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Clinical Studies |
Division of Endocrinology and Metabolism, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom W12 0NN
Address all correspondence and requests for reprints to: Prof. S. R. Bloom, Division of Endocrinology and Metabolism, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London, United Kingdom W12 0NN. E-mail: sbloom{at}rpms.ac.uk
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Abstract |
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Plasma adrenomedullin concentrations were increased in patients with renal impairment (14.1 ± 0.9 pmol/L) compared to those in healthy volunteers (8.1 ± 0.7 pmol/L), with a good correlation (r = 0.86) between circulating adrenomedullin and plasma creatinine.
The circulating concentration of adrenomedullin necessary to affect blood pressure greatly exceeds that observed in healthy volunteers and in patients with a range of pathological conditions. Thus, adrenomedullin may be a paracrine regulator of vascular smooth muscle in humans.
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Introduction |
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In animal studies, it has been shown to have pulmonary (6, 7) and systemic (8, 9) hypotensive properties. We have previously demonstrated that the recently cloned adrenomedullin receptor (10) is expressed in several rat tissues, with particularly high levels in the lung (11). In animals with pharmacologically induced pulmonary hypertension, adrenomedullin dramatically reduces pulmonary pressures (6, 7), and a possible role for adrenomedullin in this disease in humans has been suggested. Ishimitsu et al. (12) found increased circulating plasma concentrations of adrenomedullin in patients with essential hypertension and proposed that it acts to protect the cardiovascular system from the effects of hypertension.
The effects of adrenomedullin in human subjects have not been investigated to date. The present study was designed to elucidate the pharmacokinetics of adrenomedullin and to investigate whether adrenomedullin has a role in the regulation of blood pressure. The gene expression of adrenomedullin is higher in endothelial cells than in other tissues, including the adrenal (2), and for this reason we also studied several patients with diseases known to cause endothelial damage, such as diabetic retinopathy or the vasculitides such as systemic lupus erythematosus (SLE) or Wegener’s granulomatosis.
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Materials and Methods |
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The 52-residue peptide amide was synthesized in an Applied Biosystems 431A peptide synthesizer (Foster City, CA). The product comprised one major peak that was purified to homogeneity by reverse phase high performance liquid chromatography. The peptide was fully active when given intracerebroventricularly to rats (13).
Human infusions of adrenomedullin
Eight healthy male volunteers (aged 24–33 yr) were studied. Informed consent was obtained from each subject, and all experiments had prior approval from the Royal Postgraduate Medical School ethical committee. After an overnight fast, subjects were infused with either adrenomedullin or saline in random order into the antecubital vein of the left arm. There was an interval of at least 7 days between each infusion. Infusions were commenced with a 30-min period when only saline was infused. To minimize peptide adsorption to the infusion system (14), adrenomedullin was dissolved in 5 mL of the volunteer’s own plasma, which was then diluted to 50 mL with 0.9% saline. The infusion rate, initially 3.2 pmol/kg·min, was increased every 10 min to a maximum of 13.4 pmol/kg·min, which was maintained for 40 min. Subjects were supine throughout the study, except for measurement of standing blood pressure during the period of maximum adrenomedullin infusion. An iv cannula was inserted into the antecubital vein of the right arm for blood sampling. Pulse and blood pressure were recorded every 5 min. Blood was collected in tubes containing heparin and aprotinin from the cannula in the antecubital vein of the right arm and centrifuged immediately. Preliminary experiments (results not shown) indicated that assay of plasma after storage at -20 C is fully comparable with assay of the fresh plasma. Plasma was thus frozen on dry ice and stored at -20 C for assay of adrenomedullin, cortisol, glucose, and the pituitary hormones PRL, LH, FSH, ACTH, and TSH.
Pharmacokinetics were studied in seven other volunteers, aged 24–29 yr. A calculated loading dose of 20 pmol/kg·min adrenomedullin was infused over 10 min, and an infusion of 6.5 pmol/kg·min was maintained for 60 min to achieve a steady state. Blood was collected every 10 min for adrenomedullin assay to confirm that a steady state had been achieved. At the end of this period, the infusion was discontinued, and frequent samples were taken. The mean basal concentration of adrenomedullin was subtracted from the mean plateau concentration and from each subsequent sample. The postinfusion values were normalized by expressing them as a percentage of the previous steady state concentration. These values were plotted for each volunteer, and the half-life was derived from the resulting decay curve.
The concentration of adrenomedullin was measured in a sample of each volunteer’s infusate to confirm the infusion rate. The MCR of adrenomedullin was calculated for each volunteer from the steady state concentration (CSS) and infusion rate at which this concentration was stable, where MCR = infusion rate/CSS. The apparent volume of distribution (VD) was calculated from the half-life and the steady state clearance, where VD = MCR x half-life x 1.44
Circulating adrenomedullin concentrations in various diseases
The study population consisted of 11 healthy volunteers, 17
patients with background diabetic retinopathy, 8 patients suffering
from end-stage renal failure on continuous ambulatory peritoneal
dialysis, 6 patients with SLE, 12 patients with Wegener’s
granulomatosis, 5 subjects with chronic stable asthma, and 4 subjects
with rheumatoid arthritis. All patients were attending the out-patient
department at Hammersmith Hospital and were being venesected for
routine plasma electrolyte and creatinine determinations. Blood was
also collected from several other patients attending the out-patients
clinic who were having their creatinine levels measured. Additional
patient details are given in Table 2
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Samples from volunteers receiving adrenomedullin infusions were assayed
directly without extraction because plasma concentrations during the
infusion were well above the detection limit for the assay. Aliquots of
plasma from both patients and volunteers during infusion were analyzed
by gel permeation chromatography to characterize immunoreactive
adrenomedullin. The samples were applied to a Sephadex G-50 column
(60 x 0.9 cm) and eluted with 0.06 mol/L sodium phosphate buffer
containing 0.3% (wt/vol) BSA and 0.2 mol/L sodium chloride. Fractions
(0.6 mL) were collected and submitted for direct assay. The elution
coefficient (Kav) for each fraction was
calculated relative to the elution positions of the markers dextran
blue and Na125I according to the method of Laurent and
Killander (16) (Figs. 2 and 5).
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Adrenomedullin antiserum was raised in a rabbit against synthetic human adrenomedullin conjugated to BSA using carbodiimide (17) and used in the assay at a final dilution of 1:10,000. The detection limit was 2 fmol/tube at 95% confidence limits, and the assay did not cross-react with synthetic CGRP, islet amyloid polypeptide, or calcitonin. The intra- and interassay coefficients of variation were 8% and 12.5%, respectively.
Synthetic human adrenomedullin was used as the standard, and radiolabeled ligand was prepared using the adrenomedullin-(22–52) fragment by the Iodogen method (18) and purified by reverse phase high performance liquid chromatography. The specific activity of the tracer was 22.1 becquerels/fmol. Assays were performed in a final volume of 700 µL using 100 µL plasma with 0.06 mol/L sodium phosphate (pH 7.2) containing 0.3% (wt/vol) BSA, 10 mmol/L ethylenediamine tetraacetate, and 7 mmol/L sodium azide and incubated at 4 C for 3 days. Bound and free tracers were separated using dextran-coated charcoal.
Other assays
Glucose was measured by the glucose oxidase method using a
Yellow Springs YSI 2300 glucometer (Yellow Springs, OH). Plasma LH,
FSH, TSH, PRL, and cortisol were measured using an automated analyzer.
Plasma ACTH was determined using a two-site immunoradiometric assay kit
(19) (Euro-Diagnostica, Europath Ltd., Cornwall, UK). Samples and
standards were incubated overnight at 4 C with 100 µl each of
N-terminally directed 125I-labeled sheep anti-ACTH antibody
and C-terminally directed rabbit anti-ACTH antibody. The bound
radioactive complex was separated from the free radioactive antibody by
the addition of sheep antirabbit IgG and centrifugation. The pellet was
counted using a 
-counter for 60 s. The ACTH concentration in
the samples was determined by comparison with a standard curve. The
sensitivity of the ACTH immunoradiometric assay was 0.8 ng/L.
Statistical analysis
Blood pressure and plasma levels of pituitary hormones during infusion of either saline or adrenomedullin were expressed as the mean ± SEM and compared by ANOVA with post-hoc Tukey’s test using the Systat computer package (Systat, Evanston, IL). ANOVA was also used to compare plasma adrenomedullin concentrations in patients with different conditions.
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Results |
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Cardiovascular effects. There was no change in pulse or blood
pressure when adrenomedullin was infused at 3.2 pmol/kg·min,
achieving a circulating concentration of 52 pmol/L. Higher dose
adrenomedullin infusions (13.4 ± 0.5 pmol/kg·min) were well
tolerated with no adverse effects apart from facial flushing. At this
infusion rate, the plasma adrenomedullin concentration was 448 ±
58 pmol/kg. Diastolic blood pressure was significantly reduced,
accompanied by tachycardia, although there was no change in systolic
blood pressure. The fall in diastolic blood pressure was not associated
with any postural hypotension. Standing diastolic blood pressure at the
maximum infusion rate was significantly higher than supine diastolic
blood pressure (Fig. 1). Gel filtration chromatography
confirmed that the majority of the immunoreactivity eluted in the
position of synthetic adrenomedullin standard from samples taken during
both high dose infusion and recovery (Fig. 2
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There was no change in plasma concentrations of ACTH, LH, FSH, or TSH
during either infusion. There was no difference between adrenomedullin
and saline (data not shown) in the fall in cortisol seen during the
course of infusion.
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) with a steady state
infusion rate of 6.45 ± 0.36 pmol/kg·min. A decline in the
plasma concentration of adrenomedullin was observed when the infusion
was discontinued. From this rate of decline, the plasma half-life of
adrenomedullin in humans was calculated to be 22 ± 1.6 min. The
mean MCR was 27.4 ± 3.6 mL/kg·min, and the apparent
distribution space was 880 ± 150 mL/kg.
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The mean circulating concentration of adrenomedullin was
significantly elevated in patients with any cause of renal failure
(Table 2 and Fig. 4). Adrenomedullin was
not increased in patients with normal renal function. Patients with
conditions known to cause endothelial damage, such as the vasculitides
Wegener’s granulomatosis and SLE, also have normal plasma
adrenomedullin levels, provided that renal function is normal.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These results strongly suggest that circulating adrenomedullin plays no role in the control of systemic blood pressure in humans. The proposal by Ishimitsu et al. (12) that circulating adrenomedullin is involved in a defense mechanism, preserving the integrity of the cardiovascular system in hypertension, is not supported by our findings. Adrenomedullin is more likely to have a paracrine role in the control of vascular tone. Endothelial cells actively secrete adrenomedullin (2), which can directly stimulate vascular smooth muscle cells through specific adrenomedullin receptors (20, 21, 22). The proximity of vascular smooth muscle cells to endothelial cells means that the concentration of adrenomedullin around these cells is likely to be much higher than the basal concentrations that we have found in plasma and may be similar to those achieved by our maximal infusion rate. Adrenomedullin has been shown to inhibit endothelin production (23) and to be an antimigration factor (24) in vascular smooth muscle cells. Cultured vascular smooth muscle cells express adrenomedullin messenger ribonucleic acid at a 3- to 4-fold higher concentration than that in adrenal gland as demonstrated by Northern blot analysis (3). In addition, adrenomedullin messenger ribonucleic acid appears to be under hormonal regulation in endothelial and vascular smooth muscle cells (25, 26), suggesting that adrenomedullin has an important function in these cell types.
Plasma samples were prepared by solid phase extraction of medium and
low mol wt proteins as previously described (15). This technique is
commonly used in RIAs to remove the nonspecific high mol wt
antigen-antibody uncoupling factors (interference factors) (27). In the
case of our adrenomedullin infusion studies, we have shown the
chromatographic profile obtained in unextracted plasma to illustrate
that exogenous adrenomedullin does not alter the high mol wt
interference factor component in a particular individual. Thus,
Sep-Pak-ing is not required for the infusion studies where comparison
is made of a volunteer’s plasma at different times after
adrenomedullin infusion. The interference factor remains unchanged.
Sep-Pak-ing of plasma completely removes this interference factor and,
hence, removes this variable, which is essential when comparing basal
adrenomedullin levels between individuals. The profile in Fig. 5 shows an unextracted profile. The high mol wt peak is
completely removed by Sep-Pak-ing.
The half-life and apparent volume of distribution of adrenomedullin are larger than those of other related peptides. Rat CGRP has a plasma half-life of 6.9 min and a MCR of 11.3 mL/kg·min in humans (28). Human calcitonin has a plasma half-life of 10.1 min and a MCR of 8.4 mL/kg·min (29). Amylin has a half-life of 11.8 min, a MCR of 5.7 mL/kg·min, and an apparent distribution space of 94 mL/kg (30). The very high apparent distribution space for adrenomedullin suggests that adrenomedullin is extensively tissue bound, possibly to the receptors found both on the endothelium (8, 31) and in vascular smooth muscle cells (20, 21).
Plasma adrenomedullin was reported to be raised by 26% in patients with hypertension without organ damage (12) and by 78–214% in patients with renal impairment. We found a similar increase in patients with renal impairment and a significant correlation between plasma adrenomedullin and degree of renal impairment as previously described (32). Circulating adrenomedullin concentrations were normal in our patients with normal renal function, even when they had diseases known to affect the endothelium, including Wegener’s granulomatosis, systemic lupus erythematosus, or background diabetic retinopathy. It is likely that adrenomedullin is metabolized or cleared at least in part by the kidney, and that this metabolism is impaired in patients with renal failure. The small increase in plasma adrenomedullin reported in patients with hypertension (12) may indicate early renal impairment. Creatinine clearance was not checked in their study (12).
Adrenomedullin has been proposed to act through CGRP1 receptors in the isolated perfused mesenteric vascular bed of rats (33), although the effect on blood pressure in the intact animal is known not to act through these receptors (8, 9). The change in diastolic blood pressure during our human infusions did not have a postural component and was associated with facial cutaneous flushing, suggesting that the effect may have occurred distal to the arterioles at the capillary level. Intravenous CGRP caused similar facial flushing when infused at between 0.96–1.92 pmol/kg·min (achieved plasma concentration of 184 ± 9 pmol/L) in humans (28).
Samson et al. proposed a paracrine role for adrenomedullin in the pituitary based on their studies demonstrating that adrenomedullin inhibits ACTH release from dispersed rat anterior pituitary cells (5). We found that high dose adrenomedullin infusion was associated with increased release of PRL, but no change in other pituitary hormones, including ACTH. This would suggest a possible role for adrenomedullin as a regulator of lactotroph function. A paracrine rather than an endocrine effect is likely because the high dose iv adrenomedullin infusion may achieve local concentrations around the pituitary cells, consistent with those of a paracrine peptide. Adrenomedullin is known to be synthesized in the anterior pituitary (34).
A possible role for adrenomedullin in the management of primary pulmonary hypertension has been suggested after studies of its effects in animal models of this disease (6, 7). Under conditions of resting (low) pulmonary vasomotor tone, intralobar arterial injection of adrenomedullin had little effect on baseline lobar arterial or systemic blood pressure. In contrast, when pulmonary vasomotor tone was actively increased by intralobar arterial infusion of the thromboxane A2 mimic U-46619, adrenomedullin decreased lobar arterial pressure in a dose-dependent manner, with minimal effects on systemic blood pressure.
There is at present no pulmonary vasodilator available that does not cause systemic hypotension. Angiotensin-converting enzyme inhibitors, calcium antagonists (35), CGRP (36), prostacyclin (37, 38), nitric oxide (35), and oxygen have been used with minimal success. We have shown that high dose adrenomedullin is well tolerated in human volunteers, and that adrenomedullin has a minimal effect on systemic blood pressure. Some patients with elevated pulmonary pressure might respond to infusion of adrenomedullin with improved pulmonary pressure and consequent improvement in ventilation-perfusion matching. Adrenomedullin is known to be metabolized or cleared in the lung (4), as concentrations are higher in the pulmonary artery than in the aorta. This may be because the lung has a large number of adrenomedullin receptors.
In conclusion, we found that adrenomedullin could lower blood pressure in humans, as predicted from animal and tissue experiments (8). The circulating concentrations required to achieve this effect, however, were well above those found in plasma taken from patients with a variety of conditions. Thus, we conclude that adrenomedullin is likely to influence vascular tone mainly through paracrine mechanisms.
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Footnotes |
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2 United Kingdom Medical Research Council Research Fellow.
3 Wellcome Trust Research Fellow.
4 Wellcome Trust Prize student.
Received June 10, 1996.
Revised August 21, 1996.
Accepted August 23, 1996.
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