help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lainchbury, J. G.
Right arrow Articles by Nicholls, M. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lainchbury, J. G.
Right arrow Articles by Nicholls, M. G.
Right arrowPubmed/NCBI databases
*Substance via MeSH
Medline Plus Health Information
*Hormones
The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 3 1016-1020
Copyright © 2000 by The Endocrine Society

Original Studies

Hemodynamic, Hormonal, and Renal Effects of Short-Term Adrenomedullin Infusion in Healthy Volunteers1

John G. Lainchbury, Richard W. Troughton, Lynley K. Lewis, Timothy G. Yandle, A. Mark Richards and M. Gary Nicholls

The Christchurch Cardioendocrine Research Group, Christchurch Hospital and Christchurch School of Medicine, Christchurch, New Zealand

Address correspondence and requests for reprints to: Prof. M. G. Nicholls, Department of Medicine, Christchurch Hospital, Riccarton Avenue, Christchurch, New Zealand. E-mail: gary.nicholls{at}chmeds.ac.nz


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The actions of adrenomedullin (ADM), a 52-amino acid peptide, are not well defined in man. We, therefore, studied eight normal volunteers aged 18–32 yr in a placebo-controlled crossover study. On the 2 study days, subjects received, in random order, ADM in "low" and "high" dose (2.9 pmol/kg·min and 5.8 pmol/kg·min for 2 h each) or vehicle (hemaccel) infusion on day 4 of a metabolic diet (Na+ 80 mmol/day, K+ 100 mmol/day). Achieved plasma ADM levels were in the pathophysiological range, and plasma cAMP values rose 5 pmol/L during the higher dose. Compared with time-matched vehicle infusion, high-dose ADM increased peak heart rate by 10 beats per minute (P < 0.05) and lowered diastolic (by 5 mm Hg, P < 0.01) blood pressure. Cardiac output increased in both phases of ADM (low dose, 7.6 L/min; high dose, 10.2 L/min; vehicle, 6 L/min; P < 0.05 for both). Despite a 2-fold rise in PRA during high-dose ADM (P < 0.01), aldosterone levels were unaltered. Norepinephrine levels increased by 50% during high-dose ADM (P < 0.001), but epinephrine levels were unchanged. Plasma PRL levels increased during high-dose ADM (P = 0.014). ADM had no significant effect on urine volume and sodium excretion. Infusion of ADM to achieve pathophysiological plasma levels produced significant hemodynamic effects, stimulated renin but inhibited the aldosterone response to endogenous angiotensin II, and activated the sympathetic system and PRL without altering urine sodium excretion in normal subjects.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ADRENOMEDULLIN (ADM), a 52-amino acid peptide, was isolated from human pheochromocytoma tissue in 1993 (1). The human gene is located on chromosome 11 (2), and expression has been demonstrated in numerous tissues and organs (3, 4). Regulation of gene transcription and ADM production has been studied, particularly in vascular smooth muscle cells and endothelial cells (5, 6, 7, 8) where gene expression is particularly high. Circulating levels of the peptide are in the low picomolar range in healthy man, but are elevated in chronic renal failure, heart failure, severe hypertension, diabetes mellitus, hepatic disease, pulmonary hypertension, subarachnoid hemorrhage, sepsis, hyperthyroidism, during cardiac surgery, and in pregnancy (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20).

The biological importance of ADM remains to be established. There is evidence from experimental studies in animals that it has a role within the central nervous system to modulate salt appetite (21, 22). A variety of biological responses has been documented with its administration into the central nervous system, into the general circulation, or directly into the renal circulation (9, 21, 22). However, doses administered have often been high, and physiological relevance is, therefore, unclear.

There have been few reports of the biological effects of ADM infused iv into healthy volunteers. It has been claimed that even high-dose infusion has little or no effect on arterial pressure but stimulates PRL release (23). By contrast, we observed that very low-dose infusions of the peptide had statistically significant, if small, effects on arterial pressure without modification of renal function or circulating vasoactive hormone levels (24).

In the present study, we infused ADM iv at doses aimed to achieve plasma ADM levels within the pathophysiological range to document hemodynamic, hormonal, and renal effects.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The protocol was approved by the Ethics Committee of the Southern Regional Health Authority. Eight healthy male volunteers aged 18–32 yr underwent this placebo-controlled, crossover study. The subjects were not taking medication of any type. Each took a diet of constant dietary sodium (80 mmol/day) and potassium (100 mmol/day) for 4 days prior to infusion of ADM in hemaccel or vehicle (hemaccel only). On both experimental days, the volunteers took breakfast at 0745 h; completed a 24-h urine collection at 0800 h for sodium, potassium, and creatinine measurement; then remained seated in an easy chair until 1500 h, except every 30 min when standing to urinate. Venous cannulae were placed in either forearm, one for infusion of ADM or vehicle, the other for blood sampling. At 1000 h, ADM in hemaccel was infused at 16 ng/kg·min for 120 min, then at 32 ng/kg·min for an additional 120 min. Alternatively, vehicle alone (50 mL hemaccel over 240 min) was administered. Subjects were blinded as to which infusion was given; four received ADM first and four received vehicle. Venous samples were drawn before, during, and subsequent to each infusion for measurements of ADM (25), PRA (26), and plasma levels of aldosterone (27), norepinephrine and epinephrine (28), cAMP (commercial kit, Biotrak; Amersham Pharmacia Biotech, England), brain natriuretic peptide (BNP) (29), atrial natriuretic peptide (ANP) (30), and cortisol (31). Venous blood was also taken on four occasions for plasma PRL levels but not for any other pituitary hormones due to blood volume. All samples from an individual were analyzed in a single assay. Intra-assay coefficients of variation were less than 9%. Venous samples were drawn also for measurements of plasma sodium and potassium and for hematocrit determination before and at the completion of ADM and vehicle infusions.

On both infusion days, arterial pressure and heart rate were recorded in duplicate at 30-min intervals using an automatic sphygmomanometer (Electronics Services Limited). Every 30 min, after venous sampling, the subjects stood to pass urine for measurements of sodium, potassium, and creatinine. Cardiac output was measured with the thoracic impedance method (Minnesota Impedance Cardiograph model 304B; Instrumentation for Medicine Inc.).

Human 52-amino acid ADM for infusion was purchased from CLINALFA AG, Switzerland.

Results were analyzed using two-way ANOVA with "treatment" and time as repeated measures (32). A P value of 0.05 or less was taken to indicate statistical significance. Values are given as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
No volunteer reported subjective responses to ADM. Collection of data was completed.

Plasma ADM levels on the day of vehicle infusion remained steady and generally below 10 pmol/L, whereas on the day of peptide infusion levels increased to 16 ± 2 and 42 ± 7 pmol/L at the completion of the two infusion rates. Thereafter, ADM levels declined but remained significantly above time-matched vehicle values 90 min after completion of infusion (Fig. 1Go). Using the same assay methodology, we have observed ADM levels of 8–60 pmol/L (23 ± 2.7 pmol/L, mean ± SEM) in 23 patients with reduced left ventricular ejection fraction after myocardial infarction (unpublished observations).



View larger version (25K):
[in this window]
[in a new window]
  		Figure 1. Plasma levels of ADM, cAMP, ANP, and BNP with ADM and control infusions. Results are mean ± SEM, n = 8. *, P < 0.05; +, P < 0.01; #, P <= 0.001.

 
Plasma levels of cAMP were unaltered by the lower dose of ADM, increased approximately 5 pmol/L during the higher infusion rate, and thereafter declined to time-matched vehicle control values (Fig. 1Go).

Plasma levels of BNP exhibited little obvious change, although there was a statistically significant decrease during ADM vs. vehicle infusion (P = 0.05), and this effect was dose dependent. Plasma ANP levels were not altered by ADM (Fig. 1Go).

PRA remained stable during vehicle infusion, but increased in a dose-dependent fashion with ADM, peak levels being approximately double those of time-matched levels obtained during vehicle infusion (P < 0.01; Fig. 2Go). By contrast, plasma levels of aldosterone were not altered significantly, and the correlation between concomitant PRA and aldosterone levels over the period of ADM infusion (r = 0.07) fell well short of statistical significance. Whereas plasma epinephrine levels were similar on vehicle and ADM infusion days, plasma norepinephrine levels exhibited a dose-dependent increase with ADM (P < 0.001) and declined toward time-matched vehicle levels on cessation of infusion (Fig. 2Go). A tight and positive relationship between plasma norepinephrine and PRA values was observed on the day of ADM administration (r = 0.70, P < 0.001).



View larger version (26K):
[in this window]
[in a new window]
  		Figure 2. Levels of PRA and plasma aldosterone, epinephrine and norepinephrine with ADM and control infusions. Results are mean ± SEM, n = 8. *, P < 0.05; +, P < 0.01; #, P <= 0.001.

 
Plasma PRL levels increased in a dose-dependent fashion with ADM (P = 0.014). The difference in PRL levels between the two experimental days at the termination of the higher-dose infusion was approximately 70 pmol/L, and values were virtually identical 60 min after termination of the infusions (Fig. 3Go).



View larger version (16K):
[in this window]
[in a new window]
  		Figure 3. Plasma PRL levels with ADM and control infusions in eight healthy volunteers. *, P < 0.05.

 
Heart rate tended to fall during vehicle infusion but increased in a dose-dependent fashion with ADM administration (P < 0.005), then declined promptly to time-matched vehicle values (Fig. 4Go). Systolic arterial pressure was not altered significantly (P = 0.07), but diastolic arterial pressure exhibited a dose-dependent decline with ADM (P < 0.05). The maximum mean difference in diastolic arterial pressure between ADM and vehicle infusions was 7 mm Hg at the completion of the higher dose (Fig. 4Go). Cardiac output was quite stable throughout vehicle infusion, but showed a dose-dependent and striking increase with ADM (P < 0.05), especially during the higher dose, but was significantly stimulated also toward the end of the lower-dose infusion (Fig. 4Go). The difference between the 2 experimental days was approximately 3 L/min by the end of the infusion period. Cessation of ADM infusion resulted in a rapid fall in cardiac output to time-matched control values (Fig. 4Go). On the day of ADM administration, plasma norepinephrine levels correlated closely and in a positive fashion, with both heart rate (r = 0.69, P < 0.001) and cardiac output (r = 0.77, P < 0.001). Furthermore, heart rate and cardiac output showed a tight relationship on that same day (r = 0.70, P < 0.001).



View larger version (25K):
[in this window]
[in a new window]
  		Figure 4. Hemodynamic effects of ADM and control infusion in healthy volunteers. Results are mean ± SEM, n = 8. *, P < 0.05; +, P < 0.01; #, P <= 0.001.

 
Urine volume, sodium, and potassium excretion were not significantly different between ADM and vehicle infusion days (Fig. 5Go). This was so whether indices were adjusted according to creatinine excretion, or not. Furthermore, change and percentage change in urine volume, urine sodium, and urine potassium were not significantly different between the 2 experimental days. Plasma sodium, potassium, and creatinine and hematocrit were similar on both experimental days and were not altered by ADM infusion (data not shown).



View larger version (31K):
[in this window]
[in a new window]
  		Figure 5. Urine volume, sodium excretion, and potassium excretion in eight healthy volunteers before, during, and after ADM and control infusion. Results are shown as mean ± SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Administration of ADM under highly experimental circumstances in animals has been shown to have a variety of biological effects (33). Fewer studies have been performed in healthy volunteers, and it remains unclear as to whether the hormone has biological effects at physiological or pathophysiologic circulating levels. On the one hand, Meeran et al. (23) claimed that ADM (52 amino acid) infused at approximately 19 ng/kg·min had little or no effect on arterial pressure or heart rate, and much higher doses (approximately 80 ng/kg·min) were required to show distinct hemodynamic effects. By contrast, our group reported subtle blood pressure lowering effects from 90-min infusions of ADM at 2 and 8 ng/kg·min, in healthy volunteers (24). At these low infusion rates, we found no effect of ADM on vasoactive hormone systems, particularly the renin-angiotensin system, aldosterone, ANP, BNP, and plasma norepinephrine, nor on urinary electrolyte excretion (24). There are a number of differences in study protocols that might explain the discrepant results from the above two studies. In particular, duration of peptide infusion and the presence or otherwise of a time-matched vehicle infusion are key issues.

The present study was of healthy males who took a diet of set sodium and potassium intake with a time-matched vehicle infusion to allow accurate interpretation of data during ADM infusion, and taking into account diurnal fluctuations in the indices of interest. Body posture was strictly controlled, and medications were avoided. Under these carefully controlled circumstances, we observed that ADM, at plasma levels seen for example, after acute myocardial infarction and in heart failure, had clear-cut effects on some vasoactive hormone systems and hemodynamics, but no discernible effect on urine volume or electrolyte excretion.

In regard to vasoactive hormone systems, there was vigorous stimulation of PRA and plasma norepinephrine consistent with renin release and activation of the sympathetic system. In view of the parallel increments in norepinephrine and PRA, it is possible that enhanced sympathetic traffic to the juxtaglomerular apparatus accounted for activation of the renin-angiotensin system. Because in vitro studies using mouse juxtaglomerular cells indicate a direct renin-stimulating action of ADM (34), it is possible that such a mechanism contributed also to the vigorous PRA response we observed.

Notwithstanding activation of the renin-angiotensin system, plasma aldosterone levels were not significantly altered, consistent with most, but not all (35), earlier reports from in vitro studies using rodent or human adrenal tissue that the response of the zona glomerulosa to angiotensin II can be inhibited by ADM (36, 37, 38, 39, 40). Plasma ANP levels were not altered, but plasma BNP levels did decline in a statistically significant fashion, perhaps due to a decline in cardiac afterload. We hesitate to suggest these subtle changes in plasma BNP levels would have physiological significance, at least in the short term.

cAMP is considered to be one second messenger of ADM (41, 42, 43). In this regard, the rise in plasma levels of cAMP during the higher dose of ADM infusion is unsurprising. It is perhaps noteworthy that some biological effects were clearly seen earlier than the increase in plasma levels of cAMP.

In common with Meeran et al. (23), we observed ADM to have a stimulatory effect on plasma levels of PRL. Whether ADM is a physiologically important regulator of PRL production or release remains to be determined.

In regard to hemodynamic indices, ADM induced clear-cut increases in heart rate and cardiac output and a decline in diastolic arterial pressure. The parallel increase in circulating norepinephrine and heart rate suggests that activation of the sympathetic system was contributory, although additional effects, including inhibition of parasympathetic activity, remain possibilities. In that ADM has been demonstrated from animal and human studies to be an arterial dilator (21, 44), we presume the decline in arterial pressure resulted in large part from such an action. It seems unlikely that a decline in plasma volume was contributory because hematocrit was unaltered and urine volume did not change with ADM administration.

ADM elicited a rise in cardiac output even during the lower of the two infusion rates, and the magnitude of change with the higher dose was striking. It is possible that this response was accounted for by an increase in heart rate, by sympathetic stimulation of myocardial contractility, and by a direct positive inotropic effect of ADM—an effect well demonstrated under experimental circumstances in animals (45, 46). Our study does not permit dissection of the relative contribution of these three factors to the change in cardiac output.

Notwithstanding evidence from animal studies that ADM can enhance urine sodium excretion (21, 33), we observed no change under the conditions of our study. This is not to say that under other circumstances, such as with a high salt diet, in hypertension, or heart failure (47), or with longer-term infusions, a natriuresis might be observed. We can say, however, that under the present study conditions, the threshold for some renal effects of ADM are higher than for actions on neurohormonal systems and hemodynamics.

In conclusion, our study demonstrates that ADM infusion, which achieved plasma levels of the peptide in the pathophysiological range, stimulates plasma levels of cAMP, the renin-angiotensin system, and the sympathetic system, as well as PRL, reduces arterial pressure and stimulates heart rate and cardiac output without altering urine sodium, potassium, or volume. These data suggest that ADM may play a role under pathophysiological circumstances in regulation of vasoactive hormone and hemodynamic indices. The threshold for renal effects, at least under the circumstances of the present study, is higher than for vasoactive hormone and hemodynamic actions.


   Acknowledgments
 
We are grateful to Barbara Griffin for secretarial assistance.


   Footnotes
 
1 Financial assistance provided by the Health Research Council of New Zealand and the National Heart Foundation of New Zealand. Back

Received June 22, 1999.

Revised November 4, 1999.

Accepted November 19, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Kitamura K, Kangawa K, Kawamoto M, et al. 1993 Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun. 192:553–560.[CrossRef][Medline]
  2. Ishimitsu T, Kojima M, Kangawa K, et al. 1994 Genomic structure of human adrenomedullin gene. Biochem Biophys Res Commun. 203:631–639.[CrossRef][Medline]
  3. Sakata J, Shimokubo T, Kitamura K, et al. 1994 Distribution and characterization of immunoreactive rat adrenomedullin in tissue and plasma. FEBS Lett. 352:105–108.[CrossRef][Medline]
  4. Cameron VA, Fleming AM. 1998 Novel sites of adrenomedullin gene expression in mouse and rat tissues. Endocrinology. 139:2253–2264.[Abstract/Free Full Text]
  5. Sugo S, Minamino N, Kangawa K, et al. 1994 Endothelial cells actively synthesize and secrete adrenomedullin. Biochem Biophys Res Commun. 201:1160–1166.[CrossRef][Medline]
  6. Minamino N, Shoji H, Sugo S, Kangawa K, Matsuo H. 1995 Adrenocortical steroids, thyroid hormones and retinoic acid augment the production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun. 211:686–693.[CrossRef][Medline]
  7. Sugo S, Minamino N, Shoji H, et al. 1995 Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun. 207:25–32.[CrossRef][Medline]
  8. Isumi Y, Shoji H, Sugo S, et al. 1998 Regulation of adrenomedullin production in rat endothelial cells. Endocrinology. 139:838–846.[Abstract/Free Full Text]
  9. Richards AM, Nicholls MG, Lewis L, Lainchbury JG. 1996 Adrenomedullin. Clin Sci. 91:3–16.[Medline]
  10. Sato K, Hirata Y, Imai T, Iwashina M, Marumo F. 1995 Characterization of immunoreactive adrenomedullin in human plasma and urine. Life Sci. 57:189–194.[CrossRef][Medline]
  11. Kobayashi K, Kitamura K, Etoh T, et al. 1996 Increased plasma adrenomedullin levels in chronic congestive heart failure. Am Heart J. 131:994–998.[CrossRef][Medline]
  12. Kitamura K, Ichiki Y, Tanaka M, et al. 1994 Immunoreactive adrenomedullin in human plasma. FEBS Lett. 341:288–290.[CrossRef][Medline]
  13. Hayashi M, Shimosawa T, Isaka M, Yamada S, Fujita R, Fujita T. 1997 Plasma adrenomedullin in diabetes. Lancet. 350:1449–1450.[CrossRef][Medline]
  14. Guevara M, Ginès P, Jimènez W, et al. 1998 Increased adrenomedullin levels in cirrhosis: relationship with hemodynamic abnormalities and vasoconstrictor systems. Gastroenterology. 114:336–343.[CrossRef][Medline]
  15. Kakishita M, Nishikimi T, Okano Y, et al. 1999 Increased plasma levels of adrenomedullin in patients with pulmonary hypertension. Clin Sci. 96:33–39.[Medline]
  16. Kikumoto K, Kubo A, Hayashi Y, et al. 1998 Increased plasma concentration of adrenomedullin in patients with subarachnoid hemorrhage. Anesth Analg. 87:859–863.[Abstract/Free Full Text]
  17. Hirata Y, Mitaka C, Sato K, et al. 1996 Increased circulating adrenomedullin, a novel vasodilatory peptide, in sepsis. J Clin Endocrinol Metab. 81:1449–1453.[Abstract]
  18. Taniyama M, Kitamura K, Ban Y, Eto T, Katagiri T. 1996 Elevated plasma adrenomedullin level in hyperthyroidism. Eur J Clin Invest. 26:454–456.[CrossRef][Medline]
  19. Nishikimi T, Hayashi Y, Iribu G, et al. 1998 Increased plasma adrenomedullin concentrations during cardiac surgery. Clin Sci. 94:585–590.[Medline]
  20. Di Iorio R, Marinoni E, Scavo D, Letizia C, Cosmi EV. 1997 Adrenomedullin in pregnancy. Lancet. 349:328.[CrossRef][Medline]
  21. Samson WK. 1998 Adrenomedullin: vascular hormone. In: Levin ER, Ellis R, Nadler JL, eds. Endocrinology of cardiovascular function. Boston, Dordrecht, and London: Kluwer; 257–278.
  22. Samson WK, Bode AM, Murphy TC, Resch ZT. 1999 Antisense oligonucleotide treatment reveals a physiologically relevant role for adrenomedullin gene products in sodium intake. Brain Res. 818:164–167.[CrossRef][Medline]
  23. Meeran K, O’Shea D, Upton PD, et al. 1997 Circulating adrenomedullin does not regulate systemic blood pressure but increases plasma prolactin after intravenous infusion in humans: a pharmacokinetic study. J Clin Endocrinol Metab. 82:95–100.[Abstract/Free Full Text]
  24. Lainchbury JG, Cooper GJS, Coy DH, et al. 1997 Adrenomedullin: a hypotensive hormone in man. Clin Sci. 92:467–472.[Medline]
  25. Lewis LK, Smith MW, Yandle TG, Richards AM, Nicholls MG. 1998 Adrenomedullin (1–52) measured in human plasma by radioimmunoassay: plasma concentration, adsorption, and storage. Clin Chem. 44:571–577.[Abstract/Free Full Text]
  26. Nussberger J, Fasanella d’ Amore T, Porchet M, et al. 1987 Repeated administration of the converting enzyme inhibitor cilazapril to normal volunteers. J Cardiovasc Pharmacol. 9:39–44.[Medline]
  27. Lun S, Espiner E, Nicholls M, Yandle T. 1983 A direct radioimmunoassay for aldosterone in plasma. Clin Chem. 29:268–271.[Abstract/Free Full Text]
  28. Goldstein DS, Feurstein G, Izzo JL, Kopin IJ, Keiser HR. 1981 Validity and reliability of liquid chromatography with electrochemical detection for measuring plasma levels of norepinephrine and epinephrine in man. Life Sci. 28:467–475.[CrossRef][Medline]
  29. Yandle TG, Richards AM, Gilbert A, Fisher S, Holmes S, Espiner EA. 1993 Assay of brain natriuretic peptide (BNP) in human plasma: evidence for high molecular weight BNP as a major plasma component in heart failure. J Clin Endocrinol Metab. 76:832–838.[Abstract]
  30. Florkowski CM, Richards AM, Espiner EA, Yandle TG, Frampton C. 1994 Renal, endocrine, and hemodynamic interactions of atrial and brain natriuretic peptides in normal men. Am J Physiol. 266:R1244–R1250.
  31. Lewis JG, Manley L, Whitlow JC, Elder PA. 1992 Production of a monoclonal antibody to cortisol: application to a direct enzyme-linked immunosorbent assay of plasma. Steroids. 57:82–85.[CrossRef][Medline]
  32. Jenrich R, Sampson P, Frane J. 1983 P2Y analysis of variance and covariance including repeated measures. In: BMDP statistical software manual. Los Angeles: University of California Press; 359–387.
  33. Schell DA, Vari RC, Samson WK. 1996 Adrenomedullin: a newly discovered hormone controlling fluid and electrolyte homeostasis. Trends Endocrinol Metab. 7:7–13.
  34. Jensen BL, Kramer BK, Kurtz A. 1997 Adrenomedullin stimulates renin release and renin mRNA in mouse juxtaglomerular granular cells. Hypertension. 29:1148–1155.[Abstract/Free Full Text]
  35. Hinson JP, Thomson LM, Kapas S. 1998 Adrenomedullin and CGRP receptors mediate different effects in the rat adrenal cortex. Endocr Res, 24:725–728.
  36. Yamaguchi T, Baba K, Doi Y, Yano K. 1995 Effect of adrenomedullin on aldosterone secretion by dispersed rat adrenal zona glomerulosa cells. Life Sci. 56:379–387.[Medline]
  37. Mazzocchi G, Rebuffat P, Gottardo G, Nussdorfer GG. 1996 Adrenomedullin and calcitonin gene-related peptide inhibit aldosterone secretion in rats, acting via a common receptor. Life Sci. 58:839–844.[CrossRef][Medline]
  38. Andreis PG, Mazzocchi G, Rebuffat P, Nussdorfer GG. 1997 Effects of adrenomedullin and proadrenomedullin N-terminal 20 peptide on rat zona glomerulosa cells. Life Sci. 60:1693–1697.[CrossRef][Medline]
  39. Andreis PG, Neri G, Prayer-Galetti T, et al. 1997 Effects of adrenomedullin on the human adrenal glands: an in vitro study. J. Clin Endocrinol Metab. 82:1167–1170.
  40. Belloni AS, Andreis PG, Rossi GP, et al. 1998 Inhibitory effect of adrenomedullin (ADM) on the aldosterone response of human adrenocortical cells to angiotensin-II: role of ADM(22–52)-sensitive receptors. Life Sci. 63:2313–2321.[CrossRef][Medline]
  41. Ishizaka Y, Ishizaka Y, Tanaka M, et al. 1994 Adrenomedullin stimulates cyclic AMP formation in rat vascular smooth muscle cells. Biochem Biophy Res Commun. 200:642–646.[CrossRef][Medline]
  42. Shimekake Y, Nagata K, Ohta S, et al. 1995 Adrenomedullin stimulates two signal transduction pathways, cAMP accumulation and Ca2+ mobilization, in bovine aortic endothelial cells. J Biol Chem. 270:4412–4417.[Abstract/Free Full Text]
  43. Barker S, Kapas S, Corder R, Clark AJL. 1996 Adrenomedullin acts via stimulation of cyclic AMP and not via calcium signalling in vascular cells in culture. J Hum Hypertens. 10:421–423.[Medline]
  44. Cockroft JR, Noon JP, Gardner-Medwin J, Bennett T. 1997 Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels. Br J Clin Pharmacol. 44:57–60.[CrossRef][Medline]
  45. Szokodi I, Kinnunen P, Ruskoaho H. 1996 Inotropic effect of adrenomedullin in the isolated perfused rat heart. Acta Physiol Scand. 156:151–152.[CrossRef][Medline]
  46. Szokodi I, Kinnunen P, Tavi P, Weckstrom M, Toth M, Ruskoaho H. 1998 Evidence for cAMP-independent mechanisms mediating the effects of adrenomedullin, a new inotropic peptide. Circulation. 97:1062–1070.[Abstract/Free Full Text]
  47. Rademaker MT, Charles CJ, Lewis LK, et al. 1997 Beneficial hemodynamic and renal effects of adrenomedullin in an ovine model of heart failure. Circulation. 96:1983–1990.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. Kjolby and P. Bie
Chronic activation of plasma renin is log-linearly related to dietary sodium and eliminates natriuresis in response to a pulse change in total body sodium
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R17 - R25.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
E. Bisping, G. Tenderich, P. Barckhausen, B. Stumme, S. Bruns, D. von Lewinski, and B. Pieske
Atrial myocardium is the predominant inotropic target of adrenomedullin in the human heart
Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3001 - H3007.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
C. Gibbons, R. Dackor, W. Dunworth, K. Fritz-Six, and K. M. Caron
Receptor Activity-Modifying Proteins: RAMPing up Adrenomedullin Signaling
Mol. Endocrinol., April 1, 2007; 21(4): 783 - 796.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
K. Caron, J. Hagaman, T. Nishikimi, H.-S. Kim, and O. Smithies
Adrenomedullin gene expression differences in mice do not affect blood pressure but modulate hypertension-induced pathology in males
PNAS, February 27, 2007; 104(9): 3420 - 3425.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
L. J Pearson, C. Rait, M G. Nicholls, T. G Yandle, and J. J Evans
Regulation of adrenomedullin release from human endothelial cells by sex steroids and angiotensin-II.
J. Endocrinol., October 1, 2006; 191(1): 171 - 177.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
C J Charles, D L Jardine, M G Nicholls, and A M Richards
Adrenomedullin increases cardiac sympathetic nerve activity in normal conscious sheep
J. Endocrinol., November 1, 2005; 187(2): 275 - 281.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. M. Taylor, J. R. Baker, and W. K. Samson
Brain-derived adrenomedullin controls blood volume through the regulation of arginine vasopressin production and release
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1203 - R1210.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
G. T. Dorner, G. Garhofer, K.-H. Huemer, E. Golestani, C. Zawinka, L. Schmetterer, and M. Wolzt
Effects of Adrenomedullin on Ocular Hemodynamic Parameters in the Choroid and the Ophthalmic Artery
Invest. Ophthalmol. Vis. Sci., September 1, 2003; 44(9): 3947 - 3951.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
E. Dobrzynski, D. Montanari, J. Agata, J. Zhu, J. Chao, and L. Chao
Adrenomedullin improves cardiac function and prevents renal damage in streptozotocin-induced diabetic rats
Am J Physiol Endocrinol Metab, December 1, 2002; 283(6): E1291 - E1298.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
R. Nakamura, J. Kato, K. Kitamura, H. Onitsuka, T. Imamura, K. Marutsuka, Y. Asada, K. Kangawa, and T. Eto
Beneficial effects of adrenomedullin on left ventricular remodeling after myocardial infarction in rats
Cardiovasc Res, December 1, 2002; 56(3): 373 - 380.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
D. O. McGregor, R. W. Troughton, C. Frampton, K. L. Lynn, T. Yandle, A. M. Richards, and M. G. Nicholls
Hypotensive and Natriuretic Actions of Adrenomedullin in Subjects With Chronic Renal Impairment
Hypertension, May 1, 2001; 37(5): 1279 - 1284.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
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]

Home page
 J. Clin. Endocrinol. Metab.Home page
F. Piquard, A. Charloux, B. Mettauer, E. Epailly, E. Lonsdorfer, S. Popescu, J. Lonsdorfer, and B. Geny
Exercise-Induced Increase in Circulating Adrenomedullin Is Related to Mean Blood Pressure in Heart Transplant Recipients
J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2828 - 2831.
[Abstract] [Full Text]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
R. D. Reidelberger, L. Kelsey, and D. Heimann
Effects of amylin-related peptides on food intake, meal patterns, and gastric emptying in rats
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2002; 282(5): R1395 - R1404.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lainchbury, J. G.
Right arrow Articles by Nicholls, M. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lainchbury, J. G.
Right arrow Articles by Nicholls, M. G.
Right arrowPubmed/NCBI databases
*Substance via MeSH
Medline Plus Health Information
*Hormones

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals