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The Department of Medicine, The Christchurch School of Medicine, Christchurch 8001, New Zealand
Address all correspondence and requests for reprints to: Dr V. Cameron, Department of Medicine, The Christchurch School of Medicine, P.O. Box 4345, Christchurch 8001, New Zealand.
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The tissue distribution of these peptides varies somewhat in reports from various species. In human tissues, AM immunoreactivity (AM-IR) has been reported to be highest in adrenal medulla, with lower levels in cardiac atrium and pancreas (10). Messenger RNA (mRNA) for human (2) and porcine AM (3) detected by Northern blot has been reported in adrenal medulla, cardiac ventricle, kidney, and lung. However, in the rat, the order of intensity of expression by Northern blot is lung, adrenal gland, heart, kidney, and spleen, with weaker hybridization in duodenum and submandibular glands (4). No study of the cellular localization of AM expression in adult animals has been published to date, although a comprehensive study of expression and immunoreactivity of AM, PAMP, and AM receptor was performed in mouse and rat embryos (11). In that study, the tissues found to have the highest levels of AM expression were heart, arterial vasculature, spinal cord, dorsal root ganglia, skeletal muscle, chondrocytes, cartilage, osteoblasts, skin, intestine, and kidney metanephric duct derivatives.
To determine the tissue distribution and cellular localization of AM expression in adult tissues, we have performed an in situ hybridization study using two nonoverlapping probes to the PAMP peptide and AM peptide regions of mouse pro-AM, and a larger cDNA probe spanning both the PAMP- and AM peptide-coding regions. We report here the distribution of AM gene expression in adult mouse and rat peripheral tissues and pituitary gland.
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Materials and Methods |
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AM-A primer, 5'-CTTGGTGACACTAGACAG-3'
AM-D primer, 5'-CAGCATTGAGACAGTTATTG-3'
The amplified product was subcloned using the pCR-Script Amp SK+ kit (Stratagene, La Jolla, CA), and the full sequence was obtained by automated cycle sequencing using the ABC system (Perkin-Elmer, Foster City, CA). This clone extended from 610 bases upstream of the ATG start codon to the 3'-tail of the AM gene.
A probe of 172 bp spanning the region of the mature AM peptide, and subsequently referred to as the AM probe, was generated by PCR from mouse tail genomic DNA using the following primers:
AM-5'-primer, 5'-CAGCCCACATTCGAGTCAAA-3'
AM-3'-primer, 5'-ATAGCCTTGAGGGCTGATCT-3'
The sequence of this fragment was confirmed by cycle sequencing with radiolabeled chain termination using Thermosequenase (Amersham, Little Chalfont, UK). This probe spanned nucleotides 436–607 of the mouse cDNA. A second, nonoverlapping, 379-bp cDNA probe was generated, spanning the region of the gene that encodes the PAMP peptide (nucleotides 53–431 of the mouse cDNA). Because this region of the gene is interrupted by an intron, the PAMP probe was generated by RT-PCR of mRNA extracted from mouse kidney. Total mouse kidney RNA was prepared by Trizol extraction (GIBCO BRL, Gaithersburg, MD), RT was performed with Superscript II (GIBCO BRL) with an oligo-dt primer, and then PCR was done with the following primers:
AM-B primer, 5'-TCTCGGCTCCTCATCCG-3'
AM-C primer, 5'-TCTGATTGCTGGCTTGTAG-3'
The sequence of this fragment was confirmed by cycle sequencing as above. A third probe of 555 bp, referred to as the pro-AM probe, extended the combined cDNA length of the two former probes (nucleotides 53–607 of the mouse cDNA). The pro-AM probe was generated by RT-PCR from mouse kidney RNA using the primers AM-B and AM-3' given above.
To synthesize riboprobes from the PCR-generated templates, they were extended by PCR so that the 5'-ends of each strand encoded the T3 or T7 RNA polymerase promoter sequences (12, 13). This method of probe generation gives a stronger signal with a low background than in vitro transcription from cDNA cloned into a plasmid, because it eliminates hybridization of intervening plasmid sequences with ribosomal RNA. Briefly, a second round of PCR amplification was performed on each of the AM gene fragments above, with primers bearing 5'-extensions encoding the T3 and T7 RNA polymerase promoter sequences on the sense and antisense strands, respectively, as illustrated by the following primer set. The RNA polymerase promoter sequence is underlined, and the AM-specific sequence is in bold.
AM 5'(T3) primer,
5'-CAGAGATGCAATTAACCCTCACTAAAGGAGAATTC-CAGCCCACATTCGAGTCAAA-3'
AM 3' (T7) primer,
5'-CCAAGCTTCTAATACGACTCACTATAGGG-ATATCATAGCCTTGAGGGCTGATCT-3'
The PCR reaction used for generating T3/T7 extensions on the AM gene fragments was performed with the following PCR parameters: hot start 98 C, 5 min, 54 C, 1 min; (followed by addition of 1 U Taq polymerase); four cycles of 94 C for 1 min, 54 C for 2 min, 72 C for 3 min; followed by 36 cycles of 94 C for 1 min, 65 C for 1 min, 72 C for 3 min, concluding with a 10-min extension at 72 C. After amplification of each AM fragment, a single PCR product, approximately 70 bases larger than the original fragment, was visualized on a 0.75% agarose gel and confirmed by cycle sequencing. The procedure for in vitro transcription incorporating 35S-labeled cytidine triphosphate (CTP) has been described previously for riboprobe synthesis from plasmid DNA (14). The specific activities of the probes were approximately 1.0 x 108 dpm/µg.
In situ hybridization
Adult Swiss Random mice, BALB/c mice (three male and three
female of each strain), and Sprague-Dawley rats (five male and five
female) were deeply anesthetized with halothane, and tissues were fixed
by transcardiac perfusion with ice-cold saline followed by 4%
paraformaldehyde in 0.1 M borate buffer (pH 9.5). Tissues
were transferred to the same solution containing 10% sucrose as a
cryoprotectant 1 day before sectioning. The experimental protocol was
approved by the Animals Ethics Committee of the Christchurch School of
Medicine.
Tissues were frozen in blocks in O.C.T. Compound embedding medium (Miles Inc, Elkhart, IN). The hybridization protocol was performed on 20-µm cryostat sections following the methods of Simmons et al. (15). Hybridization was performed at 55 C overnight with 2 x 106 dpm/ml probe in 100 µl hybridization solution under coverslips. Posthybridization washes included an incubation in ribonuclease A (RNase A) (20 µg/ml) at 37 C for 30 min and a high-stringency wash of 0.1 x standard saline citrate (SSC) at 65 C. The slides were exposed to x-ray film (Hyperfilm-MP, Amersham) for 1 to 2 days and then dipped in NTB-2 nuclear track emulsion (Kodak, Rochester, NY). After 14–21 days exposure, the slides were developed and counterstained with hematoxylin and eosin. As a control, adjacent sections were hybridized with the respective sense probes complementary to each of the three AM probes. A further set of controls was performed by hybridizing adjacent sections with a 50-fold excess of unlabeled, cold pro-AM probe. The cold probe was synthesized by in vitro transcription as above, except that unlabeled ribonucleotides were incorporated, and was hybridized with the sections for 4 h before the usual amount of radiolabeled probe was added.
Northern blot analysis
Rat tissues were snap-frozen in liquid nitogen, and total RNA
was isolated using Trizol Reagent. Total RNA (10 µg) was separated by
electrophoresis on 1% agarose, 20 mM guanidine
isothiocyanate gels run in a 0.5x Tris-borate, 20 mM
guanidine isothiocyanate buffer (16). The RNA was transfered onto
Genescreen Plus nylon membrane (DuPont, Boston, MA) and cross-linked by
UV radiation. The blot was prehybridized for 3.5 h at 65 C in 10
ml prehybridization solution containing 5x Denhart’s solution, 10%
dextran sulfate, 1% SDS, 1 M NaCl, and 100 µg/ml herring
sperm DNA. The membrane was hybridized at 60 C overnight in the same
solution with the addition of 2 x 106 cpm/ml
-32P-labeled PAMP riboprobe, synthesized by in
vitro transcription as above but incorporating
[-32P] rCTP. The membrane was washed with increasing
stringency, terminating with four, 30-min washes at 46 C in 0.2 x SSC
and 0.1% SDS. The membrane was exposed to Biomax film (Kodak) for
21 h at -80 C.
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illustrate sections hybridized
with the pro-AM probe or its sense control.
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, A–D), this expression was extremely
intense and appeared to be uniformly distributed throughout the cells
of the medulla. In the rat, the overall density of grains was lower
(Fig. 1, E–H), and a slightly greater density of positive cells was
apparent adjacent to the medullary veins. Under high magnification,
very weak expression was apparent in the adrenal cortex (zona
reticularis and zona fasiculata) of both mouse and rat adrenals.
In the kidney, moderately strong AM mRNA expression was detected in the
cortex (Fig. 2). In the kidney cortex, AM
mRNA was located in the densely clustered cells of the glomerulus, and
to a lesser extent in the cells lining the walls of the cortical distal
tubules. Weak, diffuse AM expression was also observed over cells of
the cortical proximal tubules, so that the entire kidney cortex
exhibited widespread hybridization with the AM probes. There was,
however, an abrupt demarcation between kidney cortex and medulla, where
no AM expression was detected.
Expression of AM in reproductive tissues
The uterus displayed intense AM mRNA expression. In the mouse,
extremely high levels of AM message were observed in the endometrium
throughout the length of the uterine horn (Fig. 3). This was especially intense in the
columnar epithelial cells lining the uterus but was also strong in the
endometrial stromal cells. Although AM message was absent in the glands
of the endometrium, there was a concentration of positive cells in the
endometrium surrounding the glands. Isolated areas of AM expression
were also observed in clusters of cells in the smooth muscle of the
uterine wall. However, in the myometrium, AM expression was very much
less than in the endometrium, and there was an abrupt demarcation
between these layers.
Both mouse and rat ovary (Fig. 4) also
expressed AM mRNA to a moderate degree, particularly within the
degenerating corpora lutea. Low levels of message were detectable in
active and atresic follicles and in the ovarian stroma. In the testis
of the male (Fig. 5), no AM mRNA
expression was detectable in either mouse or rat.
Expression of AM in the pituitary gland
In the rat, there was notable expression of AM in the posterior
lobe of the pituitary (Fig. 6), located
particularly around the margins of the posterior lobe adjacent to the
pars intermedia. This AM expression was especially intense in the
posterior pituitaries of female rats. However, intensities of
expression in the posterior pituitary varied markedly among the
rats studied, suggesting that mRNA was up-regulated in certain
individuals, possibly with stage of the estrous cycle, which was not
identified. A lower level of expression was detected in the anterior
lobe of the rat pituitary gland than in the posterior lobe. In the
mouse, there was modest expression of AM, which was equivalent in
anterior and posterior lobes.
Expression of AM in the lung
In the lung, cells expressing AM mRNA were observed around the
lining of the bronchioles (Fig. 7, A–D).
This expression was located in the simple ciliated columnar epithelial
cells lining the airways. There was also a low level of message
expression throughout the lung parenchyma, located around the walls of
the pulmonary alveoli.
Expression of AM in the heart
Both mouse and rat hearts displayed a low level of message
throughout the myocardium (Fig. 7, E and F). No marked regional
differences in AM expression were apparent within the heart but,
rather, expression tended to be relatively uniform across both atrium
and ventricle.
Expression of AM in gastrointestinal tract
Moderate levels of expression were observed in the stomach and
small intestine in both mice (Fig. 8, A
and B) and rats (Fig. 8, C–F). This expression was located in the
mucosa and submucosa but not in the muscularis or serosa. In the small
intestine, the microvilli on the surface of the plicae circulares
expressed AM mRNA strongly, in addition to diffuse expression in the
mucosa and submucosa. Sections from the colon were examined, but
expression at sites distal to the small intestine were extremely
weak.
Other tissues
Moderate expression was detected in the spleen (Fig. 8, G and H),
with occasional positive cells scattered through the red pulp,
especially adjacent to the margins of the periarteriolar lymphoid
sheaths (white pulp). Within the white pulp itself, frequent isolated
cells positive for AM mRNA were observed toward the periphery of the
periarteriolar lymphoid sheath. In the pancreas (Fig. 8, I and J), a
very low density of expression was detected evenly distributed
throughout the lobules, with a slightly higher density clustered around
the pancreatic ducts and outer margins of the islets. Weak AM mRNA was
detected in the submandibular gland. This was diffusely distributed
across the lobules, around the excretory ducts, and along the
connective tissue septa. No detectable expression was seen in the
thymus, skeletal muscle, or liver.
Differences between mouse and rat tissues
Although the distribution of expression seen in rats was similar
to that in mice, there were subtle differences between the two species.
Although in the rat, strong AM expression was observed in adrenal
medulla and uterus, in these organs, levels were less intense in the
rat compared with the mouse when sections from both species were
processed in tandem and hybridized in the same batch. In contrast,
expression of AM in the posterior lobe of the rat pituitary was
stronger, especially in female rats, than in any of the mice
studied.
Northern blot
A Northern blot of total RNA isolated from rat tissues selected
for their expression of AM was hybridized with the PAMP probe (Fig. 9). The autoradiograph displayed a single
transcript in all tissues of the expected size of approximately 1.6 kb.
The strongest hybridization was observed with RNA extracted from kidney
cortex, uterus, and ovary. The ethidium bromide photograph indicated
that RNA loading of samples was even in all lanes.
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The present findings confirm a previous report of AM expression in selected rat tissues by RNA Northern blotting (4). In that paper, AM expression appeared to be strongest in lung, followed by adrenal glands, heart, spleen, kidney, duodenum, and submandibular glands. There appeared to be weak expression in liver and brain but no detectable expression in pancreas or testis. This order of intensity of expression is similar to that found in the current study, considering that uterus, ovary, and pituitary were not examined in the paper by Sakata et al. The expression of AM detected in rat lung in the Northern blot appeared to be stronger than in the adrenal glands (presumably medulla and cortex combined). Likewise, we found that AM expression in the adrenal medulla of the rat is only moderate compared with mouse adrenal.
The relative intensities of AM mRNA in rat and mouse tissues reported here and by Sakata and co-workers are rather different from those in human or porcine tissues. In a paper reporting Northern blotting of human AM (2), the AM mRNA transcript was detected most strongly in pheochromocytoma tissue, followed by adrenal medulla, cardiac ventricle, and lung, with weaker expression in kidney and a very faint signal in pancreas. Other tissues examined but found to be negative include brain, liver, intestine, and spleen. In Northern blots of porcine tissues (3), the strongest signal was seen in adrenal medulla, followed by lung and kidney, with weak expression in intestine, spleen, and thyroid. Together, these results indicate that there are marked differences in the pattern of AM gene expression between species.
In the adrenal medulla, the tissue from which AM was first isolated (1), intense AM mRNA was observed in the mouse. However, in the rat adrenal medulla, AM expression levels were lower than those of several other tissues, including uterus, ovary, and pituitary. In the adrenal, AM appears to be stored and cosecreted with catecholamines (17), and it has been proposed that PAMP has a role in inhibition of catecholamine secretion (18). In addition, AM has been reported to inhibit the secretion of aldosterone via CGRP receptors in cultured human adrenocortical cells (19). Expression of AM receptor mRNA has also been detected in tissue extracts of rat adrenal capsule and whole adrenal gland by Northern blotting (20).
In mice, the strongest site of AM mRNA expression was the uterus. AM-IR and mRNA have been previously reported in rat uteri by Upton et al. (21), with levels of AM mRNA being increased (1.8-fold) in uterus from 20-day pregnant rats compared with nonpregnant uterus. The density of AM receptor-binding sites, but not AM receptor mRNA, was also increased (10-fold) in pregnant uterus. Furthermore, administration of human AM to isolated rat uterine horns significantly reduced uterine contraction induced by galanin, possibly mediated by CGRP receptors. It is of interest that AM mRNA is chiefly located in the endometrium, whereas the only reported biological effect in the uterus is relaxation of the myometrium, suggesting that AM might act in a paracrine manner in the uterus.
In the present study, high levels of AM mRNA were identified in rat posterior pituitary, especially from female rats. Levels of AM expression from individual females varied considerably, possibly due to hormonal changes during the estrous cycle, which were not determined before these rats were killed. While previous studies have observed AM-IR or mRNA in the pituitary gland (22), none have noted expression in the female posterior lobe. In other studies the gender of the subjects was not reported. Very low expression of the AM receptor has also been reported in the rat pituitary (20). It is possible that AM in posterior pituitary may have a neuroendocrine role, as AM has also been detected in hypothalamus. AM-IR has been identified in the paraventricular and supraoptic nuclei of both human (23) and rat (24) hypothalamus. In the rat, dual immunostaining colocalized AM with both oxytocin and vasopressin in various hypothalamic nuclei. As AM has been shown to inhibit drinking (25) and salt appetite in rats (26), there may be a link between AM and volume regulation via vasopressin. Alternatively, since AM is strongly expressed in uterus, especially in pregnancy (21), reproductive actions of AM may be functionally related to oxytocin. In addition, AM has been shown to inhibit both basal and CRF-stimulated ACTH release from dispersed anterior pituitary cells (27). Overall, the current results, together with past findings, suggest that AM may have neuroendocrine roles in both the anterior and posterior lobes of the pituitary in rodents.
Strong expression of AM mRNA was also observed in the lung. This is consistent with the finding that AM is a powerful bronchodilator of the guinea pig lung (28). However, in the current study, AM mRNA was concentrated particularly in the epithelial cells lining the bronchioles and in the alveoli. Although this distribution does not exclude a paracrine action of AM on bronchiolar smooth muscle, it suggests that AM may have additional functions in lung, such as antimicrobial actions (29). AM receptor expression (20) and AM-binding sites (16) are stronger in the lung than any other tissue, and the binding is specific for AM since it is not displaced by CGRP. This suggests that the lung could be a principal target for the biological actions of AM.
The current finding of AM expression in rat and mouse heart is consistent with previous reports of AM mRNA (4) and AM-IR (30) in rat hearts, as well as in human hearts (10, 31). Concentrations of AM-IR are reportedly increased in failing human ventricles (31), possibly contributing the increased circulating levels of AM in congestive heart failure (32, 33) and hypertensive patients (34). Levels of AM mRNA in rat heart have been demonstrated to increase with acute pressure overload (35), and AM mRNA and AM-IR were raised in the hearts of Dahl salt-sensitive hypertensive rats fed a high-salt diet (36). Therefore, cardiac expression of AM mRNA appears to be related to blood pressure, sodium status, and hypertension.
Actions of AM on the heart include raised cardiac output and heart rate (6, 37) after administration of AM to conscious sheep in vivo. A direct inotropic effect of AM was also observed in isolated, perfused rat hearts (38). However, the synthesis of AM within the vasculature itself may prove to be of greater importance to the cardiovascular actions of AM than its production by the heart. AM is very strongly expressed in endothelial cells (39) and in vascular smooth muscle cells (40) and has been found to be a potent vasodilator (41).
Expression of AM was also detected in the kidney cortex, in cells of the glomeruli, and in scattered cells of the cortical distal and proximal tubules. It was not possible to resolve expression within the glomeruli to mesangial cells or endothelial cells of the capillaries. A previous study has shown AM-IR in glomeruli, cortical distal tubules, and medullary collecting ducts (42). AM expression was not detected in the kidney medulla in the present study. Binding sites for AM have previously been identified in cultured rat mesangial cells (43). AM has a number of renal effects, including renal vasodilation (44), diuresis, natriuresis (42), and stimulation of renin release (45).
AM mRNA was also identified in the gastrointestinal tract. Cells expressing AM were detected in both mouse and rat stomach and small intestine. A previous study demonstrated AM-IR throughout the gastrointestinal tract, colocalized to serotonin-containing, enterochromaffin cells (46). The current study found a different distribution of AM mRNA, with the greatest intensity of expression tending to be on the surface microvilli. Further research will be needed to resolve this discrepancy.
The only previous in situ study to examine AM expression was performed in mouse and rat embryos (11). Montuenga and co-workers also detected AM in the pregnant uterus, as well as in the placenta (maternal decidua) and yolk sac. In the embryo, the highest levels of AM mRNA and AM-IR were found in the heart, with expression also in arterial vasculature, Rathke’s pouch and developing anterior pituitary, spinal cord, dorsal root ganglia, skeletal muscle, chondrocytes, cartilage, osteoblasts, skin, intestine, and kidney metanephric duct derivatives. There are clear similarities between the distribution of AM expression in adult mouse and rat reported here and that in embryos from as early as day 8 of development.
To determine the biological functions of AM in these tissues, further information about the localization and forms of AM receptors is essential. At present, a single AM receptor (20) has been cloned and identified as a member of the seven-transmembrane, G protein-linked receptor superfamily. Using Northern blots, expression of this receptor was shown to be strongest in the rat lung, followed by the adrenal and the ovary. Other tissues also expressing AM receptor mRNA include the heart, spleen, adrenal capsule, cerebellum, and cerebral cortex, but receptor mRNA was not detected in the uterus in that study. However, Upton et al. (21) detected AM binding in rat uterus and mRNA for the AM receptor cloned by Kapas. Thus there is a relatively good match between the sites of AM expression and this AM receptor. However, evidence for the existence of further AM receptors has recently been reported (47). Others have demonstrated putative AM-binding sites in rat heart, lung, spleen, liver, soleus, diaphram, gastrocnemius, and spinal cord membranes (16). However, in many tissues, binding of AM is displaced by CGRP, indicating that AM cross-reacts with CGRP receptors. Specific binding sites for PAMP, a second translated product of the AM gene, have also been demonstrated in aorta and adrenal glands and at lower levels in other tissues (48). Until the entire family of AM receptors has been described, only tentative conclusions can be made about the tissue-specific actions of AM.
In summary, this study of the cellular localization of AM mRNA in mice and rats has confirmed that there are marked differences in the pattern of AM gene expression between different species. The findings of AM expression in uterus and ovary indicate that AM may have a formerly unrecognized role in reproductive function, possibly linked to its expression in female posterior pituitary. The finding of AM in vasculature, lung, and uterus is consistent with reported vasorelaxation, bronchodilation, and relaxation of uterine muscle by AM. It would appear that AM may have a role in relaxation of smooth muscle in several organ systems, possibly also including the gut. However, AM mRNA tends not to be located in smooth muscle in these tissues, but is located in cells lining the uterus, airways, and gastrointestinal tract. This may be related to the recent finding of antimicrobial activity by AM. Overall, the study suggests a need to revise the earlier classification of AM as a cardiovascular hypotensive hormone; AM may in fact have multiple endocrine roles.
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Acknowledgments |
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Footnotes |
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Received October 3, 1997.
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 S Kaufman, P Andrew, R Sultanian, and Y Deng Adrenomedullin increases fluid extravasation from the splenic circulation of the rat J. Physiol., July 15, 2001; 534(2): 527 - 533. [Abstract] [Full Text] [PDF]
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L.L. Nikitenko, N.S. Brown, D.M. Smith, I.Z. MacKenzie, R. Bicknell, and M.C.P. Rees Differential and cell-specific expression of calcitonin receptor-like receptor and receptor activity modifying proteins in the human uterus Mol. Hum. Reprod., July 1, 2001; 7(7): 655 - 664. [Abstract] [Full Text] [PDF]
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D. Naot, K. E. Callon, A. Grey, G. J. S. Cooper, I. R. Reid, and J. Cornish A Potential Role for Adrenomedullin as a Local Regulator of Bone Growth Endocrinology, May 1, 2001; 142(5): 1849 - 1857. [Abstract] [Full Text]
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V. Santiemma, F. Rossi, L. Guerrini, A. Markouizou, G. Pasimeni, S. Palleschi, and A. Fabbrini Adrenomedullin Inhibits the Contraction of Cultured Rat Testicular Peritubular Myoid Cells Induced by Endothelin-1 Biol Reprod, February 1, 2001; 64(2): 619 - 624. [Abstract] [Full Text]
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 R. W. Troughton, L. K. Lewis, T. G. Yandle, A. M. Richards, and M. G. Nicholls Hemodynamic, Hormone, and Urinary Effects of Adrenomedullin Infusion in Essential Hypertension Hypertension, October 1, 2000; 36(4): 588 - 593. [Abstract] [Full Text] [PDF]
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L.L. Nikitenko, I.Z. MacKenzie, M.C.P. Rees, and R. Bicknell Adrenomedullin is an autocrine regulator of endothelial growth in human endometrium Mol. Hum. Reprod., September 1, 2000; 6(9): 811 - 819. [Abstract] [Full Text] [PDF]
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 J. P. Hinson, S. Kapas, and D. M. Smith Adrenomedullin, a Multifunctional Regulatory Peptide Endocr. Rev., April 1, 2000; 21(2): 138 - 167. [Abstract] [Full Text]
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 M. Jougasaki and J. C. Burnett Jr Adrenomedullin as a renal regulator peptide Nephrol. Dial. Transplant., March 1, 2000; 15(3): 293 - 295. [Full Text] [PDF]
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 J. G. Lainchbury, R. W. Troughton, L. K. Lewis, T. G. Yandle, A. M. Richards, and M. G. Nicholls Hemodynamic, Hormonal, and Renal Effects of Short-Term Adrenomedullin Infusion in Healthy Volunteers J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1016 - 1020. [Abstract] [Full Text]
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