a cross-reactivity for all NP hormones (ANP, BNP, and CNP), in contrast to other NPRs, which are more restricted in their specificity. In order to elucidate the structural determinants for the binding specificity and cross-reactivity of NPR-C with NP hormones, we have determined the crystal structures of the complexes of NPR-C with atrial natriuretic peptide (ANP), and with brain natriuretic peptide (BNP). A structural comparison of these complexes, with the previous structure of the NPR-C/CNP complex, reveals that NPR-C uses a conformationally inflexible surface to bind three different, highly flexible, NP ligands. The complex structures support a mechanism of rigid promiscuity rather than conformational plasticity by the receptor. While ANP and BNP appear to adopt similar receptor-bound conformations, the CNP structure diverges, yet shares sets of common receptor contacts with the other ligands. The degenerate versus selective hormone recognition properties of different NPRs appears to derive largely from two cavities on the receptor surfaces, pocket I and pocket II, that serve as anchoring sites for hormone side-chains and modulate receptor selectivity.     

Circadian Rhythm of Prohormone Atrial Natriuretic Peptides 1-30, 31-67 and 99-126 in Man

Two peptides consisting of amino acids 1-30 and 31-67 of the N-terminal end of the prohormone of the atrial natriuretic factor (pro ANF), vasodilate aortas in vitro, lower blood pressure in vivo, and have natriuretic properties similar to the atrial natriuretic factor (ANF, amino acids 99-126 of the prohormone). It has been recently discovered that pro ANF 1-30 and pro ANF 31-67 as well as ANF circulate in man. To determine if these three peptide hormones have a circadian variation in their circulating plasma concentrations, eight housestaff volunteers were studied on a day when they were in the hospital for 24 hr. These 5 men and 3 women, ages 25 to 39 had blood samples taken at 0800, 1200, 1600, 2000, 0000, 0400 and 0800 on the following day. One-half of these house officers were up all night while the other half went to sleep from midnight to 0800 and had their 0400 plasma samples drawn while in a supine position. The peak level for all three peptide hormones was at 0400 for both supine and upright subjects. It was concluded that there are circadian rhythms in normal, active people of these three peptide hormones, whose peak levels are at 0400 irrespective of posture.     

Cloning of a cDNA encoding porcine brain natriuretic peptide

Complimentary DNA (cDNA) clones encoding porcine brain natriuretic peptide (BNP) were isolated from a porcine atrial cDNA library. The longest of the cDNA clones (1507 nucleotides) apparently originated from an unprocessed messenger RNA, since the nucleotide sequence encoding BNP-26 was interrupted by an intron of 554 nucleotides. A partial cDNA clone representing processed BNP mRNA was prepared by polymerase chain reaction. A comparison of the sequence of these two cDNAs reveals the presence of an additional intron within the sequence encoding the BNP precursor. The identification of these introns suggests that the BNP gene structure differs from the atrial natriuretic peptide gene in the location of intron 2. BNP mRNA encodes a propeptide of 131 amino acids, including a signal peptide domain (25 amino acids) and a prohormone domain (106 amino acids). Like atrial natriuretic peptide, the bioactive BNP sequence is localized at the carboxyl terminus of the prohormone. Although the carboxyl-terminal peptide sequences of porcine atrial natriuretic peptide and BNP are well conserved, there is relatively little homology within their propeptide regions.     

Elevated renal norepinephrine in proANP gene-disrupted mice is associated with increased tyrosine hydroxylase expression in sympathetic ganglia

The sympatholytic properties of atrial natriuretic peptide (ANP) contribute to its vasodilatory and natriuretic effects. High circulating catecholamine levels, along with renal dysfunction, present in proANP gene-disrupted (-/-) mice are thought to contribute to the hypertension characteristic of this model. To further understand the mechanism by which the absence of ANP leads to stimulation of sympathetic activity we measured tyrosine hydroxylase expression in mice with and without ANP. The adrenal and prevertebral ganglionic expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine production, was significantly increased in ANP -/- mice. ANP's sympatholytic properties include the depression of ganglionic and adrenal TH expression and catecholamine production. Thus, these results suggest that the absence of ANP's sympatholytic effects is not completely compensated for in ANP -/- mice. In addition, mice devoid of ANP display an increase in renal sympathetic nerve activity from birth through to adulthood which may lead to structural and/or functional changes in the early postnatal kidney that contribute to the hypertensive phenotype of ANP -/- mice. The over-activation of the sympathetic nervous system in mice lacking ANP confirms the important role of this peptide in the modulation of sympathetic nerve activity and its contribution to blood pressure homeostasis.     

Genome-wide analyses reveal a role for peptide hormones in planarian germline development

Bioactive peptides (i.e., neuropeptides or peptide hormones) represent the largest class of cell-cell signaling molecules in metazoans and are potent regulators of neural and physiological function. In vertebrates, peptide hormones play an integral role in endocrine signaling between the brain and the gonads that controls reproductive development, yet few of these molecules have been shown to influence reproductive development in invertebrates. Here, we define a role for peptide hormones in controlling reproductive physiology of the model flatworm, the planarian Schmidtea mediterranea. Based on our observation that defective neuropeptide processing results in defects in reproductive system development, we employed peptidomic and functional genomic approaches to characterize the planarian peptide hormone complement, identifying 51 prohormone genes and validating 142 peptides biochemically. Comprehensive in situ hybridization analyses of prohormone gene expression revealed the unanticipated complexity of the flatworm nervous system and identified a prohormone specifically expressed in the nervous system of sexually reproducing planarians. We show that this member of the neuropeptide Y superfamily is required for the maintenance of mature reproductive organs and differentiated germ cells in the testes. Additionally, comparative analyses of our biochemically validated prohormones with the genomes of the parasitic flatworms Schistosoma mansoni and Schistosoma japonicum identified new schistosome prohormones and validated half of all predicted peptide-encoding genes in these parasites. These studies describe the peptide hormone complement of a flatworm on a genome-wide scale and reveal a previously uncharacterized role for peptide hormones in flatworm reproduction. Furthermore, they suggest new opportunities for using planarians as free-living models for understanding the reproductive biology of flatworm parasites.     

The endocrine heart and natriuretic peptides: histochemistry, cell biology, and functional aspects of the renal urodilatin system

 This review focuses on some selected aspects of the endocrine heart and natriuretic peptides. The endocrine heart is composed of specific myoendocrine cells of the cardiac atria. The myoendocrine cells synthesize and secrete the natriuretic peptide hormones which exhibit natriuretic, diuretic, and vasorelaxant properties. Immunohistochemical analyses show that natriuretic peptides of the A-type and B-type are localized not only in the specific granules of these myoendocrine cells but also in many other organs including the brain, adrenal medulla, and kidney. Also, their receptors are detected in many organs showing the multiple functions of these regulatory peptides. Of the members of the natriuretic peptide family, ANP (ANP for atrial natriuretic peptide; also denominated cardiodilatin, CDD), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and the A-type, including its renal form, urodilatin, are emphasized in this review. Urodilatin is localized in the kidney, differentially processed, and secreted into the urine. The intrarenal synthesis and secretion is the basis for a paracrine system regulating water and sodium reabsorption at the level of the collecting duct. CDD/ANP-1-126, cleaved from a precursor of 126 amino acids in the heart to a 28-amino acid-containing circulating molecular form (CDD/ANP-99-126), and urodilatin (CDD/ANP-95-126) share similar biochemical features and biological functions, but urodilatin may be more involved in the regulation of body fluid volume and water–electrolyte excretion, while circulating CDD/ANP-99-126 is responsible for blood pressure regulation. The physiological and pharmacological properties of these peptides have great clinical impact, and as a consequence urodilatin is involved in drug development for the treatment of acute renal failure, cardiomyopathia, and acute asthma. Accepted: 8 July 1998