adrenomedullin and Hypotension

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Antihypertensive Agents; Blotting, Northern; Cardiovascular Diseases; Humans; Hypertension; Hypotension; Molecular Sequence Data; Peptide Fragments; Peptides; Proteins; Radioimmunoassay; Rats

Topics: Adrenal Gland Neoplasms; Adrenomedullin; Amino Acid Sequence; Animals; Blood Platelets; Blood Pressure; Calcitonin Gene-Related Peptide; Cyclic AMP; History, 20th Century; Humans; Hypotension; Molecular Sequence Data; Pheochromocytoma; Rats

Sustained hypotension during hemodialysis (HD) is an important clinical issue. Plasma adrenomedullin (AM) is increased in HD patients with sustained hypotension, but little is known about whether removing AM can improve hypotension. The objective of this study was to investigate the beneficial effects of hemodialysis using a high-flux dialyzer on removal of increased plasma AM levels and improving low blood pressure in elderly HD patients with sustained hypotension.. Forty-eight elderly patients (age 65 or older) who had undergone maintenance HD for more than one year were recruited and studied. We evaluated plasma levels of AM in sustained hypotension (SH; n = 28) and normotensive (NT; n = 20) patients. The patients with hypotension were further divided into two subgroups and treated with either high-flux dialyzer or low-flux dialyzer for 3 months. Plasma adrenomedullin levels and blood pressure were analyzed at days 0 and 181.. Plasma levels of AM were significantly higher in SH than in NT patients ((24.92 ± 3.7) ng/L vs. (15.52 ± 6.01) ng/L, P < 0.05), and were inversely correlated with mean arterial blood pressure (MAP) at pre-HD. After 3 months, the level of plasma AM in high-flux group was decreased ((24.58 ± 4.36) ng/L vs. (16.18 ± 5.08) ng/L, P < 0.05), but MAP was increased ((67.37 ± 4.31) mmHg vs. (74.79 ± 3.59) mmHg, P < 0.05). There was no obvious change in low-flux group.. Plasma AM levels were significantly elevated in elderly HD patients with SH. High-flux dialyzer therapy can decrease plasma AM level and improve hypotension.

Topics: Adrenomedullin; Aged; Female; Humans; Hypotension; Male; Renal Dialysis

Cerebrospinal fluid (CSF) adrenomedullin (ADM) levels are increased in female, but remain unchanged in male, piglets after fluid percussion injury (FPI) of the brain. Subthreshold vascular concentrations of ADM restore impaired hypotensive pial artery dilation after FPI more in males than females. Extracellular signal-related kinase (ERK) mitogen-activated protein kinase (MAPK) is upregulated and contributes to reductions in cerebral blood flow (CBF) after FPI. We hypothesized that ADM prevents sex-dependent impairment of autoregulation during hypotension after FPI through inhibition of ERK MAPK upregulation. FPI increased ERK MAPK more in males than in females. CBF was unchanged during hypotension in sham animals, was reduced more in males than in females after FPI during normotension, and was further reduced in males than in females during hypotension and after FPI. ADM and the ERK MAPK antagonist U 0126 prevented reductions in CBF during hypotension and FPI more in males than in females. Transcranial Doppler (TCD) blood flow velocity was unchanged during hypotension in sham animals, was decreased during hypotension and FPI in male but not in female pigs, and was ameliorated by ADM. Intracranial pressure (ICP) was increased after FPI more in male than in female animals. ADM blunted elevated ICP during FPI and hypotension in males, but not in females. ADM prevented reductions in cerebral perfusion pressure (CPP) during FPI and hypotension in males but not in females. The calculated autoregulatory index was unchanged during hypotension in sham animals, but was reduced more in males than females during hypotension and FPI. ADM prevented reductions in autoregulation during hypotension and FPI more in males than females. These data indicate that ADM prevented loss of cerebral autoregulation after FPI in a sex-dependent and ERK MAPK-dependent manner.

Topics: Adrenomedullin; Animals; Animals, Newborn; Brain; Brain Injuries; Cerebrovascular Circulation; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases; Female; Homeostasis; Hypotension; Immunohistochemistry; Intracranial Pressure; Male; Sex Characteristics; Swine; Ultrasonography, Doppler, Transcranial; Up-Regulation

Traumatic brain injury contributes to morbidity and mortality in children and boys are disproportionately represented. Hypotension is common and worsens outcome after traumatic brain injury. Extracellular signal-related kinase mitogen-activated protein kinase is upregulated and reduces cerebral blood flow after fluid percussion brain injury in piglets. We hypothesized that increased cerebral perfusion pressure through phenylephrine sex dependently reduces impairment of cerebral autoregulation during hypotension after fluid percussion brain injury through modulation of extracellular signal-related kinase mitogen-activated protein kinase.. Prospective, randomized animal study.. University laboratory.. Newborn (1- to 5-day-old) pigs.. Cerebral blood flow, pial artery diameter, intracranial pressure, and autoregulatory index were determined before and after fluid percussion brain injury in untreated, preinjury, and postinjury phenylephrine (1 microg/kg/min intravenously) treated male and female pigs during normotension and hemorrhagic hypotension. Cerebrospinal fluid extracellular signal-related kinase mitogen-activated protein kinase was determined by enzyme-linked immunosorbent assay.. Reductions in pial artery diameter, cerebral blood flow, cerebral perfusion pressure, and elevated intracranial pressure after fluid percussion brain injury were greater in males, which were blunted by phenylephrine pre- or postfluid percussion brain injury. During hypotension and fluid percussion brain injury, pial artery dilation was impaired more in males. Phenylephrine decreased impairment of hypotensive pial artery dilation after fluid percussion brain injury in females, but paradoxically caused vasoconstriction after fluid percussion brain injury in males. Papaverine-induced pial artery vasodilation was unchanged by fluid percussion brain injury and phenylephrine. Cerebral blood flow, cerebral perfusion pressure, and autoregulatory index decreased markedly during hypotension and fluid percussion brain injury in males but less in females. Phenylephrine prevented reductions in cerebral blood flow, cerebral perfusion pressure, and autoregulatory index during hypotension in females but increased reductions in males. Cerebrospinal fluid extracellular signal-related kinase mitogen-activated protein kinase was increased more in males than females after fluid percussion brain injury. Phenylephrine blunted extracellular signal-related kinase mitogen-activated protein kinase upregulation in females but increased extracellular signal-related kinase mitogen-activated protein kinase upregulation in males after fluid percussion brain injury.. These data indicate that elevation of cerebral perfusion pressure with phenylephrine sex dependently prevents impairment of cerebral autoregulation during hypotension after fluid percussion brain injury through modulation of extracellular signal-related kinase mitogen-activated protein kinase. These data suggest the potential role for sex-dependent mechanisms in cerebral autoregulation after pediatric traumatic brain injury.

Topics: Adrenomedullin; Animals; Animals, Newborn; Brain Injuries; Cerebrovascular Circulation; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases; Female; Hypotension; Male; Phenylephrine; Phosphorylation; Prospective Studies; Sex Factors; Swine; Up-Regulation; Vasoconstrictor Agents

Intermedin (IMD) is a newly identified member of the calcitonin family of peptides that shares structural and functional homology with adrenomedullin (AM). In vivo cardiovascular effects of AM have been described, but relatively little is known of the in vivo actions of IMD. The purpose of this study was to compare the regional haemodynamic effects of IMD with those of AM in conscious rats, and investigate possible underlying mechanisms.. Measurements of blood pressure, heart rate and renal, mesenteric and hindquarters haemodynamics were made in conscious, chronically-instrumented rats.. IMD caused tachycardia and vasodilatation in all three vascular beds, associated with modest hypotension. At an equimolar dose (1 nmol.kg(-1)), most of the cardiovascular effects of IMD were greater than those of AM. The AM receptor antagonist, AM(22-52), was equally effective in attenuating the renal and mesenteric vasodilator effects of IMD (1 nmol.kg(-1)) and AM (3 nmol.kg(-1)), but inhibition of NO synthase was more effective at reducing the vasodilator effects of IMD than AM. Vascular K(ATP) channel blockade with U-37883A did not inhibit the vasodilator effects of either peptide.. In vivo, the regional haemodynamic profile of IMD resembles that of AM, and some of the vasodilator effects of IMD are mediated by AM receptors and NO, but not by K(ATP) channels. The cardiovascular effects of AM have been implicated in various pathological conditions, but whether or not endogenous IMD fulfils a similar role remains to be determined.

Topics: Adrenomedullin; Animals; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Hemodynamics; Hypotension; Kidney; Male; Neuropeptides; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Splanchnic Circulation; Tachycardia; Vasodilation; Vasodilator Agents

The vasodilator and vascular regulatory peptide adrenomedullin (AM), a member of the calcitonin gene-related peptide family of peptides, is predicted to play a pivotal protective role in cardiovascular dysfunction. The principle AM (AM1) receptor is composed of a G protein-linked calcitonin receptor-like receptor and a receptor activity-modifying protein (receptor activity-modifying protein 2). There is little knowledge of the receptors via which AM acts in diseases. Using smooth muscle-targeted receptor activity-modifying protein 2 transgenic mice with increased vascular density of functional AM1 receptors, we demonstrate that receptor activity-modifying protein 2 transgenic mice are not protected against angiotensin II-induced hypertension or cardiac hypertrophy. However, vascular hypertrophy, together with vascular cell adhesion molecule 1 and monocyte chemotactic protein 1 expression, is significantly reduced in the aortic walls of transgenic mice, as determined by histological techniques. This indicates that the AM1 vascular smooth muscle receptor can mediate local protection in vivo. This is supported by proliferation studies in cultured smooth muscle cells. By comparison, levels of hypotension and inflammation in a shock model were similar to those in wild-type mice. Thus, a role of the AM1 receptor in the vasoactive component could not be detected, and evidence is provided to show that the hypotensive response to AM is subject to desensitization in vivo. The finding that the vascular smooth muscle AM1 receptor acts at a local level to protect against hypertension-induced vascular hypertrophy and inflammation provides evidence that targeting this receptor may be a beneficial therapeutic approach.

Topics: Adrenomedullin; Angiotensin II; Animals; Blood Pressure; Cardiomegaly; Cells, Cultured; Disease Models, Animal; Female; Hypertension; Hypertrophy; Hypotension; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Peptide; Vasculitis

Cerebrovascular dysregulation during hypotension occurs after fluid percussion brain injury (FPI) in the newborn pig owing to impaired K channel function. This study was designed to (1) determine the role of gender and K channel activation in adrenomedullin (ADM) cerebrovasodilation, (2) characterize the role of gender in the loss of hypotensive cerebrovasodilation after FPI, and (3) determine the role of gender in the ability of exogenous ADM to modulate hypotensive dysregulation after FPI. Lateral FPI (2 atm) was induced in newborn male and female newborn pigs (1 to 5 days old) equipped with a closed cranial window, n=6 for each protocol. Adrenomedullin-induced pial artery dilation was significantly greater in female than male piglets and blocked by the K(ATP) channel antagonist glibenclamide, but not by the K(ca) channel antagonist iberiotoxin. Cerebrospinal fluid ADM was increased from 3.8+/-0.7 to 14.6+/-3.0 fmol/mL after FPI in female but was unchanged in male piglets. Hypotensive pial artery dilation was blunted to a significantly greater degree in male versus female piglets after FPI. Topical pretreatment with a subthreshold vascular concentration of ADM (10(-10) mol/L) before FPI reduced the loss of hypotensive pial artery dilation in both genders, but protection was significantly greater in male versus female piglets. These data show that hypotensive pial artery dilation is impaired after FPI in a gender-dependent manner. By unmasking a gender-dependent endogenous protectant, these data suggest novel gender-dependent approaches for clinical intervention in the treatment of perinatal traumatic brain injury.

Topics: Adenosine Triphosphate; Adrenomedullin; Animals; Animals, Newborn; Arteries; Brain Injuries; Female; Glyburide; Hypotension; Male; Peptides; Potassium Channels; Sex Characteristics; Swine; Vasodilation

Activated protein C (APC) is an important modulator of vascular function that has antithrombotic and anti-inflammatory properties. Studies in humans have shown modulation of endotoxin-induced hypotension by recombinant human APC, drotrecogin alfa (activated), however, the mechanism for this effect is unclear. We have found that APC suppresses the induction of the potent vasoactive peptide adrenomedullin (ADM) and could downregulate lipopolysaccharide (LPS)-induced ADM messenger RNA (mRNA) and nitrite levels in cell culture. This effect was dependent on signaling through protease-activated receptor 1. Addition of 1400W, an irreversible inducible nitric oxide synthase (iNOS) inhibitor, inhibited LPS-induced ADM mRNA, suggesting that ADM induction is NO mediated. Furthermore, in a rat model of endotoxemia, APC (100 microg/kg, i.v.) prevented LPS (10 mg/kg, i.v.)-induced hypotension, and suppressed ADM mRNA and protein expression. APC also inhibited iNOS mRNA and protein levels along with reduction in NO by-products (NOx). We also observed a significant reduction in iNOS-positive leukocytes adhering to vascular endothelium after APC treatment. Moreover, we found that APC inhibited the expression of interferon-gamma (IFN-gamma), a potent activator of iNOS. In a human study of LPS-induced hypotension, APC reduced the upregulation of plasma ADM levels, coincident with protection against the hypotensive response. Overall, we demonstrate that APC blocks the induction of ADM, likely mediated by IFN-gamma and iNOS, and suggests a mechanism that may account for ameliorating LPS-induced hypotension. Furthermore, our data provide a new understanding for the role of APC in modulating vascular response to insult.

Topics: Adrenomedullin; Animals; Blotting, Western; Cell Line; Cell Movement; Cyclic AMP; Cyclic GMP; Endothelial Cells; Gene Expression; Humans; Hypotension; Interferon-gamma; Leukocytes; Lipopolysaccharides; Lung; Male; Nitric Oxide Synthase Type II; Nitrites; Nitrogen Oxides; Protein C; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are potent vasodilators and exert positive chronotropic and inotropic effects on the heart. Receptors for CGRP and AM are calcitonin receptor-like receptor (CLR)/receptor-activity-modifying protein (RAMP) 1 and CLR/RAMP2 heterodimers, respectively. The present study was designed to delineate distinct cardiovascular effects of CGRP and AM. Thus a V5-tagged rat CLR was expressed in transgenic mice in the vascular musculature, a recognized target of CGRP. Interestingly, basal arterial pressure and heart rate were indistinguishable in transgenic mice and in control littermates. Moreover, intravenous injection of 2 nmol/kg CGRP, unlike 2 nmol/kg AM, decreased arterial pressure equally by 18 +/- 5 mmHg in transgenic and control animals. But the concomitant increase in heart rate evoked by CGRP was 3.7 times higher in transgenic mice than in control animals. The effects of CGRP in transgenic and control mice, different from a decrease in arterial pressure in response to 20 nmol/kg AM, were suppressed by 2 micromol/kg of the CGRP antagonist CGRP(8-37). Propranolol, in contrast to hexamethonium, blocked the CGRP-evoked increase in heart rate in both transgenic and control animals. This was consistent with the immunohistochemical localization of the V5-tagged CLR in the superior cervical ganglion of transgenic mice. In conclusion, hypotension evoked by CGRP in transgenic and control mice was comparable and CGRP was more potent than AM. Unexpectedly, the CLR/RAMP CGRP receptor overexpressed in postganglionic sympathetic neurons of transgenic mice enhanced the positive chronotropic action of systemic CGRP.

Topics: Adrenergic beta-Antagonists; Adrenomedullin; Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Dimerization; Heart; Heart Rate; Hexamethonium; Hypotension; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Mice, Transgenic; Myocardial Contraction; Myocardium; Nicotinic Antagonists; Peptide Fragments; Propranolol; Rats; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; Recombinant Fusion Proteins; Superior Cervical Ganglion; Sympathetic Fibers, Postganglionic; Sympathetic Nervous System; Tachycardia

To investigate whether adrenomedullin, a potent vasodilator peptide, plays a role in the circulatory disturbance in cirrhosis.. Cirrhosis was induced in rats by weekly gavage of carbon tetrachloride. Hemodynamic studies were performed in vivo using radioactive microspheres and in vitro using isolated aortic rings. The adrenomedullin concentrations were measured by radioimmunoassay.. Acute administration of adrenomedullin to the control rats reduced the systemic arterial pressure along with an increase of serum levels of the stable metabolite of nitric oxide (NOx), in a dose-dependent manner. Chronic infusion of adrenomedullin reduced the vascular resistance and increased the blood flow in the systemic and splanchnic circulation. Intravenous administration of anti-adrenomedullin antibody did not affect any hemodynamic parameters in the cirrhotic rats, whereas this antibody ameliorated the blunted contractile response to phenylephrine, alpha-adrenergic receptor agonist, in the aortic rings of the cirrhotic rats. The adrenomedullin concentrations in the aorta were higher in the cirrhotic rats than in the controls, and correlated with the mean arterial pressure in the cirrhotic rats. Moreover, adrenomedullin blunted the contractile response to phenylephrine in both of the control aorta and cirrhotic aorta, but not in the presence of NG-nitro-L-arginine methyl ester, an NO synthase inhibitor.. Adrenomedullin overproduced in the vascular wall may contribute to the circulatory disturbance in cirrhosis as a local regulator of the vascular tonus rather than a circulating hormone.

Topics: Adrenomedullin; Animals; Blood Pressure; Cardiac Output, High; Hypotension; Liver Cirrhosis, Experimental; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptides; Phenylephrine; Rats; Rats, Sprague-Dawley; Vascular Resistance; Vasoconstriction

Sustained and/or episodic hypotension during hemodialysis (HD) is an important clinical issue. Plasma adrenomedullin (AM) is increased in HD patients with sustained hypotension, but little is known about its implications for episodic hypotension. Ghrelin may also contribute to the pathophysiology of hypotension in HD patients. We evaluated plasma levels of AM and total ghrelin in sustained hypotensive (SH; n = 23), episodic hypotensive (EH; n = 30) and normotensive (NT; n = 23) HD patients. In the EH group, the relationship between low blood pressure during HD and circulating levels of AM and ghrelin was also evaluated. Plasma levels of AM were significantly higher in SH (34.3 +/- 8.3 fmol/ml, p<0.01) than in NT patients (27.6 +/- 5.2 fmol/ml), but not in EH patients (30.8 +/- 6.1 fmol/ml). There was no significant difference of plasma total ghrelin in SH (548.1 +/- 426.5 fmol/ml) and in EH patients (544.6 +/- 174.3 fmol/ml), compared with NT patients (400.0 +/- 219.7 fmol/ml). On the other hand, in EH patients, the "suppressed blood pressure ratio" during HD significantly correlated with plasma AM (r = 0.77, p<0.001) and with total ghrelin levels (r = 0.44, p<0.05). Our results suggest that ghrelin, as well as AM, may play an important role as vasodilator local hormones and regulation of blood pressure during HD, especially the occurrence of EH. Further studies are necessary to clarify the implication of these hormones in the control of hypotension during HD.

Topics: Adrenomedullin; Aged; Case-Control Studies; Female; Ghrelin; Humans; Hypotension; Male; Middle Aged; Osmolar Concentration; Peptide Hormones; Peptides; Renal Dialysis; Vasodilator Agents

We recently demonstrated that prolonged simulated microgravity (SMG) induced hypotension and hypoaldosteronism in rats, and gathered preliminary evidence for an involvement of circulating adrenomedullin (AM). Thus, we aimed to investigate whether short-term SMG elicits the same effects, and whether up-regulation of adrenal AM system plays a relevant role. Rats were exposed for 8 days to SMG in the form of hindlimb unweighting, and then, along with control animals, were given an intraperitoneal injection of AM22-52 and/or angiotensin-II (Ang-II) (100 nmoles/kg) or the saline vehicle. Systolic blood pressure (SBP) was measured by tail-cuff sphygmomanometry. The adrenal expression of AM was assayed by semiquantitative RT-PCR. The plasma concentrations of aldosterone (PAC) and AM, and adrenal AM content were measured by RIA. Short-term SMG induced significant decreases in SBP and PAC. Conversely, both the plasma and adrenal levels of AM, and adrenal AM mRNA were enhanced in SMG-exposed animals. The SMG-induced hypotension and hypoaldosteronism were reversed by AM22-52, an AM-receptor antagonist, thereby demonstrating a causal link between these effects and the up-regulation of AM system. SMG hampered SBP and PAC responses to Ang-II; the co-administration of AM22-52 restored these responses. These findings accord well with the known ability of AM to counteract the effects of Ang-II on both blood vessels and adrenocortical cells. Taken together, our findings allow us to conclude that up-regulation of the adrenal AM system i) occurs early and takes part in the adaptative changes occurring during SMG conditions; and ii) may account for both hypotension and hypoaldosteronism on returning to the normogravitational environment.

Topics: Adrenomedullin; Aldosterone; Angiotensin II; Animals; Blood Pressure; DNA, Complementary; Ethidium; Hypoaldosteronism; Hypotension; Hypoxia; Male; Peptides; Polymerase Chain Reaction; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Up-Regulation; Weightlessness

MMPs (matrix metalloproteinases) play a major role in the pathogenesis of hypertension by altering the extracellular matrix during cardiovascular remodelling. In the present study we show that MMP-2, but not MMP-9, cleaves the vasodilator peptide AM (adrenomedullin). Addition of the AM-binding protein, complement factor H, prevents this cleavage, providing a hitherto unknown mechanism of action for this binding protein. We identified the signature cleavage fragments and found some of them in human urine, suggesting that MMP-2 processing of AM may occur in vivo. Synthetic AM fragments regulated blood pressure in rats. The larger peptides are vasodilators, as is intact AM, whereas intermediate fragments did not affect blood pressure. In contrast, AM(11-22) elicited vasoconstriction. Studies of AM receptor activation in Rat2 cells confirm that the larger AM cleavage peptides activated this receptor, whereas AM(11-22) did not. The present study defines a new mechanism through which MMP-2 may regulate blood pressure by simultaneously eliminating a vasodilator and generating a vasoconstrictor.

Topics: Adrenomedullin; Animals; Blood Pressure; Cell Line; Chemical Fractionation; Chromatography, High Pressure Liquid; Cyclic AMP; Fibroblasts; Humans; Hypertension; Hypotension; Male; Matrix Metalloproteinase 2; Peptide Fragments; Peptides; Rats; Rats, Inbred Lew; Receptors, Adrenomedullin; Receptors, Peptide; Substrate Specificity; Urine; Vasoconstrictor Agents; Vasodilator Agents

The peptides derived from post-translational processing of preproadrenomedullin are produced in and act on areas of the autonomic nervous system important for blood pressure regulation. We examined the role of endogenous, brain-derived adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in the central nervous system arm of the baroreflex by using passive immunoneutralization to block the actions of the endogenous peptides. Our results indicate that the preproadrenomedullin-derived peptides do not play a role in sensing changes in blood pressure (baroreflex sensitivity), but the adrenomedullin peptides do regulate the speed with which an animal returns to a normal, stable blood pressure. These findings suggest that endogenous, brain-derived AM and PAMP participate in the regulation of autonomic activity in response to baroreceptor activation and inactivation.

Topics: Adrenomedullin; Animals; Baroreflex; Blood Pressure; Hypertension; Hypotension; Male; Peptides; Phenylephrine; Rats; Rats, Sprague-Dawley; Systole; Triazenes

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are potent hypotensive peptides that are generated from the same precursor and expressed in a variety of mammalian tissues. The purpose of this study was to elucidate the distribution and endogenous molecular forms of AM and PAMP. To this end, we used new radioimmunoassays that recognize the ring structure of AM and the C-terminal region of PAMP to compare the distribution of AM and PAMP in porcine gastrointestinal tissues. Immunoreactive AM was abundant in the duodenum (0.334+/-0.132 fmol/mg) and ileum (0.439+/-0.235 fmol/mg), and ubiquitous in other gastrointestinal tissues. The duodenal and ileal concentrations of AM were about 4 to 14 times higher than those in other gastrointestinal tissues. Similarly, immunoreactive PAMP was abundant in the duodenum (0.577+/-0.417 fmol/mg) and ileum (1.575+/-1.445 fmol/mg) and ubiquitous in other gastrointestinal tissues. The concentrations of immunoreactive AM and PAMP were highest in the ileum. Characterization of these peptides in the ileum, using high-performance liquid chromatography, showed that they were authentic. Furthermore, the concentrations of immunoreactive AM and PAMP in the mucosa and submucosa of the ileum were significantly higher than those in whole ileum. These results suggest that AM and PAMP play physiological roles in the porcine small intestine.

Topics: Adrenomedullin; Animals; Digestive System; Humans; Hypotension; Nitrogen; Peptide Fragments; Peptides; Proteins; Radioimmunoassay; Swine

Adrenomedullin (ADM) is a novel peptide with actions which include reduction of arterial pressure and interaction with a number of hormone systems. In order to assess possible interactions with the renin-angiotensin system (RAS) and the hypothalamo-pituitary-adrenal (HPA) axis, we have examined neurohumoral responses to hypotensive haemorrhage (15 ml/kg over 15 min) with or without co-infusions of ADM (5.5 pmol/kg per min) in six non-pregnant and eight pregnant conscious sheep. Haemorrhage induced a greater decrease in arterial pressure, but a blunted increase in heart rate in pregnant sheep. There was no significant effect of ADM on haemodynamic responses to haemorrhage in either group. In non-pregnant sheep, haemorrhage-induced activation of both RAS and HPA was significantly augmented by ADM, as indicated by greater increases in plasma renin activity (P<0.01), angiotensin II (P<0.05) and arginine vasopressin (P<0.01). In contrast, ADM did not augment these responses to haemorrhage in pregnant sheep. Rather, plasma concentrations of aldosterone (P=0.039) and adrenocorticotrophic hormone (P=0.012) were decreased by ADM. In conclusion, ADM-induced augmentation of the RAS and HPA responses to hypotensive haemorrhage is abolished in the pregnant state.

Topics: Adrenocorticotropic Hormone; Adrenomedullin; Aldosterone; Angiotensin II; Animals; Arginine Vasopressin; Female; Hemorrhage; Hypotension; Hypothalamo-Hypophyseal System; Models, Animal; Peptides; Pituitary-Adrenal System; Pregnancy; Pregnancy Complications, Cardiovascular; Renin; Renin-Angiotensin System; Sheep; Vasodilator Agents

Sustained hypotension in end-stage renal disease patients is characterized, despite an overactivation of the sympathetic and renin-angiotensin systems, by decreased vascular resistance and a blunted vascular response to pressor stimuli. An increased production of one or more vasodilator substances might play a role in the reduced vascular resistance and response to pressor stimuli in these patients. We evaluated the possible role of an increased production of nitric oxide and/or adrenomedullin (ADM) in the pathophysiology of chronic hypotension in hemodialysis (HD) patients.. Three groups of hypotensive (N = 9), normotensive (N = 10), and hypertensive (N = 9) HD patients were included in the study. Plasma renin activity (PRA) and plasma levels of catecholamines, ADM, nitrite/nitrate (an estimator of nitric oxide production), tumor necrosis factor (TNF), and interleukin-1beta (IL-1beta) were measured. Plasma volume and left ventricular ejection fraction (LVEF) were also evaluated.. Plasma levels of nitrite/nitrate and ADM were elevated in HD patients with respect to the reference values in normal subjects. Plasma ADM levels, but not nitrite/nitrate levels, were higher in hypotensive (368.1 +/- 25.4 pg/mL) than normotensive (225 +/- 9.9 pg/mL) and hypertensive HD patients (278.2 +/- 15.5 pg/mL, P < 0.01). When considering hypotensive and normotensive patients together, the mean blood pressure inversely correlated with time on HD (r = -0. 53, P < 0.05) and plasma ADM levels (r = -0.78, P < 0.01).. Plasma ADM and nitrite/nitrate levels are increased in HD patients, but only ADM levels were higher in hypotensive than in normotensive and hypertensive HD patients. The higher plasma levels of this peptide in hypotensive patients and its inverse correlation with mean arterial pressure suggest that ADM may be involved in the pathophysiology of chronic hypotension in HD patients.

Topics: Adrenomedullin; Adult; Blood Pressure; Blood Volume; Female; Humans; Hypotension; Interleukin-1; Iodine Radioisotopes; Kidney Failure, Chronic; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Norepinephrine; Peptides; Renal Dialysis; Tumor Necrosis Factor-alpha; Vasodilation

Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. To determine the extent to which chronic AM overproduction affects circulatory physiology under normal and pathological conditions, we used a preproendothelin-1 promoter to establish transgenic mouse lines overexpressing AM in their vasculature.. Transgenic mice overexpressing AM mainly in vascular endothelial and smooth muscle cells exhibited significantly lower blood pressure (BP) and higher plasma cGMP levels than their wild-type littermates. Blockade of NO synthase with N(G)-monomethyl-L-arginine elevated BP to a greater degree in AM transgenic mice, offsetting the BP difference between the 2 groups. Despite their lower basal BP, administration of bacterial lipopolysaccharide elicited smaller declines in BP and less severe organ damage in AM transgenic mice than in wild-type mice. Furthermore, the 24-hour survival rate after induction of lipopolysaccharide shock was significantly higher in the transgenic mice.. A chronic increase in vascular AM production reduces BP at least in part via an NO-dependent pathway. In addition, smaller responses to LPS in transgenic mice suggest that AM is protective against the circulatory collapse, organ damage, and mortality characteristic of endotoxic shock.

Topics: Adrenomedullin; Animals; Blood Pressure; Blood Vessels; Disease Susceptibility; Endothelin-1; Endothelins; Hypotension; Lipopolysaccharides; Liver; Mice; Mice, Transgenic; Peptides; Protein Precursors; Shock

The possible involvement of adrenomedullin (ADM) in the endotoxin-induced hypotension has been investigated in the rat. Lipopolysaccharide (LPS, 500 micrograms/kg intraperitoneum) caused a severe decrease in the blood pressure (BP), reaching maximum 2-3 h after the injection and subsiding after 12 h. The putative ADM-receptor antagonist ADM(22-52) (3 nmol/kg) counteracted LPS-induced BP lowering at 1 and 2 h, and reversed it at 3 and 6 h. CGRP(8-37), a selective antagonist of the CGRP1 receptors, was ineffective. Both ADM(22-52) and CGRP(8-37) did not evoke significant changes in the basal BP. Our findings provide strong support to the view ADM overproduction plays a major role in the LPS-induced decrease in BP, and suggest a potentially important therapeutic effect of the blockade of ADM(22-52)-sensitive receptors during endotoxic shock.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Blood Pressure; Calcitonin Gene-Related Peptide; Endotoxins; Hypotension; In Vitro Techniques; Lipopolysaccharides; Male; Peptide Fragments; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Adrenomedullin; Receptors, Peptide

Topics: Acid-Base Imbalance; Adrenomedullin; Analysis of Variance; Animals; Blood Pressure; Cardiac Output; Central Venous Pressure; Dogs; Hypotension; Peptides; Random Allocation; Shock, Hemorrhagic; Time Factors; Vascular Resistance; Vasodilator Agents

Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide found in the N-terminal portion of the precursor of adrenomedullin (AM). Although PAMP and AM originate from the same precursor and exert both a potent hypotensive action, they seem to control blood pressure through different mechanisms. To gain new insight into the anticholinergic actions of PAMP, we determined the effects of PAMP on the tyrosine hydroxylase (TH)- and dopamine beta-hydroxylase (DBH) mRNA expression in the rat pheochromocytoma cell line PC12 stimulated by nicotine. PAMP (> or =1 microM) significantly inhibited the nicotine-induced increases of TH- and DBH mRNA expression in a concentration-dependent manner. Also, PAMP at the concentrations (> or =1 microM) significantly inhibited nicotine-induced cyclic adenosine monophosphate (cAMP) production. These results indicate that the anticholinergic hypotensive actions of PAMP can be explained, at least in part, by its inhibition of the expression of mRNAs coding for catecholamine-synthesizing enzymes, and that the inhibitory effect is mediated by the cAMP/protein kinase A pathway.

Topics: Adrenomedullin; Animals; Cyclic AMP; Dopamine beta-Hydroxylase; Hypotension; Nicotine; PC12 Cells; Peptide Fragments; Peptides; Proteins; Rats; RNA, Messenger; Tyrosine 3-Monooxygenase

The hypotensive effect of proadrenomedullin N-terminal 20 peptide (PAMP) was examined in conscious pregnant (8, 14, and 20 days of pregnancy) and nonpregnant rats. Intravenous administration of PAMP (3-60 nmol/kg) produced a dose-dependent depressor response in both pregnant and nonpregnant rats. However, the maximum decrease in blood pressure was significantly attenuated in pregnant rats in mid- and late-gestation (14 and 20 days), but not in early gestation (8 days), than in nonpregnant rats. In ovariectomized rats, the depressor responses in 17beta-estradiol (E2)-treated, progesterone (P)-treated, and E2+P-treated rats were significantly attenuated compared with the control rats. We also demonstrated that treatment of sex hormones reduces the depressor response to PAMP in 8-day pregnant rats. In addition, we showed that treatment of sex hormone receptor antagonists partially prevents the attenuation of the depressor response to PAMP in 20 day pregnant rats. These findings suggested that the hypotensive response to PAMP was more attenuated in pregnant rats in mid- and late-gestation than in nonpregnant rats, and that the changes in depressor response that occur at term in pregnant rats may be mediated by sex hormones. PAMP may play some important role in cardiovascular regulation during pregnancy.

Topics: Adrenomedullin; Animals; Blood Pressure; Dose-Response Relationship, Drug; Estradiol; Female; Hormone Antagonists; Hypotension; Mifepristone; Ovariectomy; Peptide Fragments; Peptides; Pregnancy; Pregnancy, Animal; Progesterone; Proteins; Rats; Rats, Wistar; Tamoxifen; Time Factors

Topics: Adrenomedullin; Animals; Blood Pressure; Consciousness; Hypotension; Male; Peptide Fragments; Peptides; Proteins; Rats; Rats, Wistar; Sympathetic Nervous System; Vasodilator Agents

1. The hypotensive effect of chronically infused human adrenomedullin (hAM), a potent vasodilator peptide that has been reported to have a natriuretic action, was examined in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Conscious WKY rats and SHR were infused with 200 ng/h synthetic hAM for 14 days by means of osmotic minipumps. Control groups were infused at the same schedule with 0.9% saline. Systolic blood pressure (SBP) and daily urinary excretion of Na+ and K+ were measured before and during the infusion period. In addition, plasma renin activity (PRA), aldosterone and hAM concentrations were measured on day 14 of infusion. 3. A significant reduction in SBP was observed in hAM-treated SHR at day 2 and SBP remained significantly lower throughout the experiment compared with control SHR. Similarly, SBP in the hAM-treated WKY rats was found to be significantly lower than in control WKY rats during infusion. However, the hypotensive effect was not accompanied by any significant increase in urinary volume or Na+ excretion in hAM-treated rats of either strain. Chronic infusion with hAM significantly suppressed PRA and lowered the concentration of plasma aldosterone in WKY rats but not in SHR. The plasma aldosterone in WKY rats and SHR were 0.9 +/- 0.4 and 0.6 +/- 0.2 fmol/mL, respectively. 4. These findings demonstrate that chronically infused hAM has a hypotensive effect in both WKY rats and SHR without an increase in urinary volume or Na+ excretion at a plasma AM concentration within the physiological limit.

Topics: Adrenomedullin; Aldosterone; Animals; Antihypertensive Agents; Humans; Hypotension; Infusion Pumps, Implantable; Infusions, Parenteral; Male; Peptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Renin-Angiotensin System; Vasodilator Agents

The heptadecapeptide nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein coupled receptor, ORL1. In the present study responses to intravenous administration of nociceptin were investigated in the systemic vascular bed of the rat. Nociceptin induced dose-related decreases in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. In terms of relative vasodepressor activity, nociceptin was approximately 10-fold more potent than the nitric oxide donor, DEA/NO, and 10-fold less potent than adrenomedullin. The duration of the vasodepressor response to nociceptin was shorter than adrenomedullin but longer than DEA/NO. These results show that nociceptin has significant vasodepressor activity in the rat.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Blood Pressure; Dose-Response Relationship, Drug; Female; Hydrazines; Hypotension; Ligands; Male; Molecular Sequence Data; Nitrogen Oxides; Nociceptin; Nociceptin Receptor; Opioid Peptides; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Vasoconstrictor Agents; Vasodilator Agents

Adrenomedullin (AM) inhibited the pressor action caused by transmural electrical stimulation in perfused isolated canine mesenteric arteries. The inhibitory potency of AM was greater than that of calcitonin gene-related peptide (CGRP) or proadrenomedullin NH2-terminal 20 peptide (PAMP). [8-37]CGRP did not affect the inhibitory action of AM, but suppressed the CGRP-induced inhibition. It may be concluded that AM has an ability to inhibit adrenergic neuronal transmission without the mediation of CGRP1 receptors in the peripheral vasculature, and this inhibition partly participates in the potent hypotensive action of AM.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Dogs; Electric Stimulation; Female; Hypotension; Male; Mesenteric Arteries; Miotics; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Peptide Fragments; Peptides; Proteins; Synaptic Transmission; Vasodilator Agents

Proadrenomedullin N-terminal 20 peptide (PAMP-20) is a potent hypotensive peptide processed from the adrenomedullin (AM) precursor. We developed a specific radioimmunoassay which recognizes the C-terminal region of PAMP-20. Using this radioimmunoassay, the distribution of immunoreactive (ir-) PAMP was determined in porcine tissues. High concentrations of ir-PAMP were observed in the adrenal medulla and in the atrium, and these values were comparable to the corresponding concentrations of ir-AM. The concentration of ir-PAMP was almost the same as that of ir-AM in the kidney, while ir-PAMP was significantly lower than ir-AM in the ventricle, lung, and aorta. Reversed-phase high performance liquid chromatography in each porcine tissue sample revealed that two major peaks of ir-PAMP existed: one emerged at a position identical to that of authentic porcine PAMP-20; the other unknown peak was eluted earlier. The unknown peptide was purified to homogeneity from porcine adrenal medulla, and its complete amino acid sequence was determined. This peptide was found to be PAMP[9-20] with a C-terminal amide structure, and was named PAMP-12. Intravenous injections of PAMP-12 in anesthetized rats showed a significant hypotensive effect in a dose-dependent fashion, and the effect was comparable to that of PAMP-20. These data indicate that PAMP-12, a major component of ir-PAMP, is processed from the AM precursor, as is PAMP-20, and may participate in cardiovascular control.

Topics: Adrenal Medulla; Adrenomedullin; Animals; Chromatography, High Pressure Liquid; Hypotension; Kidney; Lung; Myocardium; Peptide Fragments; Peptides; Proteins; Radioimmunoassay; Rats; Sequence Analysis; Swine; Vasodilator Agents

Proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM) are novel hypotensive peptides. Although they are derived from the same gene product, proadrenomedullin, their hypotensive mechanisms are different; PAMP inhibits the release of norepinephrine from the peripheral sympathetic nerve endings, whereas AM fosters vasodilation by elevating intracellular cAMP, possibly via activation of cholera toxin-sensitive G proteins. In PC12 cells, PAMP inhibited N-type calcium channel via activation of pertussis toxin-sensitive mechanisms. To clarify the relationship between the hypotensive effect of PAMP and pertussis toxin-sensitive mechanisms, we administered pertussis vaccine intraperitoneally into rats for 3 consecutive days. By using mesenteric artery preparation, we showed that PAMP's ability to decrease norepinephrine overflow was significantly attenuated in pertussis toxin-treated rat (-18.5 +/- 6.9%; P<.05 versus control rats). In electrically stimulated pithed rat, PAMP (20 and 40 nmol/kg) showed a hypotensive effect (-13 +/- 5 and -18 +/- 7 mm Hg, respectively; P<.05, P<.01), whereas in pertussis vaccine-treated rat it did not (-2 +/- 3 and -8 +/- 9 mm Hg, respectively; P=NS). Also, in pithed rat, plasma norepinephrine level was significantly elevated by electrical stimulation in both control (0.323 +/- 0.035 ng/mL) and pertussis vaccine-treated groups (0.355 +/- 0.079 ng/mL). After injection of PAMP (40 nmol/kg), plasma norepinephrine level significantly decreased in the control group (0.225 +/- 0.044 ng/mL; P<.01) but not in the pertussis vaccine-treated group (0.392 +/- 0.021 ng/mL; P=NS). Moreover, in conscious rats, intravenous administration of PAMP (40 nmol/kg) did not evoke hypotension after pertussis vaccine treatment, although untreated controls had significantly decreased arterial pressure (-5 +/- 2 versus -20 +/- 3 mm Hg; P<.01). In contrast to PAMP, the administration of AM (1 nmol/kg) significantly reduced the blood pressure of pertussis vaccine-treated as well as control rats (-20 +/- 5 versus -18 +/- 7 mm Hg; P=NS). These results demonstrate that the ability of PAMP to inhibit norepinephrine release from peripheral sympathetic nerve endings and to decrease blood pressure is pertussis toxin sensitive. Our findings thus suggest that despite being derived from the same gene, PAMP and AM apparently produce hypotension by activating different signaling pathways.

Topics: Adrenomedullin; Animals; Blood Pressure; Body Weight; Decerebrate State; Hypotension; Male; Nerve Endings; Norepinephrine; Peptide Fragments; Peptides; Pertussis Toxin; Proteins; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System; Vasodilator Agents; Virulence Factors, Bordetella

Adrenomedullin (ADM) is a potent vasoactive peptide. In this study, we explored the effects of a continuous supply of ADM by somatic gene delivery on spontaneously hypertensive rats (SHR). DNA constructs containing the human ADM cDNA fused to either the cytomegalovirus promoter (CMV-cADM) or Rous Sarcoma virus 3'-long terminal repeat (RSV-cADM) were intravenously injected into SHR through the tail vein. Expression of human ADM in SHR was identified in the kidney, adrenal gland, heart, and lung by radioimmunoassay and reverse transcription-polymerase chain reaction followed by Southern blot analysis. A single injection of ADM plasmid DNA in young adult SHR (7 wk old) caused a significant reduction in systolic blood pressure for up to 5 wk (p < 0.05). A second injection of CMV-cADM 5 wk after the first delivery resulted in a further reduction in blood pressure for another 3 wk (p < 0.001). A maximal blood pressure reduction of 22 mmHg in SHR was observed 7 wk after injection of CMV-cADM plasmid DNA (185 +/- 1.7 mmHg, n = 6, p < 0.001), and a reduction of 15 mmHg was observed after injection of RSV-cADM (192 +/- 2.7 mmHg, n = 6, p < 0.001), as compared with control rats given vector DNA (207 +/- 2.4 mmHg, n = 6). Similarly, injection of CMV-cADM plasmid DNA in adult SHR (10 wk old) resulted in a significant reduction in blood pressure for up to 6 wk. Antibodies to either human ADM or its plasmid DNA were not detected in rat sera after the second injection. These studies indicate that intravenous injection of the human ADM gene in hypertensive rats results in expression of the foreign gene and induces a long-lasting reduction in blood pressure.

Topics: Adrenomedullin; Animals; Antibody Formation; Avian Sarcoma Viruses; beta-Galactosidase; Blood Pressure; Cytomegalovirus; DNA, Complementary; DNA, Recombinant; Gene Expression; Genetic Therapy; Humans; Hypertension; Hypotension; Injections, Intravenous; Kidney; Lung; Peptides; Rats; Rats, Inbred SHR; RNA, Messenger; Spleen; Tissue Distribution; Transfection

The potent vasodilator peptide, adrenomedullin, has been shown to be present in plasma, suggesting a physiological role in cardiovascular control. Here we investigated the hypotensive action of adrenomedullin in vivo, using the anaesthetised rat as the bioassay model, and adrenomedullin binding sites using ligand binding assays on rat blood vessel membranes. Rat alpha CGRP and both human and rat adrenomedullins induced dose-dependent, powerful and long-lasting hypotensive effects. At peptide doses used in this study (0.02-2 nmol/kg), the efficacy of both human and rat adrenomedullins was lower than that of rat alpha CGRP. The CGRP1-receptor antagonist, human CGRP(8-37) (200 nmol/kg) was able to completely inhibit the hypotensive effect of rat alpha CGRP (0.2 nmol/kg) but not that of rat adrenomedullin (2 nmol/kg), implying that the adrenomedullin action is independent of CGRP1-receptors. Ligand binding assays confirmed the presence of both CGRP and adrenomedullin binding sites in rat blood vessels. The 125I-rat adrenomedullin binding site has a Kd = 0.32 +/- 0.12 nM (n = 4) for rat adrenomedullin but has a Ki > 10(-6) M for rat alpha CGRP. Chemical cross-linking and SDS-PAGE analysis revealed theadrenomedullin binding protein to have a M(r) of 83000 with a minor band of M(r) = 99000. The results suggest that the hypotensive effect of adrenomedullin may be mediated via specific adrenomedullin binding sites, in vivo.

Topics: Adrenomedullin; Animals; Binding Sites; Binding, Competitive; Blood Vessels; Calcitonin Gene-Related Peptide; Cross Reactions; Dose-Response Relationship, Drug; Female; Humans; Hypotension; Membrane Proteins; Peptide Fragments; Peptides; Rats; Rats, Wistar; Receptors, Adrenomedullin; Receptors, Peptide; Vasodilator Agents

1. Male, Long Evans rats were chronically instrumented with pulsed Doppler flow probes and intravascular catheters to permit assessment of the regional haemodynamic responses to human and rat adrenomedullin, to compare the responses to human adrenomedullin to those of human alpha-CGRP in the absence and presence of the CGRP1-receptor antagonist, human alpha-CGRP [8-37], and to determine the involvement of nitric oxide (NO)-mediated mechanisms in the responses to human adrenomedullin, relative to human alpha-CGRP. 2. Human and rat adrenomedullin (0.3, 1, and 3 nmol kg-1, i.v.) caused dose-dependent hypotension and tachycardia, accompanied by increases in renal, mesenteric and hindquarters flows and vascular conductances. At the lowest dose only, the hypotensive and mesenteric vasodilator effects of rat adrenomedullin were significantly greater than those of human adrenomedullin. 3. Human alpha-CGRP at a dose of 1 nmol kg-1 caused hypotension, tachycardia and increases in hindquarters flow and vascular conductance, but reduction in renal and mesenteric flows, and only transient vasodilatations in these vascular beds. These effects were substantially inhibited by human alpha-CGRP [8-37] (100 nmol kg-1 min-1), but those of human adrenomedullin (1 nmol kg-1) were not; indeed, the mesenteric haemodynamic effects of the latter peptide were enhanced by the CGRP1-receptor antagonist. 4. In the presence of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 183 nmol kg-1 min-1), there was only a slight, but significant, inhibition of the hindquarters hyperaemic vasodilator effect of human adrenomedullin, but not that of human alpha-CGRP. 5. These results indicate that the marked regional vasodilator effects of human (and rat) adrenomedullin are largely independent of NO and, in vivo, do not involve CGRP1-receptors.

Topics: Adrenomedullin; Angiotensin II; Animals; Antihypertensive Agents; Arginine; Blood Pressure; Calcitonin Gene-Related Peptide; Catheterization, Peripheral; Dose-Response Relationship, Drug; Heart Rate; Hemodynamics; Humans; Hypertension; Hypotension; Laser-Doppler Flowmetry; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptide Fragments; Peptides; Random Allocation; Rats; Regional Blood Flow; Renal Circulation; Tachycardia; Vasopressins

To investigate a possible pathophysiological role of human adrenomedullin (AM), we measured the plasma concentration of immunoreactive-AM (ir-AM) in 38 patients with end-stage renal disease (ESRD) on hemodialysis (HD) and 38 healthy subjects (age and sex matched). In addition, plasma ir-AM was characterized by a reverse-phase high performance liquid chromatography. The mean value (+/- SEM) of plasma AM in the patients before HD (10.1 +/- 0.67 fmol/ml) was markedly higher than that in the control group (2.9 +/- 0.13 fmol/ml, p < 0.001), but plasma AM levels were not altered by HD. There was a significant correlation between plasma AM levels and mean blood pressure (MBP) in a group of subjects including both patients before HD and healthy subjects (p < 0.01). In chromatographic study, the major peak of ir-AM in the plasma from patients on HD, as well as healthy subjects, emerged at an elution time identical to that of synthetic AM, indicating that the active form of AM was present in the circulating blood. The secretion of AM seemed to be increased in response to the conditions elicited by ESRD such as hypervolemia and/or hypertension, and reduced renal excretion of the peptide may also contribute to its high plasma level.

Topics: Adrenomedullin; Blood Pressure; Chromatography, High Pressure Liquid; Creatinine; Female; Humans; Hypertension, Renal; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Peptides; Renal Dialysis