(Hypertension. 1995;25:1185-1190.)
© 1995 American Heart Association, Inc.
Articles |
Inhibition of Endothelin Production by Adrenomedullin in Vascular Smooth Muscle Cells
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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Abstract Adrenomedullin recently has been found to potently stimulate cAMP formation in cultured rat vascular smooth muscle cells (VSMCs). In the present study, we examined the effect of adrenomedullin on the production of a vasoconstrictive and growth-promoting peptide, endothelin-1, after stimulation with a clotting enzyme, thrombin, and a potent mitogen, platelet-derived growth factor (PDGF), in cultured rat VSMCs. Thrombin and PDGF stimulated endothelin-1 production in a dose-dependent manner. Rat adrenomedullin significantly inhibited thrombin- and PDGF-stimulated endothelin-1 production in a dose-dependent manner between 10-7 and 10-9 mol/L. Inhibition by rat adrenomedullin of thrombin- and PDGF-stimulated endothelin-1 production was paralleled by an increase in the cellular level of cAMP. Human adrenomedullin also inhibited thrombin- and PDGF-stimulated endothelin-1 production and increased cAMP levels. The addition of 8-bromo-cAMP, a cAMP analogue, reduced thrombin- and PDGF-induced endothelin-1 production. Furthermore, forskolin, a potent activator of adenylate cyclase, reduced thrombin- and PDGF-induced endothelin-1 production. In contrast, basal production of endothelin-1 was not altered by rat or human adrenomedullin. These results indicate that adrenomedullin inhibits not basal but thrombin- and PDGF-induced ET-1 production in cultured VSMCs probably through a cAMP-dependent process. Taken together with the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, adrenomedullin may modulate vascular tone as a paracrine regulator partially through the inhibition of VSMC endothelin-1 production in some pathophysiological states.
Key Words: endothelin • receptors, platelet-derived growth factor • thrombin • muscle, smooth, vascular
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Introduction |
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Adrenomedullin, a potent vasorelaxant peptide, 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 approximately 20% homology with calcitonin gene–related peptide (CGRP).1 Adrenomedullin injected intravenously causes a potent and long-lasting hypotensive effect in anesthetized rats and binds to specific receptors on platelet membranes to increase intracellular cAMP.1
Recently, Ishizaka et al2 and Eguchi et al3 have demonstrated that adrenomedullin stimulates cAMP formation in rat vascular smooth muscle cells (VSMCs). Eguchi et al3 have also shown that the rat adrenomedullin–induced cAMP response is inhibited by the CGRP receptor antagonist human CGRP (8-37); therefore, VSMCs possess specific receptors functionally coupled to adenylate cyclase with which CGRP interacts. Subsequently, we4 showed that adrenomedullin stimulates cAMP formation in rat glomerular mesangial cells as well as in rat VSMCs. 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 cells and proposed to function in vivo as a paracrine regulator of adjacent VSMCs.5 6 This peptide is present in human and rat plasma7 8 and is at high levels in patients or rat models with renal failure,9 10 severe hypertension,7 8 11 and advanced atherosclerosis.12 13 It is now evident that VSMCs can also produce and secrete ET-1 and that expression of preproET-1 transcripts and peptide synthesis in VSMCs are increased by a clotting enzyme, thrombin, and a potent mitogen, platelet-derived growth factor (PDGF).14 15 16 Therefore, we examined the effect of rat adrenomedullin on basal and PDGF- and thrombin-induced ET-1 production in cultured rat VSMCs. In addition, we also examined the effect on ET-1 production in these cells of human adrenomedullin (1-52), which is the major secretory form of adrenomedullin in humans.17
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Methods |
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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. Dulbecco's modified Eagle's medium (DMEM), trypsin, Versine, and fetal calf serum (FCS) 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. Purified human thrombin was a gift from Sankyo Co.
Cell Cultures
Rat VSMCs were grown from the explants of
Sprague-Dawley rat aorta and were cultured in DMEM containing
10% FCS, as previously described.18 19 Cells were
identified as VSMCs according to their morphological and growth
characteristics.18 19 The cultured cells were maintained
at 37°C with atmospheric air and 5% CO2, and
subculture was carried out after treatment with Versine followed by
trypsin.
Cells after 3 to 7 passages were used for this experiment. Cultured cells were normally maintained in DMEM containing 10% FCS, but before some experimentation VSMCs were rendered quiescent by 48 hours of serum deprivation.
Pharmacological Treatment
The culture medium was removed, and the cell monolayers were
washed twice with serum-free DMEM. Cells were exposed to different
concentrations of thrombin (0.2 and 2 U/mL) or PDGF (0.5 and 5 ng/mL)
for 4, 8, and 12 hours.
In separate experiments, effects of various concentrations (10-10, 10-9, 10-8, and 10-7 mol/L) of rat and human adrenomedullin on ET-1 production in cells treated with 2 U/mL thrombin or 5 ng/mL PDGF were examined. All experiments were performed with 2 mL serum-free DMEM. After incubation, the medium was aspirated and centrifuged at 3000g for 10 minutes, and the supernatant was collected and stored at -80°C until radioimmunoassay. Serum-free DMEM was used to avoid the presence of hormones and enzymes that could have masked the effects of the pharmacological agent added.
Extraction of ET-1
ET-1 was extracted as previously described.20 21
Briefly, 1.5 mL from each sample was diluted with 4 mL of 4% acetic
acid. After centrifugation, the solution was pumped at 1 mL/min through
a Sep-Pak C18 cartridge (Millipore). After evaporation of the extracts
by a centrifugal evaporator (model RD-31, Yamato Scientific), the dry
residue was dissolved in the assay buffer described below. The recovery
rate was found by the addition of three different quantities of cold
ET-1 (10, 50, and 100 pg/mL) to serum-free DMEM. The recovery rates of
10, 50, and 100 pg/mL of ET-1 were 72±3% (n=4), 71±2% (n=4), and
71±2% (n=4), respectively.
Radioimmunoassay of ET-1
ET-1 concentration was assayed using 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, angiotensin II, or arginine vasopressin.
Radioimmunoassay was performed in an assay buffer of 0.01 mol/L sodium phosphate, pH 7.4, containing 0.05 mol/L NaCl, 0.1% bovine serum albumin, 0.1% Nonidet P-40, and 0.01% NaN3, as described previously.20 21 In brief, rehydrated antiserum (100 µL) was added to 100 µL of the sample or 100 µL 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 effective range of the standard curve was between 0.2 and 200 pg of ET-1 per assay tube. The 50% intercept was at 21 pg of ET-1. The interassay variation was 13% and the intra-assay variation 7%.
Rat and human adrenomedullin did not interfere with the radioimmunoassay.
cAMP Measurement
After preincubation, the cell monolayers were washed twice with
serum-free medium and then stimulated for 30 minutes with various
concentrations (10-10, 10-9,
10-8, and 10-7 mol/L) of rat or human
adrenomedullin dissolved in medium that contained 5x10-4
mol/L IBMX. The reaction was stopped by rapid aspiration and the
addition of 2 mL ice-cold 65% ethanol, as previously
described.4 20 After evaporation by a centrifugal
evaporator, the dry residue was dissolved in an acid bath as previously
described.4 20 cAMP levels were determined by
radioimmunoassay with the cAMP assay kit. The minimal detection limit
of the assay was 0.31 pmol per assay tube. The 50% intercept was at
3.2 pmol per assay tube.
Calculations and Statistical Analysis
The statistical significance of differences was evaluated by
one-way ANOVA combined with Scheffé's analysis for multiple
comparisons.22 Values are expressed as mean±SD.
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Results |
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Effect of Thrombin and PDGF on ET-1 Production
In confluent, quiescent cultured VSMCs, thrombin and PDGF potently stimulated ET-1 production in a time-dependent manner (Table 1). The stimulatory effects of thrombin and PDGF were dose dependent. Nonstimulated quiescent VSMCs also produced a small but significant amount of ET-1 (Table 1).
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Effect of Adrenomedullin on Basal ET-1 Production
Rat and human adrenomedullin had no significant effects on basal
ET-1 production compared with control levels (Table 2).
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Effect of Adrenomedullin on Thrombin- and PDGF-Induced ET-1
Production
Rat adrenomedullin potently inhibited thrombin (2 U/mL)–induced
ET-1 production in a dose-dependent manner between 10-9
and 10-7 mol/L (Fig 1, left). Rat
adrenomedullin at 10-10 mol/L did not significantly alter
thrombin-induced ET-1 production. Human adrenomedullin also attenuated
the effect of thrombin on ET-1 production at 10-8 and
10-7 mol/L (Fig 1, right).
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Rat adrenomedullin potently inhibited PDGF (5 ng/mL)–induced ET-1 production in a dose-dependent manner between 10-9 and 10-7 mol/L (Fig 2, left). Human adrenomedullin also inhibited PDGF-induced ET-1 production at 10-8 and 10-7 mol/L (Fig 2, right).
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Effects of rat and human adrenomedullin on thrombin- and PDGF-induced ET-1 production were also examined in the presence of IBMX, and the results were compared with values observed in the absence of IBMX (Table 3). Rat and human adrenomedullin at 10-7 mol/L significantly inhibited thrombin- and PDGF-induced ET-1 production in both the presence and absence of IBMX. However, the inhibitory effects of rat and human adrenomedullin on thrombin-induced ET-1 production were significantly enhanced by the presence of IBMX. The inhibitory effect of rat adrenomedullin on PDGF-induced ET-1 production was also enhanced by the presence of IBMX.
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Fig 3 shows the effects of rat and human adrenomedullin on cAMP levels in cells treated with thrombin (left) or PDGF (right). In parallel with the inhibition of ET-1 production, cellular cAMP increased after treatment with rat and human adrenomedullin in both thrombin- and PDGF-treated cells.
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In addition, to check the integrity of adrenomedullin after 8 hours of incubation, we examined the effects of rat and human adrenomedullin incubated with cultured VSMCs for 8 hours at 37°C on the cellular level of cAMP (Table 4). Rat and human adrenomedullin (10-7 mol/L) after 8 hours of incubation significantly increased cAMP levels, although these stimulatory effects were significantly weaker than 10-7 mol/L of rat and human adrenomedullin before incubation. Therefore, the stimulatory effect of rat and human adrenomedullin on cAMP levels appeared to be maintained after 8 hours of incubation.
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Effect of 8-Bromo-cAMP and Forskolin on ET-1 Production
To determine whether the inhibitory effects of rat and human
adrenomedullin on ET-1 production after stimulation with thrombin or
PDGF are causally linked to the increase in cellular cAMP, we examined
the effect of a cAMP analogue, 8-bromo-cAMP, and a potent activator of
adenylate cyclase, forskolin, on ET-1 production in cells treated with
thrombin and PDGF.
The addition of 8-bromo-cAMP reduced thrombin- and PDGF-induced ET-1 production (Fig 4). The inhibition of 8-bromo-cAMP of thrombin-induced ET-1 production was dose dependent between 10-5 and 10-3 mol/L. On the other hand, the inhibition of PDGF-induced ET-1 production was dose dependent between 10-4 and 10-3 mol/L. The addition of forskolin also reduced thrombin- and PDGF-induced ET-1 production in a dose-dependent manner between 10-6 and 10-4 mol/L (Fig 5).
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P<.05 vs PDGF alone.
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Discussion |
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First, we have confirmed previous reports14 15 16 that cultured VSMCs produce a vasoconstrictive and growth-promoting peptide, ET-1, in a time-dependent manner and that thrombin and PDGF stimulate this production in these cells. The amount of ET-1 stimulated by thrombin and PDGF in cultured VSMCs was lower than that reported in cultured vascular endothelial cells.23 Nevertheless, the ET-1 concentration in the culture medium of thrombin- and PDGF-stimulated VSMCs appears to attain levels that are within the biologically effective range for this peptide.5 Furthermore, it is important to note that ET-1 potentiates the vasoconstrictive or mitogenic action of vasoconstrictors or growth factors such as norepinephrine24 25 and PDGF.26 27 Therefore, ET-1 induced by thrombin and PDGF may act to stimulate the contraction or proliferation in concert with these vasoactive substances.
Adrenomedullin is a peptide recently isolated from pheochromocytoma1 28 that elicits vasorelaxant and long-lasting hypotensive activity in anesthetized rats.1 This peptide has been shown to be present not only in human adrenal medulla but also in lung, cardiac ventricle, kidney, and circulating blood.28 29 In the present study, we showed that both rat and human adrenomedullin significantly inhibited ET-1 production stimulated by thrombin and PDGF in cultured rat VSMCs. Under the current experimental conditions, pharmacological doses of adrenomedullin were necessary to achieve these results in comparison with plasma adrenomedullin concentrations.19 20 However, local adrenomedullin levels in vascular tissues may be much higher than plasma adrenomedullin concentrations, because adrenomedullin recently has been shown to be synthesized in and secreted from vascular endothelial cells.30 Taken together with these observations, our results raise the hypothesis that adrenomedullin may regulate ET-1 production in certain pathological states, for example, when coagulation is activated in blood vessels.
We have obtained three pieces of evidence for a causal link between cAMP production and inhibition of ET-1 production by adrenomedullin in cultured rat VSMCs. First, adrenomedullin inhibited thrombin- and PDGF-induced ET-1 production, and this effect was paralleled by an increase in the cellular level of cAMP. Second, the inhibitory effect of adrenomedullin on the thrombin- and PDGF-induced ET-1 production were enhanced by the presence of IBMX. Third, both a cAMP analogue and an activator of adenylate cyclase reduced thrombin- and PDGF-induced ET-1 production.
These results suggest that adrenomedullin inhibits thrombin- and PDGF-induced ET-1 production in cultured rat VSMCs, probably through a cAMP-dependent process. However, not only pharmacological doses of adrenomedullin but also suprapharmacological doses of 8-bromo-cAMP and forskolin were required to inhibit the thrombin and PDGF effects on ET-1 production. Therefore, the physiological meaning of this inhibition by adrenomedullin is not clear at this time. Furthermore more studies are necessary to elucidate the exact role of cAMP in the inhibition by adrenomedullin of ET-1 production in cultured VSMCs.
Basal ET-1 production was not significantly altered by rat and human adrenomedullin. Therefore, spontaneous production by VSMCs appears to be insensitive to modulation by adrenomedullin.
Overall, the present work suggests that pharmacological doses of adrenomedullin reduce the ET-1 production caused by thrombin or PDGF probably through a cAMP-dependent process. Taken together with the profound effects of ET-1 on the contraction and proliferation of VSMCs, circulating and/or local adrenomedullin from adjacent vascular endothelial cells may modulate vascular tone in part through the inhibition of thrombin- or PDGF-induced ET-1 production in VSMCs. If so, this action in VSMCs may be added to vasorelaxation as yet another effect of adrenomedullin beneficial in some pathophysiological states.
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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). The authors thank Atsumi Ohnishi and Tomoko Okuno for their technical assistance.
Received September 28, 1994; first decision January 30, 1995; accepted February 16, 1995.
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K. Terata, H. Miura, Y. Liu, F. Loberiza, and D. D. Gutterman Human coronary arteriolar dilation to adrenomedullin: role of nitric oxide and K+ channels Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2620 - H2626. [Abstract] [Full Text] [PDF]
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R. W. Troughton, L. K. Lewis, T. G. Yandle, A. M. Richards, and M. G. Nicholls Hemodynamic, Hormone, and Urinary Effects of Adrenomedullin Infusion in Essential Hypertension Hypertension, October 1, 2000; 36(4): 588 - 593. [Abstract] [Full Text] [PDF]
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Y. HOJO, U. IKEDA, T.-A. KATSUKI, K. SHIMADA;, and G F BAXTER Decreased adrenomedullin production in the coronary circulation of patients with coronary artery disease Heart, July 1, 2000; 84(1): 88 - 88. [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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 G. G. Nussdorfer, G. P. Rossi, L. K. Malendowicz, and G. Mazzocchi Autocrine-Paracrine Endothelin System in the Physiology and Pathology of Steroid-Secreting Tissues Pharmacol. Rev., September 1, 1999; 51(3): 403 - 438. [Abstract] [Full Text] [PDF]
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R. Di Iorio, E. Marinoni, C. Letizia, P. Alo, B. Villaccio, and E. V. Cosmi Adrenomedullin, a New Vasoactive Peptide, Is Increased in Preeclampsia Hypertension, October 1, 1998; 32(4): 758 - 763. [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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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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 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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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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