(Hypertension. 1996;27:663-667.)
© 1996 American Heart Association, Inc.
Articles |
Interaction of Adrenomedullin and Platelet-Derived Growth Factor on Rat Mesangial Cell Production of Endothelin
From the First Department of Internal Medicine, Osaka City (Japan) University Medical School.
Correspondence to Masakazu Kohno, MD, Division of Hypertension and Atherosclerosis, First Department of Internal Medicine, Osaka City University Medical School, 1-5-7 Asahi-machi, Abeno-ku, Osaka 545, Japan.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Abstract Adrenomedullin has recently been isolated from human pheochromocytoma. We designed the present study to examine the effect of adrenomedullin on the production of the vasoconstrictive and growth-promoting peptide endothelin-1 (ET-1) after stimulation with platelet-derived growth factor (PDGF) in cultured rat glomerular mesangial cells. PDGF stimulated ET-1 production in a concentration-dependent manner. Rat adrenomedullin inhibited this stimulated ET-1 production in a concentration-dependent manner between 10-7 and 10-8 mol/L. Rat adrenomedullin also increased the cellular level of cAMP in a concentration-dependent manner between 10-7 and 10-8 mol/L. Human adrenomedullin was less effective than rat adrenomedullin with respect to inhibiting ET-1 production and increasing cAMP levels. The addition of 8-bromo-cAMP (10-3 and 10-4 mol/L) reduced PDGF-induced ET-1 production. Furthermore, forskolin (10-4 and 10-5 mol/L), an activator of adenylate cyclase, reduced PDGF-induced ET-1 production. In contrast, the basal production of ET-1 was not significantly altered by rat and human adrenomedullin. These results indicate that adrenomedullin inhibits PDGF-induced ET-1 production in cultured rat mesangial cells, probably through a cAMP-dependent process.
Key Words: adrenomedullin • endothelin • platelet-derived growth factor • mesangium, glomerular • peptides
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
A vasorelaxant peptide, adrenomedullin, has recently been isolated from the acid extract of human pheochromocytoma.1 This peptide, consisting of 52 amino acids, has one intracellular disulfide bond and shows homology with calcitonin gene–related peptide.1 It has been reported that intravenous injection of adrenomedullin causes a long-lasting hypotensive effect in anesthetized rats and this peptide binds to specific receptors on platelet membranes to increase intracellular cAMP.1 Recently, Ishizaka et al2 and Eguchi et al3 demonstrated that adrenomedullin stimulates cAMP formation in rat vascular smooth muscle cells via its specific receptor. Subsequently, we4 showed that adrenomedullin stimulates cAMP formation in rat glomerular mesangial cells as well as rat vascular smooth muscle cells. However, it is still unclear whether adrenomedullin has other biological actions.
Endothelin-1 (ET-1) is a vasoconstrictive and growth-promoting peptide of 21 amino acids that was first isolated from porcine vascular endothelial cells5 and is proposed to function in vivo as a paracrine regulator of adjacent vascular smooth muscle cells.6 This peptide also has been shown to bind to its specific receptors7 in glomerular mesangial cells and induce the contraction and proliferation of these cells.8 9 Furthermore, previous studies demonstrated constitutive expression of ET-1 transcript and peptide secretion in cultured glomerular mesangial cells.10 11 12 13 14 This ET-1 production by mesangial cells is increased by a potent mitogen, platelet-derived growth factor (PDGF).15 16
We examined the effect of rat adrenomedullin on basal or PDGF-induced ET-1 production in cultured rat mesangial cells. In addition, we also examined in these cells the effect of human adrenomedullin-(1-52), the major circulating form of adrenomedullin in humans,17 on ET-1 production.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Materials
Angiotensin II, arginine vasopressin, PDGF, and 3-isobutyl-1-methylxanthine (IBMX) were purchased from Sigma Chemical Co. Rat and human adrenomedullin, ET-1, ET-2, ET-3, and big ET-1 [porcine-(1-39)] were purchased from Peptide Institute. RPMI-1640, trypsin, Versine, and fetal calf serum were purchased from GIBCO Laboratories. Flasks were purchased from Becton Dickinson. The cAMP assay kit was purchased from Yamasa Shoyu. ET-1 antiserum was purchased from Peninsula Laboratories, Inc. 125I–ET-1 was purchased from Amersham Japan, Inc.
Mesangial Cell Cultures
Glomeruli were isolated from
Sprague-Dawley rats
weighing 50 to 100 g by sieving with stainless steel and nylon meshes
under sterile conditions as previously reported.13 14
The
isolated glomeruli were then cultured in RPMI-1640 medium containing
20% fetal calf serum and antibiotics. The identity of the
mesangial cells was confirmed by the following criteria:
(1) morphology; (2) typical microfilaments seen by transmission
electron microscopy; (3) survival in a medium containing
D-valine substituted for L-valine, indicating
the existence of D–amino acid oxidase; (4) resistance to
puromycin aminonucleoside (10-2 g/L) but
susceptibility to mitomycin C (10-2 g/L);
(5) presence of receptors specific to angiotensin II and
contraction in response to angiotensin II; and (6) absence
of immunofluorescence with factor VIII antibody.
The cultures were maintained at 37°C with atmospheric air and 5%
CO2, and subculture was carried out after treatment
with Versene followed by trypsin. Cells from passages 3 to 7 were used
for the experiment. Before the experiment, mesangial cells
were rendered quiescent by maintaining the cells in the medium
containing 0.5% fetal calf serum for 24 hours. Six-well culture
dishes (Becton Dickinson) were used for the experiment. Six culture
wells per experiment were used except for the cAMP experiment, which
was performed with four culture wells per experiment.
Pharmacological Treatment
The culture medium was removed, and
the cell monolayers were
washed twice with serum-free RPMI-1640.
In protocol 1, we examined the effect of PDGF on ET-1 production. Cells were exposed to different concentrations of PDGF (5x10-7 and 5x10-6 g/L) for 12, 24, and 48 hours.
In protocol 2, we examined the effects of adrenomedullin on basal or PDGF-induced ET-1 production. Cells were exposed to different concentrations (10-9, 10-8, and 10-7 mol/L) of rat or human adrenomedullin with or without 5x10-6 g/L PDGF for 24 hours. Adrenomedullin and PDGF were added to the medium at the same time. In this protocol, we also examined the effect of adrenomedullin on the cellular cAMP level in cells treated with PDGF. Cells were exposed to different concentrations (10-9, 10-8, and 10-7 mol/L) of rat and human adrenomedullin in addition to 5x10-6 g/L PDGF for 30 minutes in the presence of 5x10-1 mmol/L IBMX.
In protocol 3, we examined the effects of 8-bromo-cAMP and forskolin on ET-1 production. Cells were exposed to 8-bromo-cAMP or forskolin in addition to 5x10-6 g/L PDGF for 24 hours. All experiments were performed with 2x10-3 L RPMI-1640 under quiescent (0.5% fetal calf serum) conditions. After incubation, the medium was aspirated and centrifuged at 3000g for 10 minutes, and the supernatant was collected and stored at -80°C for a few weeks until radioimmunoassay.
Measurement of ET-1
ET-1 was extracted as previously
described.18
Briefly, 1.5x10-3 L from each sample was
diluted with 4x10-3 L of 4% acetic
acid. After centrifugation, the solution was pumped at
the rate of 10-3/min through a
Sep-Pak C18 cartridge (Millipore Associates). After evaporation of the
eluate with 86% ethanol in 4% acetic acid by a centrifugal evaporator
(model RD-31, Yamato Scientific), the dry residue was dissolved in the
assay buffer described below. The recovery rate was calculated by the
addition of three different quantities of cold ET-1 (10, 50, and 100
pg/mL) (10 pg/mL=4 pmol/L) to serum-free medium. The recovery was
71±2%.
ET-1 concentration was assayed with ET-1 antiserum and 125I–ET-1 as a tracer. This antibody reacts 100% with ET-1 and cross-reacts 7% with ET-2, 7% with ET-3, and 35% with big ET-1 [porcine-(1-39)]. The antiserum did not cross-react with rat adrenomedullin, human adrenomedullin, somatostatin, ß-endorphin, human secretin, thrombin, or PDGF.
Radioimmunoassay was performed in an assay buffer of 10-2 mol/L sodium phosphate, pH 7.4, containing 5x10-2 mol/L NaCl, 0.1% bovine serum albumin, 0.1% Nonidet P-40, and 0.01% NaN3, as described previously.18 In brief, rehydrated antiserum (10-4 L) was added to 10-4 L of the sample or 10-4 L of standard ET-1 dissolved in the assay buffer, and the mixture was incubated for 24 hours at 4°C. Approximately 15 000 cpm of 125I–ET-1 was added to each reaction and incubated for an additional 24 hours. After this incubation, the precipitate was collected by centrifugation at 1700g for 30 minutes. The supernatant was removed by aspiration, and the pellet was counted for 125I with a gamma counter. The interassay variation was 13%, and the intra-assay variation was 7%.
Rat and human adrenomedullin did not interfere with the radioimmunoassay.
cAMP Measurement
After preincubation, cell monolayers were
washed twice with
serum-free medium and then stimulated for 30 minutes with various
concentrations (10-9,
10-8, and
10-7 mol/L) of rat or human
adrenomedullin dissolved in medium that contained
5x10-1 mmol/L IBMX. The reaction was
stopped by rapid aspiration and the addition of
2x10-3 L ice-cold 65% ethanol, as
previously described.4 18 After evaporation with a
centrifugal evaporator, the dry residue was dissolved in an assay
buffer. cAMP levels were determined by radioimmunoassay performed with
a cAMP kit.
Calculations and Statistical Analysis
The statistical
significance of differences in the results was
evaluated by one-way ANOVA, and P values were obtained
by Scheffé's method.19 Values are expressed as
mean±SD.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Effect of PDGF on ET-1 Production (Protocol 1)
In confluent, quiescent, cultured mesangial cells, PDGF stimulated ET-1 production in a time-dependent manner (Table 1
). The stimulatory effects of PDGF were
concentration dependent. A steady baseline production of ET-1
was apparent in nonstimulated quiescent mesangial cells and
was maintained for 48 hours.
|
Effect of Adrenomedullin on Basal or PDGF-Induced ET-1
Production (Protocol 2)
Rat and human adrenomedullin
(10-9
to 10-7 mol/L) had no significant effect
on basal ET-1 production compared with control levels (Table
2). Rat adrenomedullin inhibited PDGF
(5x10-6 g/L)–induced ET-1
production in a concentration-dependent manner between
10-8 and
10-7 mol/L (Fig 1A). Rat
adrenomedullin (10-9 mol/L) did not
significantly alter PDGF-induced ET-1 production. On the other
hand, rat adrenomedullin increased the cellular level of cAMP in a
concentration-dependent manner between
10-8 and
10-7 mol/L (Fig 2). Human
adrenomedullin appeared to be less effective than rat adrenomedullin
with respect to inhibiting ET-1 production and increasing cAMP
levels (Figs 1B and 2).
|
|
|
Effect of 8-Bromo-cAMP and Forskolin on ET-1 Production
(Protocol 3)
To determine whether the inhibiting effects of rat and
human
adrenomedullin on ET-1 production after stimulation with PDGF
are causally linked to the increase in cellular cAMP, we examined the
effect of a cAMP analogue, 8-bromo-cAMP, and an
activator of adenylate cyclase, forskolin, on
ET-1 production in cells treated with PDGF. The addition of
8-bromo-cAMP reduced PDGF-induced ET-1 production (Fig 3). This
inhibition was concentration dependent between
10-4 and
10-3 mol/L. The addition of forskolin
also reduced PDGF-induced ET-1 production in a
concentration-dependent manner between
10-5 and
10-4 mol/L (Fig 4).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
We have confirmed previous reports10 11 12 13 14 15 16 that cultured mesangial cells produce a potent vasoconstrictive and growth-promoting peptide, ET-1, in a time-dependent manner and that PDGF stimulates this production in these cells. The degree of ET-1 stimulation by PDGF in cultured mesangial cells was not so strong.18 However, it is important to note that ET-1 potentiates even at low concentration the vasoconstrictive or mitogenic action of vasoconstrictors or growth factors such as norepinephrine20 21 or PDGF.16 22 Therefore, ET-1 produced by mesangial cells may play some roles under certain pathological conditions.
Adrenomedullin is a novel peptide recently isolated from
pheochromocytoma1 23 that elicits vasorelaxant and
long-lasting depressor activity.1 This peptide has
been shown to be present not only in human adrenal medulla but also
in circulating blood.24 In the present study, we
showed for the first time that both rat and human adrenomedullin
significantly inhibited ET-1 production stimulated by PDGF in
cultured rat mesangial cells. Under the current
experimental conditions, pharmacological doses of adrenomedullin were
necessary to achieve these results compared with plasma adrenomedullin
concentrations.17 24 However, plasma adrenomedullin
concentrations are found to be high in hypertensive
patients17 25 (5.6±2.0 pmol/L
[n=45] compared with
3.0±0.3 pmol/L in normotensive subjects [n=30]).
Furthermore, local
adrenomedullin levels in the glomerulus may be higher than the plasma
adrenomedullin concentration because adrenomedullin recently has been
shown to be synthesized in and secreted from vascular
endothelial and smooth muscle cells.26
Recently, Hirata et al27 demonstrated that
adrenomedullin increases glomerular filtration rate
and urinary sodium excretion and markedly decreases renal vascular
resistance in rats. In the same study, their videomicroscopic
analysis revealed that adrenomedullin increases the diameters
of both afferent and efferent arterioles of the glomeruli. These
observations suggest two possibilities: (1) Adrenomedullin may modulate
normal renal function through the inhibition of PDGF-induced ET-1
production in these cells and (2) adrenomedullin may regulate
mesangial cell production of ET-1 in certain
pathological conditions, for example, when the coagulation cascade is
activated in the kidney. During blood clotting in the
glomerulus, PDGF is released from the 
-granules of
platelets, and released PDGF stimulates ET-1 production in
mesangial cells. In such a condition, adrenomedullin may
inhibit PDGF-induced ET-1 production.
We have obtained evidence for the involvement of the adenylate cyclase system in the mechanism of adrenomedullin inhibition of ET-1 production. First, adrenomedullin increased cAMP levels and inhibited PDGF-induced ET-1 production. Second, a cAMP analogue reduced PDGF-stimulated ET-1 production. Third, forskolin, a potent activator of adenylate cyclase, reduced PDGF-induced ET-1 production. These results suggest that adrenomedullin inhibits PDGF-stimulated ET-1 production in cultured rat mesangial cells, probably through a cAMP-dependent process. Sakamoto et al15 have demonstrated that fetal calf serum–stimulated ET-1 production can be inhibited by either an increase in intracellular cAMP or the administration of exogenous cAMP in cultured rat mesangial cells. However, not only pharmacological doses of adrenomedullin but also suprapharmacological doses of 8-bromo-cAMP and forskolin were required to inhibit the PDGF effect on ET-1 production. Therefore, the physiological significance of this inhibition by adrenomedullin remains to be clarified at this time.
The basal production of ET-1 was not significantly altered by rat and human adrenomedullin. Therefore, spontaneous production of ET-1 by mesangial cells appears to be insensitive to modulation by adrenomedullin.
In summary, the present findings suggest that adrenomedullin reduces the PDGF-induced release of ET-1, probably through a cAMP-dependent process. Taken together with the profound effects of ET-1 on the contraction and proliferation of glomerular mesangial cells, these findings suggest that adrenomedullin may modulate glomerular function in part through reducing the PDGF-induced production of ET-1 in these cells when the coagulation cascade is activated in the kidney. Recently, Chini et al28 demonstrated that adrenomedullin suppresses PDGF-induced mitogenesis in rat mesangial cells. Therefore, during coagulation in the glomerulus, adrenomedullin may inhibit the effect of increased PDGF on mesangial cell production of ET-1 and proliferation. However, additional studies will be necessary to clarify the precise interaction between adrenomedullin and PDGF in the glomerulus in vivo.
|
Acknowledgments |
|---|
This work was supported by a Grant-in-Aid for Scientific Research (grant 572-690-231-646) from the Ministry of Education, Science, and Culture, Japan. The authors thank Atsumi Ohnishi and Yuka Inoshita for their technical assistance.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Kitamura K, Kangawa K, Kawamoto M, Ichii Y, Nakamura K, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun. 1993;192:553-560. [Medline] [Order article via Infotrieve]
2. Ishizaka Y, Tanaka M, Kitamura K, Kangawa K, Minamimoto N, Matsuo H, Eto T. Adrenomedullin stimulates cyclic AMP formation in rat vascular smooth muscle cells. Biochem Biophys Res Commun. 1994;200:642-646. [Medline] [Order article via Infotrieve]
3. Eguchi S, Hirata Y, Kano H, Sato K, Watanabe TX, Nakajima K, Sakakibara S, Marumo F. Specific receptors for adrenomedullin in cultured rat vascular smooth muscle cells. FEBS Lett. 1994;340:226-230. [Medline] [Order article via Infotrieve]
4. Kohno M, Yokokawa K, Yasunari K, Kano H, Horio T, Takeda T. Stimulation by the novel vasorelaxant peptide adrenomedullin of cyclic AMP formation in cultured rat mesangial cells. Metabolism. 1995;44:10-12. [Medline] [Order article via Infotrieve]
5. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415. [Medline] [Order article via Infotrieve]
6. Murakawa K, Kohno M, Yokokawa K, Yasunari K, Horio T, Kurihara N, Takeda T. Endothelin-induced renal vasoconstriction and increase in cytosolic calcium in renal vascular smooth muscle cells. Clin Exp Hypertens A. 1990;12:1037-1048. [Medline] [Order article via Infotrieve]
7. Badr KF, Murray JJ, Breyer MD, Takahashi K, Inagami T, Harris RC. Mesangial cell, glomerular and renal vascular responses to endothelin in the rat kidney: elucidation of signal transduction pathways. J Clin Invest. 1989;83:336-342.
8. Simonson MS, Wann S, Mene P, Dubyak GR, Kester M, Nakazato Y, Sedor JR, Dunn MJ. Endothelin stimulates phospholipase C, Na+/H+ exchange, C-fos expression and mitogenesis in rat mesangial cells. J Clin Invest. 1989;83:708-712.
9. Kon V, Yoshioka T, Fogo A, Ichikawa I. Glomerular actions of endothelin in vivo. J Clin Invest. 1989;83:1762-1767.
10. Sakamoto J, Sakai S, Hirata Y, Imai T, Ando K, Ida T, Sakurai T, Yanagisawa M, Masaki T, Marumo F. Production of endothelin-1 by rat cultured mesangial cells. Biochem Biophys Res Commun. 1990;169:462-468. [Medline] [Order article via Infotrieve]
11. Zoja C, Orisio S, Perico N, Benigni A, Morigi M, Benatti L, Rambaldi A, Remuzzi G. Constitutive expression of endothelin gene in cultured human mesangial cells and its modulation by transforming growth factor-ß, thrombin, and a thromboxane A2 analogue. Lab Invest. 1991;64:16-20. [Medline] [Order article via Infotrieve]
12. Bakris G, Fairbanks R, Traish AM. Arginine vasopressin stimulates human mesangial cell production of endothelin. J Clin Invest. 1991;87:1158-1164.
13. Kohno M, Horio T, Ikeda M, Yokokawa K, Fukui T, Yasunari K, Kurihara N, Takeda T, Johchi M. Angiotensin II stimulates endothelin-1 secretion in cultured rat mesangial cells. Kidney Int. 1992;42:860-866. [Medline] [Order article via Infotrieve]
14. Kohno M, Horio T, Ikeda M, Yokokawa K, Fukui T, Yasunari K, Murakawa K, Kurihara N, Takeda T. Natriuretic peptides inhibit mesangial cell production of endothelin induced by arginine vasopressin. Am J Physiol. 1993;33:F678-F683.
15. Sakamoto H, Sakai S, Nakamura Y, Fushimi K, Marumo F. Regulation of endothelin-1 production in cultured rat mesangial cells. Kidney Int. 1992;41:350-355. [Medline] [Order article via Infotrieve]
16.
Kohno M, Horio T, Yokokawa K, Yasunari K, Kurihara N,
Takeda T. Endothelin modulates the mitogenic effect
of PDGF on glomerular mesangial cells.
Am J Physiol. 1994;266:F894-F900.
17. Kitamura K, Ichiki Y, Tanaka M, Kawamoto M, Emura J, Sakakibara S, Kangawa K, Matsuo H, Eto T. Immunoreactive adrenomedullin in human plasma. FEBS Lett. 1994;341:288-290. [Medline] [Order article via Infotrieve]
18. Kohno M, Yasunari K, Yokokawa K, Murakawa K, Horio T, Takeda T. Inhibition by atrial and brain natriuretic peptides of endothelin-1 secretion after stimulation with angiotensin II and thrombin of cultured human endothelial cells. J Clin Invest. 1991;87:1999-2004.
19.
Wallenstein S, Zucker CL, Fleiss JL. Some
statistical methods useful in circulation research.
Circ Res. 1980;47:1-9.
20. Tabuchi Y, Nakamaru M, Rakugi H, Nagano M, Ogihara T. Endothelin enhances adrenergic vasoconstriction in perfused rat mesenteric arteries. Biochem Biophys Res Commun. 1989;159:1304-1308. [Medline] [Order article via Infotrieve]
21.
Yang Z, Richard V, Segesser LV, Bauer E, Srulz P,
Turina M, Luscher TF. Threshold concentrations of endothelin-1
potentiate contractions to norepinephrine and
serotonin in human arteries: a new mechanism of
vasospasm? Circulation. 1990;82:188-195.
22. Weissberg PL, Witcell C, Davenport AP, Hesketh TR, Metcalfe JC. The endothelin peptides, ET-1, ET-2, ET-3 and sarafotoxin S6b, are co-mitogenic with platelet-derived growth factor for vascular smooth muscle cells. Atherosclerosis. 1990;85:257-262. [Medline] [Order article via Infotrieve]
23. Kitamura K, Sakata J, Kangawa K, Kojima M, Matsuo H, Eto T. Cloning and characteristics of cDNA encoding a precursor for human adrenomedullin. Biochem Biophys Res Commun. 1993;194:720-725. [Medline] [Order article via Infotrieve]
24. Ichiki Y, Kitamura K, Kangawa K, Kawamoto M, Matsuo H, Eto T. Distribution of characterization of immunoreactive adrenomedullin in human tissue and plasma. FEBS Lett. 1994;338:6-10. [Medline] [Order article via Infotrieve]
25.
Kohno M, Hanehira T, Kano H, Horio T, Yokokawa K, Ikeda
M, Minami M, Yasunari K, Yoshikawa J. Plasma adrenomedullin
concentration in essential hypertension.
Hypertension. 1996;27:102–107.
26. Sugo S, Minamino N, Kangawa K, Miyamoto N, Kitamura K, Sakata J, Eto T, Matsuo H. Endothelial cells actively synthesize and secrete adrenomedullin. Biochem Biophys Res Commun. 1994;201:1160-1166. [Medline] [Order article via Infotrieve]
27.
Hirata Y, Hayakawa H, Suzuki Y, Ikenouchi H,
Kohmoto O, Kimura K, Kitamura K, Eto T, Kangawa K, Matsuo H, Omata
M. Mechanism of adrenomedullin-induced vasodilation in the
rat kidney. Hypertension. 1995;25:790-795.
28. Chini EN, Choi E, Grande JP, Burnett JC, Dousa TP. Adrenomedullin suppresses mitogenesis in rat mesangial cells via cAMP pathway. Biochem Biophys Res Commun. 1995;215:868-873. [Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. T. Rademaker, C. J. Charles, E. A. Espiner, M. G. Nicholls, and A. M. Richards Long-Term Adrenomedullin Administration in Experimental Heart Failure Hypertension, November 1, 2002; 40(5): 667 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Charles, M. G. Nicholls, M. T. Rademaker, and A. M. Richards Comparative actions of adrenomedullin and nitroprusside: interactions with ANG II and norepinephrine Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R1887 - R1894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. O. McGregor, R. W. Troughton, C. Frampton, K. L. Lynn, T. Yandle, A. M. Richards, and M. G. Nicholls Hypotensive and Natriuretic Actions of Adrenomedullin in Subjects With Chronic Renal Impairment Hypertension, May 1, 2001; 37(5): 1279 - 1284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Yoshihara, T. Nishikimi, I. Okano, T. Horio, C. Yutani, H. Matsuo, S. Takishita, T. Ohe, and K. Kangawa Alterations of Intrarenal Adrenomedullin and Its Receptor System in Heart Failure Rats Hypertension, February 1, 2001; 37(2): 216 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 M. KOHNO, K. YASUNARI, M. MINAMI, H. KANO, K. MAEDA, A. K. MANDAL, K. INOKI, M. HANEDA, and J. YOSHIKAWA Regulation of Rat Mesangial Cell Migration by Platelet-Derived Growth Factor, Angiotensin II, and Adrenomedullin J. Am. Soc. Nephrol., December 1, 1999; 10(12): 2495 - 2502. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||