(Hypertension. 1995;25:790-795.)
© 1995 American Heart Association, Inc.
Articles |
Mechanisms of Adrenomedullin-Induced Vasodilation in the Rat Kidney
From the Second Department of Internal Medicine, University of Tokyo (Y.H., H.H., Y.S., E.S., H.I., O.K., K. Kimura, M.O.); the First Department of Internal Medicine, Miyazaki Medical College, Miyazaki (K. Kitamura, T.E.); and Research Institute of National Cardiovascular Center, Osaka (K. Kangawa, H.M.), Japan.
Correspondence to Yasunobu Hirata, MD, Second Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
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Abstract |
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Abstract To explore the mechanisms of adrenomedullin-induced vasorelaxation, we tested the effects of adrenomedullin on renal function in rats in vivo and measured the release of endothelium-derived nitric oxide from isolated perfused rat kidney (using a chemiluminescence assay) and the diameters of the glomerular arterioles in the hydronephrotic kidney. Adrenomedullin decreased blood pressure in a dose-dependent manner (3 nmol/kg: -29±2% [SEM]; P<.01) and slightly increased the glomerular filtration rate and urinary sodium excretion (+108%; P<.05). These changes were associated with significant increases in urinary excretion of cyclic AMP (+54%; P<.05). Adrenomedullin decreased renal vascular resistance (10-7 mol/L adrenomedullin: -41±2%; P<.001) and increased release of nitric oxide (+5.1±0.7 fmol/min per gram kidney weight; P<.001) in the isolated kidney. This increase in nitric oxide release was abolished by the inhibitor NG-monomethyl-L-arginine, and it also reversed the decrease in renal vascular resistance seen with adrenomedullin. Renal responses of deoxycorticosterone acetate–salt hypertensive rats to adrenomedullin were significantly smaller than those of control rats for both release of nitric oxide (10-7 mol/L adrenomedullin: +0.8±0.2 fmol/min per gram kidney weight; P<.01 versus control) and renal vasodilation (-28±6%; P<.05). Videomicroscopic analysis revealed that adrenomedullin increased the diameters of both afferent and efferent arterioles (3 nmol/kg: +11%; P<.05). Thus, adrenomedullin-induced renal vasodilation is partially endothelium dependent and is attenuated in deoxycorticosterone acetate–salt hypertension, probably due to endothelial damage.
Key Words: calcium • nitric oxide • arteriole • endothelium • vasodilation
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Introduction |
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Adrenomedullin (AM), originally discovered in pheochromocytoma cells,1 is widely distributed in various organs and in plasma under physiological conditions.2 3 Since substantial amounts of AM and AM mRNA have been detected in the kidney,1 2 3 AM may play a role in the regulation of renal function. AM exhibits potent vasodilating activity.4 AM was purified on the basis of its cyclic AMP (cAMP)–inducing activity in platelets, and the second messenger of the vasodilator activity of AM is believed to be cAMP.1 AM has been regarded as a member of the calcitonin gene–related peptide (CGRP) family because of the similar ring structures of the cysteine residues. CGRP is the most potent vasodilator known. These findings suggest that the same mechanisms may underlie their potent vasodilator actions. However, the mechanism of its vascular action is still not clear. In particular, whether the vasodilator effect of CGRP is endothelium dependent is still being debated.5 6 7 8 9 10 11 12
To examine whether AM or CGRP stimulates nitric oxide (NO) release and how this property contributes to the regulation of renal vascular tone, the effects of AM on renal function in vivo, on NO release from the isolated kidney, and on glomerular arteriolar tone in the hydronephrotic kidney were examined. These effects were tested in normal rats and deoxycorticosterone acetate (DOCA)–salt hypertensive rats, which have marked endothelial damage.13 14 15
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Methods |
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In Vivo Renal Effects of AM
Wistar rats were unilaterally nephrectomized at 4 weeks of age under ether anesthesia. Silicone rubber containing 200 mg/kg DOCA was implanted subcutaneously. Rats were given 0.9% saline for drinking. Control rats were also unilaterally nephrectomized but given tap water. The experiments were performed 8 weeks after the surgery. On the day of the experiment, rats were anesthetized with thiobutabarbital (100 mg/kg IP). The trachea, carotid artery, jugular vein, and bladder were cannulated with polyethylene tubing. An intravenous bolus injection of 5% p-aminohippuric acid (PAH) and 5% inulin (1.67 mL/kg) was followed by continuous infusion of 1% PAH and 1% inulin in lactated Ringer's solution. After an equilibration period of 60 minutes, urine was collected for 30 minutes. Then 0.3, 1.0, and 3.0 nmol/kg of AM were sequentially injected into the jugular vein of nine DOCA-salt rats and eight control rats at intervals of 20 minutes. Blood pressure (BP) was monitored via the carotid artery throughout the study. At the midpoint of each urine collection period, 0.4 mL of arterial blood was drawn. Urinary concentrations of cyclic GMP (cGMP) and cAMP were measured by radioimmunoassay. Plasma and urinary PAH and inulin concentrations were measured colorimetrically. Glomerular filtration rate (GFR) was calculated from inulin clearance, and renal blood flow (RBF) was calculated from PAH clearance and hematocrit. Renal vascular resistance (RVR) was calculated as mean BP (MBP)/RBF. Urinary sodium concentration was determined by flame photometry. AM was synthesized by the solid-phase method.3 As a time control, vehicle instead of AM was given to five control rats, and the same parameters were measured.
Effects of AM on NO Release From Isolated Perfused Kidney
Kidneys were isolated and perfused, and NO concentration in the
venous effluent was measured with a chemiluminescence assay as
reported.14 15 In brief, seven DOCA-salt rats and seven
control rats were anesthetized with intraperitoneal pentobarbital (30
mg/kg). The right renal artery was cannulated and perfused with
Krebs-Henseleit buffer at 5 mL/min at 37°C. The buffer containing
10-6 mol/L phenylephrine was saturated with 95%
O2/5% CO2 gas. Renal perfusion pressure
(RPP) was continuously recorded at the renal artery. The venous
effluent was introduced with a plunger pump directly into a mixer and
then a chemiluminescence detector. The chemiluminescence probe,
consisting of 18 µmol/L H2O2 and 2 mmol/L
luminol, was also pumped to the mixer. The chemiluminescence was
monitored continuously. After the 60-minute equilibration period,
vehicle and 10-9, 10-8, and
10-7 mol/L AM were administered sequentially at 10-minute
intervals to kidneys from DOCA-salt and control rats. Finally,
10-4 mol/L
NG-monomethyl-L-arginine
(L-NMMA) was added to 10-7 mol/L AM. BP measured with the
tail-cuff method was 201±8 mm Hg in DOCA-salt rats and 133±3 mm Hg
in control rats (P<.001).
We also tested the effects of CGRP (Peptide Institute) on RPP and NO release and examined the effects of prior treatment with 10-6 mol/L CGRP(8-37) (Peptide Institute), a CGRP antagonist, on AM-induced changes in five Wistar rats.
Effects of AM on [Ca2+]i in
Cultured Endothelial Cells
Ca2+ concentrations in the endothelial cells
were measured to explore the mechanisms of AM-induced NO release.
Primary cultured endothelial cells from bovine carotid arteries were
passaged on coverslips in Dulbecco's modified Eagle's medium
containing 10% fetal calf serum. The culture medium was changed to
serum-free medium 24 hours before the experiment.
[Ca2+]i was measured as
described.16 17 Cultured cells on coverslips were
incubated at 37°C in culture medium containing 5 µmol/L indo 1-AM
(Dojin Kagaku) for 15 minutes and then washed in indo 1–free solution
for 30 minutes. The coverslip was placed in a flow-through cell chamber
and continuously superfused with HEPES-buffered normal Tyrode's
solution. The ratio of the fluorescence emitted at 400 nm and 480 nm
was obtained on-line through an analog-divider circuit. AM in Tyrode's
solution was superfused at 10-10,
10-9, and 10-8 mol/L, and finally
10-8 mol/L bradykinin was superfused to confirm that the
cells were capable of a normal endothelial response. The effects of
CGRP and bradykinin on [Ca2+]i were
similarly examined.
Effects of AM on Glomerular Arterioles
Wistar rats at 6 weeks of age were anesthetized with ether, and
the left ureter was ligated. Approximately 8 weeks after the surgery,
the glomeruli of the hydronephrotic kidney were observed under a
videomicroscope. The diameters of the glomerular afferent and efferent
arterioles were determined with a videoanalyzer before and after a
bolus injection of AM into the jugular vein cannula. MBP was recorded
through a carotid artery cannula.
Statistical Analysis
Values are expressed as mean±SEM. The effects of the agents
tested were assessed by ANOVA for repeated measures followed by
Dunnett's test. Comparisons between DOCA-salt and control rats were
assessed by unpaired Student's t test. P<.05
was considered statistically significant.
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Results |
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In Vivo Renal Effects
AM caused a transient reduction in BP. The peak and duration of the effect were dose dependent (Fig 1). Heart rate did not change. Urinary sodium excretion was slightly but significantly increased by 1 nmol/kg of AM (Fig 2). However, 3 nmol/kg of AM did not increase urinary sodium, probably because of the profound BP reduction. Urinary excretion of cAMP was also significantly increased by AM, with the largest effect occurring at 1 nmol/kg. Urinary excretion of cGMP did not change. AM slightly increased GFR but not RBF (Fig 3). RVR was decreased by AM in a dose-dependent manner. Vehicle administration did not change any parameters measured. DOCA-salt rats showed higher baseline BP and greater urinary excretion of sodium and cGMP than control rats. However, the responses to AM were not different between the groups.
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NO Release
Fig 4 illustrates representative tracings
of RPP and NO signals in DOCA-salt rats and control rats. Bolus
injections of AM transiently decreased RPP. The NO release occurred in
parallel with changes in RPP. These effects were dose dependent (Fig 4A). Continuous infusion of AM also decreased RPP and increased NO
signals (Fig 4B and 4C). When L-NMMA was added to the AM, RPP increased
and NO release decreased. As summarized in Fig 5, AM
decreased RPP and increased NO signals in both DOCA-salt rats and
control rats. However, the decrease in RPP and increase in NO release
by 10-7 mol/L AM were significantly smaller in DOCA-salt
rats than in controls.
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CGRP exhibited a potent depressor effect in the kidneys of normal rats. This vasodilation was also associated with an increase in NO release (10-8 mol/L CGRP: RPP, -35±2%, P<.001; NO release, +10.7±3.2 fmol/min per gram kidney weight, n=5, P<.05 versus baseline). The effects of pretreatment with a CGRP antagonist on AM-induced vasorelaxation were also examined. CGRP(8-37) at 10-6 mol/L alone did not change RPP or the NO signal. However, CGRP(8-37) significantly reduced the effects of 10-7 mol/L AM on RPP by 59±10% (P<.01) and NO release by 43±10% (P<.01).
[Ca2+]i Transients
Both AM and CGRP significantly elevated
[Ca2+]i of the cultured endothelial
cells (Fig 6). Bradykinin also increased
[Ca2+]i. The effect of CGRP on
[Ca2+]i was comparable to that of AM
but was less than that of bradykinin (P<.05).
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Glomerular Arterioles
AM lowered MBP (baseline, 135±4 mm Hg) even in rats with
hydronephrotic kidneys (3 nmol/kg: -25±7%; P<.01; n=5).
The videomicroscopic analysis revealed that AM increased the
diameters of afferent (baseline, 11.5±0.3 µm; +11±3%;
P<.05) and efferent (baseline, 10.8±0.2 µm; +12±3%;
P<.05) arterioles to a similar extent (Fig 7). The resolving power of this system was approximately
0.2 µm. In the time control study, the diameters did not change
significantly within 60 minutes. The coefficients of variance were
4.8% for the afferent arteriole and 8.5% for the efferent
arteriole.
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Discussion |
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Our data illustrate that AM is a potent renal vasodilator. The vasodilation is accompanied by an increase in urinary excretion of cAMP and an increase in NO release that could be abolished by L-NMMA, an inhibitor of NO synthase. CGRP also exerts a vasodilator effect by increasing cAMP. However, whether CGRP-induced vasodilation is endothelium dependent is still controversial. More than 10 reports showed that endothelial denudation reduces CGRP-induced vasorelaxation,5 6 7 8 while a similar number of reports observed that CGRP dilated the arteries in both the presence and absence of endothelium.9 10 11 12 This discrepancy may be due to the heterogeneity of the response of vascular beds to CGRP, even in a given species.
Both AM and CGRP increased NO release in our study, although to a relatively small extent (one third to one sixth that of acetylcholine).14 15 There is a site for phosphorylation by cAMP-dependent protein kinase on endothelial NO synthase.18 19 Although inducible NO synthase is activated by cAMP, it has not been reported that cAMP directly activates constitutive NO synthase.19 20 On the other hand, AM and CGRP increased [Ca2+]i in cultured endothelial cells. The activity of endothelial NO synthase is dependent on intracellular Ca2+ and calmodulin.18 19 Although the pathway by which AM alters [Ca2+]i transients has not been clarified, the increase in [Ca2+]i caused by AM may activate NO synthase, resulting in NO release. Therefore, our data indicate that AM-induced renal vasodilation is at least partially endothelium dependent. Nuki et al21 also showed that a CGRP antagonist, CGRP(8-37), antagonized the vasorelaxing effect of AM. In our study CGRP(8-37) suppressed not only vasodilation but also NO release by AM. It was recently reported that CGRP(8-37) inhibited the AM-induced cAMP increase in cultured vascular smooth muscle cells.22 These findings suggest an interaction between the two peptides; CGRP and AM may share the same receptor or its subtype. Furthermore, such receptors may couple to a signal transduction system, which leads to increased [Ca2+]i, which in turn stimulates NO release from endothelial cells. Bovine carotid artery endothelial cells were used in this study because it is known that bradykinin, a standard NO releaser, stimulates NO release from these cells.23 However, variations in endothelium-dependent vasodilation have been reported between different types of vessels and between species; therefore, further studies are required to confirm that the effect of AM on bovine carotid endothelium is similar to that on rat renal resistance vessels.
Although NO is known to substantially increase intracellular cGMP concentration, whether urinary cGMP reflects the activities of soluble guanylate cyclase is controversial; urinary cGMP was found to be decreased24 or unchanged25 by L-NMMA and increased26 or unchanged27 by sodium nitroprusside. It has been suggested that cGMP derived from soluble guanylate cyclase reaches the intravascular space to a lesser extent than that from particulate guanylate cyclase, which is activated by atrial natriuretic peptide as a result of reduced permeability through the endothelial layer or poor cellular egression.27 28 This may be one reason for the lack of an increase in urinary cGMP despite a possible increase in intracellular cGMP in the present study. Thus, AM may cause both endothelium-independent vasodilation, which is mediated by an increase in intracellular cAMP, and endothelium-dependent vasodilation, which is mediated by NO release. However, the relative importance between cAMP-mediated and NO-mediated vasodilation could not be determined in this study.
The vasodilator response of DOCA-salt hypertension to AM was significantly smaller than that of the controls. AM-induced NO release was also markedly attenuated in DOCA-salt rats. Endothelium-dependent but not endothelium-independent vasodilation is impaired in human and experimental hypertension, including salt-induced hypertension.29 In addition, acetylcholine-induced vasodilation and NO release were remarkably attenuated in DOCA-salt rats compared with control rats.14 15 However, the responses to sodium nitroprusside, an endothelium-independent vasodilator, did not differ. The attenuated responses in DOCA-salt rats reflect the presence of endothelial damage caused by hypertension, which may contribute to further elevation of BP. The attenuated response of DOCA-salt rats to AM also suggests that a significant part of AM-induced vasodilation is endothelium dependent.
AM dilates both glomerular afferent and efferent arterioles. We should be cautious about evaluating the response of the hydronephrotic kidney because of the lack of tubular function. However, it has been confirmed that vascular reactivity is maintained relatively intact, including vascular myogenic autoregulation.30 Since AM lowered BP, the dilation of afferent arterioles during AM administration may be due to an autoregulatory response. However, this response was associated with a significant increase in glomerular blood flow. Furthermore, autoregulatory response to BP reduction has been shown to dilate the afferent arterioles, while it did not influence efferent arterioles.30 Therefore, AM directly contributes to arteriolar dilation in the glomeruli. cAMP-related vasoactive substances such as prostaglandin E2 and parathyroid hormone decrease glomerular plasma flow.31 This effect is due to secondary activation of the renin-angiotensin system, because saralasin, an angiotensin II receptor antagonist, inhibits the glomerular action of these substances. In the present study we used the hydronephrotic kidney, which is nonfiltering. Therefore, when the intrarenal renin-angiotensin system is suppressed, the vasodilator effect of AM may be augmented. On the other hand, NO increases glomerular plasma flow via dilation of both afferent and efferent arterioles.32 33 This effect is also observed in the hydronephrotic kidney.34 Therefore, NO may be involved in glomerular arteriolar dilation by AM.
In conclusion, in addition to cAMP-related mechanisms, the renal vasodilator effects of AM may be exerted via release of NO. Although synthesis and secretion of AM have not yet been demonstrated in pathophysiological conditions, if AM participates in the regulation of in vivo renal function, the decreased response of hypertensive kidneys to AM may contribute to the elevation of BP.
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Acknowledgments |
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This study was supported in part by a grant-in-aid for Scientific Research on priority areas ("Vascular Endothelium–Smooth Muscle Coupling") and by grants-in-aid 06274209 and 06671132 from the Japanese Ministry of Education, Culture, and Science, Japan.
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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]
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T. Shindo, Y. Kurihara, H. Nishimatsu, N. Moriyama, M. Kakoki, Y. Wang, Y. Imai, A. Ebihara, T. Kuwaki, K.-H. Ju, et al. Vascular Abnormalities and Elevated Blood Pressure in Mice Lacking Adrenomedullin Gene Circulation, October 16, 2001; 104(16): 1964 - 1971. [Abstract] [Full Text] [PDF]
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 T. Yamamoto, Y. Tomura, H. Tanaka, and F. Kajiya In vivo visualization of characteristics of renal microcirculation in hypertensive and diabetic rats Am J Physiol Renal Physiol, September 1, 2001; 281(3): F571 - F577. [Abstract] [Full Text] [PDF]
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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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 T. Tokura, H. Kinoshita, S. Fujimoto, S. Hisanaga, K. Kitamura, and T. Eto Plasma levels of mature form of adrenomedullin in patients with haemodialysis Nephrol. Dial. Transplant., April 1, 2001; 16(4): 783 - 786. [Abstract] [Full Text] [PDF]
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E. Dobrzynski, C. Wang, J. Chao, and L. Chao Adrenomedullin Gene Delivery Attenuates Hypertension, Cardiac Remodeling, and Renal Injury in Deoxycorticosterone Acetate-Salt Hypertensive Rats Hypertension, December 1, 2000; 36(6): 995 - 1001. [Abstract] [Full Text] [PDF]
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M. Sata, M. Kakoki, D. Nagata, H. Nishimatsu, E. Suzuki, T. Aoyagi, S. Sugiura, H. Kojima, T. Nagano, K. Kangawa, et al. Adrenomedullin and Nitric Oxide Inhibit Human Endothelial Cell Apoptosis via a Cyclic GMP-Independent Mechanism Hypertension, July 1, 2000; 36(1): 83 - 88. [Abstract] [Full Text] [PDF]
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T. Shindo, H. Kurihara, K. Maemura, Y. Kurihara, T. Kuwaki, T. Izumida, N. Minamino, K.-H. Ju, H. Morita, Y. Oh-hashi, et al. Hypotension and Resistance to Lipopolysaccharide-Induced Shock in Transgenic Mice Overexpressing Adrenomedullin in Their Vasculature Circulation, May 16, 2000; 101(19): 2309 - 2316. [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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A. Rossler, Z. Laszlo, B. Haditsch, and H. G. Hinghofer-Szalkay Orthostatic Stimuli Rapidly Change Plasma Adrenomedullin in Humans Hypertension, November 1, 1999; 34(5): 1147 - 1151. [Abstract] [Full Text] [PDF]
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M. Kakoki, Y. Hirata, H. Hayakawa, A. Tojo, D. Nagata, E. Suzuki, K. Kimura, A. Goto, K. Kikuchi, T. Nagano, et al. Effects of Hypertension, Diabetes Mellitus, and Hypercholesterolemia on Endothelin Type B Receptor–Mediated Nitric Oxide Release From Rat Kidney Circulation, March 9, 1999; 99(9): 1242 - 1248. [Abstract] [Full Text] [PDF]
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 B. Geny, G. Brandenberger, J. Lonsdorfer, N. Chakfe, P. Haberey, and F. Piquard Circulating adrenomedullin is increased after heart transplantation Cardiovasc Res, March 1, 1999; 41(3): 731 - 736. [Abstract] [Full Text] [PDF]
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H. Hayakawa, Y. Hirata, M. Kakoki, Y. Suzuki, H. Nishimatsu, D. Nagata, E. Suzuki, K. Kikuchi, T. Nagano, K. Kangawa, et al. Role of Nitric Oxide–cGMP Pathway in Adrenomedullin-Induced Vasodilation in the Rat Hypertension, February 1, 1999; 33(2): 689 - 693. [Abstract] [Full Text] [PDF]
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O. Lisy, M. Jougasaki, J. A. Schirger, H. H. Chen, P. T. Barclay, and J. C. Burnett Jr. Neutral endopeptidase inhibition potentiates the natriuretic actions of adrenomedullin Am J Physiol Renal Physiol, September 1, 1998; 275(3): F410 - F414. [Abstract] [Full Text] [PDF]
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 S. Cormier-Regard, S. V. Nguyen, and W. C. Claycomb Adrenomedullin Gene Expression Is Developmentally Regulated and Induced by Hypoxia in Rat Ventricular Cardiac Myocytes J. Biol. Chem., July 10, 1998; 273(28): 17787 - 17792. [Abstract] [Full Text] [PDF]
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B. L. Jensen, S. Gambaryan, E. Schmaus, and A. Kurtz Effects of dietary salt on adrenomedullin and its receptor mRNAs in rat kidney Am J Physiol Renal Physiol, July 1, 1998; 275(1): F55 - F61. [Abstract] [Full Text] [PDF]
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 V. A. Cameron and A. M. Fleming Novel Sites of Adrenomedullin Gene Expression in Mouse and Rat Tissues Endocrinology, May 1, 1998; 139(5): 2253 - 2264. [Abstract] [Full Text] [PDF]
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M. T. Rademaker, C. J. Charles, L. K. Lewis, T. G. Yandle, G. J. S. Cooper, D. H. Coy, A. M. Richards, and M. G. Nicholls Beneficial Hemodynamic and Renal Effects of Adrenomedullin in an Ovine Model of Heart Failure Circulation, September 16, 1997; 96(6): 1983 - 1990. [Abstract] [Full Text]
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H. Ikenouchi, K. Kangawa, H. Matsuo, and Y. Hirata Negative Inotropic Effect of Adrenomedullin in Isolated Adult Rabbit Cardiac Ventricular Myocytes Circulation, May 6, 1997; 95(9): 2318 - 2324. [Abstract] [Full Text]
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B. L. Jensen, B. K. Kramer, and A. Kurtz Adrenomedullin Stimulates Renin Release and Renin mRNA in Mouse Juxtaglomerular Granular Cells Hypertension, May 1, 1997; 29(5): 1148 - 1155. [Abstract] [Full Text]
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W. K. Samson and T. C. Murphy Adrenomedullin Inhibits Salt Appetite Endocrinology, February 1, 1997; 138(2): 613 - 616. [Abstract] [Full Text] [PDF]
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T. Shimosawa and T. Fujita Hypotensive Effect of a Newly Identified Peptide, Proadrenomedullin N-Terminal 20 Peptide Hypertension, September 1, 1996; 28(3): 325 - 329. [Abstract] [Full Text]
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M. Kohno, K. Yasunari, K. Yokokawa, T. Horio, M. Ikeda, H. Kano, M. Minami, T. Hanehira, and J. Yoshikawa Interaction of Adrenomedullin and Platelet-Derived Growth Factor on Rat Mesangial Cell Production of Endothelin Hypertension, March 1, 1996; 27(3): 663 - 667. [Abstract] [Full Text]
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M. Kohno, T. Hanehira, H. Kano, T. Horio, K. Yokokawa, M. Ikeda, M. Minami, K. Yasunari, and J. Yoshikawa Plasma Adrenomedullin Concentrations in Essential Hypertension Hypertension, January 1, 1996; 27(1): 102 - 107. [Abstract] [Full Text]
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H. Nishimatsu, E. Suzuki, D. Nagata, N. Moriyama, H. Satonaka, K. Walsh, M. Sata, K. Kangawa, H. Matsuo, A. Goto, et al. Adrenomedullin Induces Endothelium-Dependent Vasorelaxation via the Phosphatidylinositol 3-Kinase/Akt-Dependent Pathway in Rat Aorta Circ. Res., July 6, 2001; 89(1): 63 - 70. [Abstract] [Full Text] [PDF]
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H. Nishimatsu, Y. Hirata, T. Shindo, H. Kurihara, M. Kakoki, D. Nagata, H. Hayakawa, H. Satonaka, M. Sata, A. Tojo, et al. Role of Endogenous Adrenomedullin in the Regulation of Vascular Tone and Ischemic Renal Injury: Studies on Transgenic/Knockout Mice of Adrenomedullin Gene Circ. Res., April 5, 2002; 90(6): 657 - 663. [Abstract] [Full Text] [PDF]
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