Guanylin, a peptide homologue of the bacterial heat-stable enterotoxins (ST), is an endogenous activator of guanylate cyclase C (GC-C). We have initiated a search for other members of the guanylin peptide family and in the current study describe a "guanylin-like peptide" from human urine. Bioactivity was monitored by determining the effect of urine extracts on T84 cell guanosine 3',5'-cyclic monophosphate (cGMP) levels. Purification yielded two bioactive peaks of peptides that, when sequenced by NH2-terminal analysis, possessed 15 and 16 amino acids. The sequence of the smaller peptide represented an NH2-terminal truncation of the larger peptide. We have termed the larger peptide human uroguanylin; it has the following amino acid sequence: NDDCELCVNVACTGCL. Human uroguanylin shares amino acid sequence homology with guanylin and ST. Synthetic uroguanylin increased cGMP levels in T84 cells, competed with 125I-labeled ST for receptors, and stimulated Cl- secretion as reflected by an increased short-circuit current. Thus we report the isolation from human urine of a unique peptide, uroguanylin, that behaves in a manner similar to guanylin and appears to be a new member of this peptide family.

Abstract-Adrenomedullin (AM) is a vasodilator peptide having a wide range of biological actions such as reduction of oxidative stress and inhibition of endothelial cell apoptosis. The AM gene is expressed in vascular walls, and AM was found to be secreted from cultured vascular endothelial cells, smooth muscle cells, and adventitial fibroblasts. Plasma AM levels in patients with arteriosclerotic vascular diseases are elevated in possible association with the severity of the disease. When administered over a relatively short period, AM dilates blood vessels via an endothelium-dependent or independent mechanism. Experiments in vitro have shown that AM exerts multiple actions on cultured vascular cells, which are mostly protective or inhibitory against vascular damage and progression of arteriosclerosis. Key Words: adrenomedullin Ⅲ vasodilatation Ⅲ endothelium Ⅲ smooth muscle cell Ⅲ arteriosclerosis C ardiovascular diseases secondary to arteriosclerosis of blood vessels are currently among the leading causes of death in developed countries. A number of factors, both humoral and mechanical, have been shown to modulate vascular function in humans as well as in experimental animals. 1 Blood vessel dysfunction resulting from an imbalance of those factors accelerates the process of vascular remodeling and atherosclerosis. 1 Vasoconstrictors including angiotensin II and endothelins not always but mostly act as proatherogenic factors, whereas vasodilators, either peptides or non-peptides, such as natriuretic peptides, nitric oxide (NO), and prostaglandin (PG) I 2 , have antiatherogenic properties. 1 In 1993, a new vasodilator peptide, adrenomedullin (AM), was isolated from the tissue extract of a human pheochromocytoma by monitoring cAMP levels in rat platelets. 2 Substantial levels of the AM peptide and gene expression were detected in the cardiovascular tissues including blood vessels. As listed in the Table, AM was found to exert a wide range of biological actions related to vascular functions in cultured cells, with which observations in vivo have been mostly accordant. Ever since the discovery of AM, efforts have been made to clarify the role of this bioactive peptide in blood vessels and a substantial amount of basic and clinical data has been accumulated. In this review, after summarizing the biochemical and pharmacological features of AM, we discuss its role in blood vessels, which is assumed to be protective, or inhibitory against the progression of vascular damage and remodeling. Biochemistry of AMHuman AM is a 52-aa peptide with a ring structure formed by a disulfide bond and amidated tyrosine at the C terminus ( Figure 1), both essential for binding to receptors and biological activity. 2-4 Based on sequence homology, AM is thought to belong to the calcitonin gene-related peptide (CGRP) superfamily. [2][3][4] Cloning of the cDNA encoding AM revealed the AM precursor peptide preproAM to comprise 185 amino acids, with the C terminus followed by a pair of basic amino acids, Arg-Arg, a typical processing signal (...

Adrenomedullin (AM) and atrial and brain natriuretic peptides (ANP and BNP) exert vasodilator and natriuretic actions and are thought to share roles in counteracting the progression of hypertension or heart failure as circulating or locally-acting hormones. However, little data is available with regard to their roles in subjects who have no apparent cardiovascular diseases. The present study was carried out to identify the factors that affect plasma levels of AM, ANP and BNP in the general population. We measured the plasma levels of AM, ANP and BNP in 184 local residents who had a scheduled regular health checkup, and compared the findings with those for other clinical parameters. Univariate analyses showed that the plasma levels of AM, ANP and BNP were significantly correlated with age. The plasma levels of ANP and BNP were also significantly correlated with systolic blood pressure (SBP) and with pulse pressure (PP), an indicator of the stiffness of the great vessels. Multivariate analyses conducted using a stepwise method revealed that age was a significant, independent variable for the plasma levels of AM, ANP and BNP. In addition, PP was a significant factor for the plasma levels of ANP and BNP, while the plasma AM was significantly associated with body mass index (BMI). Thus, the plasma levels of AM, ANP and BNP all increased in association with aging, and those of ANP and BNP increased in association with PP, suggesting possible relationships between the plasma levels and age-related changes in the cardiovascular system.

Adrenomedullin(AM), a potent vasodilator and natriuretic peptide, is found in human blood. To investigate the pathophysiological role of AM in essential and malignant hypertension (EHT and MHT), we measured the plasma concentrations of AM in patients with EHT of WHO stage I or II (n = 42) and in those with MHT (n = 9) by a specific radioimmunoassay, and compared these concentrations with those in normotensive controls (n = 46). The plasma concentrations of atrial and brain natriuretic peptides (ANP and BNP) in these subjects were also measured by immunoradiometric assays, and their relations to plasma AM were examined. The plasma AM level in the EHT patients (7.15 ± 0.21 pmol/l, mean ± SEM) was significantly (p < 0.01) higher than that in the normotensive controls (6.14 ± 0.25 pmol/1), and a further elevation was observed in the MHT patients (14.1 ± 3.8 pmol/l). Similar elevations of plasma ANP and BNP were seen in the two patient groups. The plasma AM level significantly (p < 0.01) correlated with not only the systolic (r = 0.44) and diastolic (r = 0.46) blood pressures, but also with the plasma levels of ANP (r= 0.43) and BNP (r= 0.43). The elevated plasma concentration of AM in the MHT patients decreased significantly (p < 0.05) after antihypertensive treatment, and the plasma ANP and BNP levels similarly declined. These results suggest that AM may participate, along with ANP and BNP, in mechanisms counteracting a further elevation of blood pressure in patients with EHT and MHT. (Hypertens Res 1999; 22: 61-65) Key Words: adrenomedullin, natriuretic peptides, essential hypertension, malignant hypertension Adrenomedullin (AM) is a potent vasodilator peptide that was first detected in a human pheochromocytoma while monitoring cyclic AMP (cAMP) in rat platelets (1). The development of a specific radioimmunoassay (RIA) revealed that AM is present not only in the normal human adrenal medulla but also in tissues such as aorta, kidney, lung, and cardiac atrium and ventricle, where AM mRNA is abundantly expressed (2, 3) . High concentrations of AM were also found to circulate in the blood of humans (4). When injected intravenously, synthetic AM exerts a potent hypotensive action, accompanied by a marked reduction of total peripheral resistance in rats (5). Ebara et al. observed increases in urinary volume and sodium excretion after an intrarenal arterial injection of AM in dogs (6). Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones thought to act against elevation of blood pressure and retention of body fluid in cardiovascular diseases such as hypertension and heart failure through their vasodilator and natriuretic effects (7) . ANP and BNP exert their biological actions via an accumulation of intracellular cyclic GMP (cGMP) (7), whereas many of the actions of AM are mediated by cAMP (8). Since the AM actions are similar to those of ANP and BNP despite differences in their intracellular signaling systems, we hypothesized that AM functions along with ANP and BNP to act against further elevati...

Dietary K+ intake may increase renal K+ excretion via increasing plasma [K+] and/or activating a mechanism independent of plasma [K+]. We evaluated these mechanisms during normal dietary K+ intake. After an overnight fast, [K+] and renal K+ excretion were measured in rats fed either 0% K+ or the normal 1% K+ diet. In a third group, rats were fed with the 0% K+ diet, and KCl was infused to match plasma [K+] profile to that of the 1% K+ diet group. The 1% K+ feeding significantly increased renal K+ excretion, associated with slight increases in plasma [K+], whereas the 0% K+ diet decreased K+ excretion, associated with decreases in plasma [K+]. In the KCl-infused 0% K+ diet group, renal K+ excretion was significantly less than that of the 1% K+ group, despite matched plasma [K+] profiles. We also examined whether dietary K+ alters plasma profiles of gut peptides, such as guanylin, uroguanylin, glucagon-like peptide 1, and glucose-dependent insulinotropic polypeptide, pituitary peptides, such as AVP, α-MSH, and γ-MSH, or aldosterone. Our data do not support a role for these hormones in the stimulation of renal K+ excretion during normal K+ intake. In conclusion, postprandial increases in renal K+ excretion cannot be fully accounted for by changes in plasma [K+] and that gut sensing of dietary K+ is an important component of the regulation of renal K+ excretion. Our studies on gut and pituitary peptide hormones suggest that there may be previously unknown humoral factors that stimulate renal K+ excretion during dietary K+ intake.