(Hypertension. 1996;27:102-107.)
© 1996 American Heart Association, Inc.
Articles |
Plasma Adrenomedullin Concentrations in Essential Hypertension
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.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Abstract We designed the present study to assess any changes in plasma concentrations of the novel vasorelaxant peptide adrenomedullin in patients with essential hypertension. Plasma adrenomedullin concentrations were measured in 45 patients with untreated essential hypertension, 15 patients with borderline hypertension, and 30 normotensive control subjects. After 4 weeks of effective calcium channel blocker–based antihypertensive therapy, adrenomedullin concentrations were measured again. The concentrations were higher in hypertensive patients with increased serum creatinine levels or decreased glomerular filtration rates compared with borderline hypertensive patients and normotensive subjects, although values in normotensive and hypertensive individuals overlapped. Plasma adrenomedullin concentrations were positively correlated with serum creatinine levels and inversely correlated with glomerular filtration rates in the hypertensive patients, whereas adrenomedullin values were not correlated with blood pressure level, left ventricular mass index, or left ventricular ejection fraction. Despite blood pressure control with antihypertensive therapy, plasma adrenomedullin concentrations were not changed. Reversed-phase high-performance liquid chromatographic analysis showed that a major component of immunoreactive adrenomedullin in the plasma of normotensive subjects and hypertensive patients is human adrenomedullin-(1-52). These results indicate that plasma adrenomedullin concentrations are elevated in many hypertensive patients with renal dysfunction and its major component is human adrenomedullin-(1-52).
Key Words: adrenomedullin • hypertension, essential • renal function • chromatography
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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A novel vasorelaxant peptide, adrenomedullin, has been isolated from the acid extract of human pheochromocytoma.1 This 52–amino acid peptide has one intracellular disulfide bond and shows homology with CGRP.1 It has been demonstrated that intravenous injection of adrenomedullin causes a potent and long-lasting hypotensive effect in anesthetized rats and that this peptide binds to specific receptors on platelet membranes to increase intracellular cAMP.1 Recently, Ishizaka et al2 and Eguchi et al3 have demonstrated that adrenomedullin potently stimulates cAMP formation in rat vascular smooth muscle cells via its specific receptors. Subsequently, we4 have shown that rat and human adrenomedullin stimulates cAMP formation in cultured rat glomerular mesangial cells. More recently, Hirata et al5 have demonstrated that adrenomedullin increases GFR and urinary sodium excretion and markedly decreases renal vascular resistance in anesthetized rats. These observations may raise the hypothesis that adrenomedullin modulates vascular tone or glomerular function in certain pathological states.
To assess any changes in plasma adrenomedullin concentrations in essential hypertension, we measured plasma immunoreactive adrenomedullin concentrations in patients with untreated essential hypertension. We compared the results with those of patients with borderline hypertension and normotensive control subjects. We also measured adrenomedullin concentrations after 4 weeks of effective calcium channel blocker–based antihypertensive therapy.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Between January and December 1994 we recruited 45 patients with established essential hypertension and 15 patients with borderline hypertension for this study from a population of approximately 200 patients seen in our department. Routine laboratory studies of all patients included assays of serum electrolytes, serum creatinine, blood urea nitrogen, and fasting blood glucose level; liver function tests; urinalysis; a chest roentgenogram; and an electrocardiogram. On the basis of the results of the laboratory tests and WHO,6 subjects were placed into one of the following three diagnostic categories: Normal BP was defined as a systolic pressure equal to or less than 140 mm Hg and a diastolic pressure equal to or less than 90 mm Hg. Hypertension was defined as a systolic pressure equal to or greater than 160 mm Hg or a diastolic pressure equal to or greater than 95 mm Hg, or both. The term borderline hypertension was used to denote BP values between the normal and hypertensive ranges as described above. Secondary hypertension was excluded by clinical history; physical examination; and routine laboratory tests, including measurements of plasma renin activity, aldosterone, catecholamine, cortisol, and thyroid hormones; and an excretory urogram or renal arteriogram. None of these patients had signs or symptoms of cardiac or hepatic failure or of diabetes. In addition, none had clinical evidence of pulmonary disease, angina pectoris, or myocardial infarction. Only hypertensive patients who had no previous antihypertensive drug treatment or whose antihypertensive drug treatment had been washed out for at least 2 weeks were included in this study.
After the initial evaluation 34 hypertensive patients, who agreed with the aim of this study, were started on antihypertensive therapy with a calcium channel blocker (slow-release nicardipine, slow-release nifedipine, barnidipine, or amlodipine). This therapy was continued in the majority of patients for 4 weeks. Fifteen of the 34 hypertensive patients required a second or third drug to adequately lower BP. Plasma adrenomedullin concentrations were determined before the initiation of therapy and after 4 weeks of effective therapy with antihypertensive drugs.
Arterial BP was measured by a mercury sphygmomanometer after the patients had rested sitting for 30 minutes in a quiet, warm room. The mean of three BP measurements was used to classify the subjects.
A blood sample (5 mL) was drawn immediately into ice-chilled tubes containing Trasylol (5x105 kallikrein inactivator units/L) and EDTA (1 g/L). Plasma was separated by centrifugation for 10 minutes at 4°C and immediately frozen and stored at -80°C until radioimmunoassay.
Immunoreactive adrenomedullin was extracted from plasma by a modified method previously described in our laboratory.7 Briefly, 2 mL of plasma was diluted with 3 mL of 4% acetic acid. After centrifugation the solution was pumped at the rate of 1 mL/min through a Sep-Pak C18 cartridge (Waters Associates). After the cartridge had been washed with distilled water, the adsorbed peptides were eluted with 4 mL of 50% acetonitrile containing 0.1% trifluoroacetic acid. After evaporation with a centrifugal evaporator (model RD-31, Yamato Scientific Co), the dry residue was dissolved in an assay buffer. The recovery rate was calculated by the addition of three amounts of cold human adrenomedullin-(1-52) (5, 20, and 100 pg/mL [0.8, 3.3, and 16.6 pmol/L]) to plasma pretreated with the Sep-Pak C18 cartridge. The recovery rate was 75±4%.
The plasma immunoreactive adrenomedullin concentration was measured
with an antibody against synthetic human adrenomedullin-(1-52) and
125I–human adrenomedullin-(1-52) (Peninsula Laboratories
Inc). This antibody does not show any cross-reactivity with human
adrenomedullin-(13-52), rat adrenomedullin-(1-50), human CGRP,
endothelin-1, 
-human atrial natriuretic
peptide-(1-28), brain natriuretic peptide-32, or C-type
natriuretic peptide-22.
Radioimmunoassay was done in the assay buffer of 0.01 mol/L sodium
phosphate, pH 7.4, containing 0.05 mol/L sodium chloride, 0.1% bovine
serum albumin, 0.1% Nonidet P-40, and 0.01% sodium azide.
Sample (100 µL) or standard human adrenomedullin (100 µL) was
dissolved in the assay buffer and then incubated for 24 hours at 4°C.
Approximately 15 000 cpm of 125I–human adrenomedullin was
added to each reaction and incubated for an additional 24 hours. After
the second 24-hour incubation, 100 µL of diluted normal rabbit serum
(Organon Teknika Corp) and 100 µL of diluted goat anti-rabbit IgG
(Peninsula Laboratories Inc) were added, and the mixture was again
incubated for 24 hours. After the third incubation the precipitate was
collected by centrifugation at 1700g for 30
minutes. The supernatant was removed by aspiration and the pellet
counted for 125I with a gamma counter. The effective range
of the standard curve was between 2 and 200 pg of human adrenomedullin
per assay tube. The 50% intercept was 19 pg of human adrenomedullin
(Fig 1
). The interassay variation was 12%, and the
intra-assay variation was 5%.
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) and normotensive control subject (
) were roughly
parallel to the standard curve (
). B/B0 indicates
percentage of maximal 125I–human adrenomedullin-(1-52)
bound.Reversed-phase HPLC was performed with an octadecylsilica column (0.46x25 cm, TSK-gel, ODS-80, TOSOH Co) eluted with a linear gradient of acetonitrile from 10% to 80% (10% to 60%, 35 minutes; 60% to 80%, 10 minutes; 80%, 5 minutes) in 0.1 mol/L sodium chloride with a flow rate of 1 mL/min by a method essentially the same as described previously.8 One-milliliter fractions were collected and assayed by radioimmunoassay. For chromatographic analysis of immunoreactive adrenomedullin, 30 mL of pooled plasma of hypertensive patients and normotensive control subjects was separated and treated by reversed-phase HPLC.
Reversed-phase HPLC profiles of immunoreactive adrenomedullin in
extracts of pooled plasma from normotensive subjects and hypertensive
patients are shown in Fig 2. Adrenomedullin
immunoreactivity in the plasma consisted of one major component, which
was eluted in the position of standard human adrenomedullin-(1-52). The
elution profile of the hypertensive patients was not different from
that of the normotensive control subjects.
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Serum sodium and potassium, serum and urinary creatinine, and blood urea nitrogen were measured by routine methods in the Department of Clinical Chemistry, Osaka City University Medical School. GFR was calculated by endogenous creatinine clearance as previously described.8
LV mass was evaluated by M-mode echocardiography
(Sonolayer SSA-270A, Toshiba) as previously described.7
Measurements were made according to the recommendations of the American
Society of Echocardiography with the
leading-edge to leading-edge convention.9 The LV
internal dimension, ventriculum septum, and LV posterior wall were
measured at end diastole as defined by the onset of the QRS
complex. Measurements made in accordance with American Society of
Echocardiography criteria were used in the formula
of Troy et al10 : LV Mass (g)=1.05x[(LV Internal
Diameter+LV Septal Wall Thickness+Posterior Wall
Thickness)3]-(LV Internal Diameter).3 LV
mass was normalized for body surface area (values are reported here as
LV mass indexes). LV ejection fraction was calculated by standard
techniques.7
Statistical analysis was done by linear regression analysis or Scheffé's test for multiple comparisons preceded by ANOVA where appropriate.11 Comparisons between the values before and after therapy were analyzed by paired ANOVA and reexamined by the method of Greenhouse and Geisser.12
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Table 1
shows various parameters of the
normotensive subjects and borderline hypertensive and hypertensive
patients. There were no significant differences in age, sex
distribution, serum sodium, and serum potassium among the three groups.
As expected, the mean arterial pressure of hypertensive
patients was significantly higher than those of normotensive subjects
and borderline hypertensive patients. Hypertensive patients had
slightly but significantly higher serum creatinine levels
and blood urea nitrogen than borderline hypertensive patients and
normotensive control subjects. The mean GFR of hypertensive subjects
was 76±19 mL/min (range, 42 to 118 mL/min). This value was slightly
but significantly lower than the mean value for GFR in age-matched
healthy subjects (P<.05, n=20, 98±9 mL/min).
Hypertensive
patients in this study had almost normal LV ejection fraction (range,
65% to 86%). The mean LV ejection fraction of age-matched healthy
subjects was 81±5% (n=15). Most hypertensive patients also had
almost
normal LV mass index, but some hypertensive patients had moderate LV
hypertrophy (range of LV mass index, 115 to 162
g/m2). The mean LV mass index of age-matched healthy
subjects was 117±4 g/m2 (n=15). The mean LV posterior
and
septal wall thicknesses of hypertensive subjects in this study were
11.4±2.4 and 10.5±1.8 mm, respectively. These values were
slightly
greater than each normal value (n=15; posterior wall thickness,
9.9±0.4 mm; septal wall thickness, 9.4±0.5 mm).
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The plasma adrenomedullin concentrations of the three groups are shown
in Fig 3. The mean concentrations in the normotensive
subjects and borderline hypertensive and hypertensive patients were
18±2, 20±4, and 34±14 pg/mL, respectively
(3.0±0.3, 3.3±0.7, and
5.6±2.0 pmol/L, respectively). The mean concentrations of the
hypertensive patients were significantly higher than those of
borderline hypertensive patients (P<.05) and normotensive
control subjects (P<.05). There was no significant
difference in plasma adrenomedullin concentrations between the
borderline hypertensive patients and normotensive subjects.
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In the hypertensive group the plasma adrenomedullin concentrations were
strongly correlated with serum creatinine levels (Fig 4A).
Adrenomedullin concentrations were also correlated
with blood urea nitrogen levels (Fig 4B), but this correlation
was
weaker compared with the correlation of adrenomedullin concentrations
and serum creatinine levels. A strong inverse correlation
between GFR and plasma adrenomedullin concentrations was found in the
hypertensive group (Fig 4C).
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In the hypertensive group adrenomedullin concentrations were not
correlated with mean arterial pressure, LV mass index, or
LV ejection fraction (Fig 5).
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Table 2 shows the plasma adrenomedullin concentrations
of hypertensive patients with or without renal dysfunction. The 28
hypertensive patients with increased serum creatinine
levels (
1.2 mg/dL [106.1 µmol/L]) or 30 patients with
decreased
GFR (
80 mL/min) had clearly higher concentrations of plasma
adrenomedullin than those of the normotensive subjects or borderline
hypertensive patients. In contrast, the hypertensive patients with
normal serum creatinine level and normal GFR did not have
higher concentrations of plasma adrenomedullin than the normotensive
subjects or borderline hypertensive patients.
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Fig 6 shows mean arterial pressure and
plasma adrenomedullin concentrations initially and 4 weeks after
effective antihypertensive therapy in 34 hypertensive patients. Mean
arterial pressure fell significantly from an initial value
of 129±7 to 111±50 mm Hg (P<.01). In contrast,
plasma
adrenomedullin concentrations were not changed (35±14 to 34±14
pg/mL
[5.8±2.3 to 5.6±2.3 pmol/L]). Serum creatinine levels
were also not changed (1.5±0.6 to 1.5±0.5 mg/dL
[132.6±53.0 to
132.6±44.2 µmol/L]).
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Fig 7 shows the correlations of plasma adrenomedullin
concentrations and serum creatinine and BP levels 4 weeks
after effective antihypertensive therapy. Adrenomedullin concentrations
were strongly correlated with serum creatinine levels,
whereas they were not correlated with mean arterial
pressure.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Adrenomedullin is a novel vasorelaxant peptide recently isolated from pheochromocytoma.1 Ichiki et al13 and Nishikimi et al14 have demonstrated that this peptide is present not only in human adrenal medulla but also in human plasma. The plasma adrenomedullin concentrations reported here were not very different from values reported by these investigators.13 14 Furthermore, we showed that adrenomedullin immunoreactivity in the plasma of hypertensive patients and normotensive subjects consisted of one major component with the same retention time as that of authentic human adrenomedullin-(1-52). It is therefore likely that human adrenomedullin-(1-52) is the major circulating form of adrenomedullin in both normotensive and hypertensive individuals.
In the current study we found that plasma immunoreactive adrenomedullin concentrations were elevated in many patients in whom renal function was impaired. In fact, adrenomedullin concentrations were positively correlated with serum creatinine levels and inversely correlated with GFR in the hypertensive group. Ishimitsu et al15 have recently demonstrated that the plasma adrenomedullin concentrations in hypertensive subjects with signs of organ damage (WHO stage II) were significantly higher than values in normotensive control subjects and hypertensive subjects without organ damage (WHO stage I). Our data seem to be compatible with their report.15 However, the present study indicates that plasma adrenomedullin concentrations are not elevated in hypertensive patients with normal renal function compared with normotensive control subjects. Indeed, plasma adrenomedullin concentrations were not correlated with BP level in both the untreated and treated hypertensive groups. Furthermore, elevated plasma adrenomedullin concentrations in hypertensive patients were not changed despite BP control by 4 weeks of antihypertensive therapy. It seems, therefore, that high BP itself is not the main factor involved in the observed elevation of plasma adrenomedullin concentrations. In addition, plasma adrenomedullin concentrations were not correlated with LV mass index or LV ejection fraction in the hypertensive group. Taken together, these observations suggest that elevation of plasma adrenomedullin concentrations in hypertensive patients is related to renal dysfunction and not to high BP itself, cardiac dysfunction, or cardiac hypertrophy, at least in our study population. In this respect, our results are different from the data reported by Ishimitsu et al.15 In their study plasma adrenomedullin concentrations were slightly but significantly elevated in uncomplicated essential hypertension (WHO stage I). The precise reasons for this difference are not clear at present. The most likely explanation is that in their study some elderly hypertensive patients classified as WHO stage I might have had modestly reduced GFR. Actually, the GFR or renal blood flow in elderly subjects with high BP is often modestly reduced16 17 18 despite normal levels of serum creatinine and blood urea nitrogen and no proteinuria.
Animal experiments suggest that adrenomedullin elicits a potent and long-lasting hypotensive activity comparable to that of CGRP.1 In addition, adrenomedullin potently stimulates cAMP formation in cultured rat vascular smooth muscle cells.2 3 Recently, adrenomedullin was shown to be synthesized in and secreted from vascular endothelial cells.19 If the elevation of plasma adrenomedullin concentration reflects increased synthesis and if the local concentration of adrenomedullin at the site of production is greater than the plasma concentration, this peptide may modulate vascular tone via paracrine effects on adjacent vascular smooth muscle. Furthermore, we have recently shown that both rat and human adrenomedullin potently stimulate cAMP formation in cultured rat glomerular mesangial cells.4 Very recently, Hirata et al5 demonstrated that adrenomedullin increases GFR 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. Adrenomedullin also inhibits the production of the vasoconstrictive peptide endothelin-1 in vascular smooth muscle cells, probably through a cAMP-dependent process.20 Although the exact mechanism of the elevation of plasma adrenomedullin concentrations in essential hypertension is not clear, these observations suggest that the observed elevation of plasma adrenomedullin in hypertensive patients may be part of a compensatory mechanism to offset further development of renal dysfunction. However, further studies will be necessary to clarify the physiological significance of adrenomedullin in essential hypertension. It is also necessary to clarify the exact pharmacokinetics of adrenomedullin, including degradation in hypertensive patients with renal functional damage.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture, Japan (572-690-231-646) and by a research grant of Osaka City University. The authors thank Atsumi Ohnishi and Yuka Inoshita for their technical assistance.
Received June 5, 1995; first decision August 8, 1995; accepted September 11, 1995.
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References |
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 H. Iwasaki, S. Eguchi, M. Shichiri, F. Marumo, and Y. Hirata Adrenomedullin as a Novel Growth-Promoting Factor for Cultured Vascular Smooth Muscle Cells: Role of Tyrosine Kinase-Mediated Mitogen-Activated Protein Kinase Activation Endocrinology, August 1, 1998; 139(8): 3432 - 3441. [Abstract] [Full Text] [PDF]
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 M. Kohno, K. Yokokawa, K. Yasunari, M. Minami, H. Kano, T. Hanehira, and J. Yoshikawa Induction by Lysophosphatidylcholine, a Major Phospholipid Component of Atherogenic Lipoproteins, of Human Coronary Artery Smooth Muscle Cell Migration Circulation, July 28, 1998; 98(4): 353 - 359. [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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T. Sumimoto, T. Nishikimi, M. Mukai, K. Matsuzaki, E. Murakami, S. Takishita, A. Miyata, H. Matsuo, and K. Kangawa Plasma Adrenomedullin Concentrations and Cardiac and Arterial Hypertrophy in Hypertension Hypertension, September 1, 1997; 30(3): 741 - 745. [Abstract] [Full Text]
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M. Kohno, K. Yokokawa, H. Kano, K. Yasunari, M. Minami, T. Hanehira, and J. Yoshikawa Adrenomedullin Is a Potent Inhibitor of Angiotensin II–Induced Migration of Human Coronary Artery Smooth Muscle Cells Hypertension, June 1, 1997; 29(6): 1309 - 1313. [Abstract] [Full Text]
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P. G. Andreis, G. Neri, T. Prayer-Galetti, G. P. Rossi, G. Gottardo, L. K. Malendowicz, and G. G. Nussdorfer Effects of Adrenomedullin on the Human Adrenal Glands: An in Vitro Study J. Clin. Endocrinol. Metab., April 1, 1997; 82(4): 1167 - 1170. [Abstract] [Full Text] [PDF]
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K. Meeran, D. O'Shea, P. D. Upton, C. J. Small, M. A. Ghatei, P. H. Byfield, and S. R. Bloom Circulating Adrenomedullin Does Not Regulate Systemic Blood Pressure but Increases Plasma Prolactin after Intravenous Infusion in Humans: A Pharmacokinetic Study J. Clin. Endocrinol. Metab., January 1, 1997; 82(1): 95 - 100. [Abstract] [Full Text] [PDF]
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 M. G. Lang, R. Paterno, F. M. Faraci, D. D. Heistad, and J. R. Kirsch Mechanisms of Adrenomedullin-Induced Dilatation of Cerebral Arterioles Stroke, January 1, 1997; 28(1): 181 - 185. [Abstract] [Full Text]
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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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