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(Circulation. 1997;96:1983-1990.)
© 1997 American Heart Association, Inc.

Articles

Beneficial Hemodynamic and Renal Effects of Adrenomedullin in an Ovine Model of Heart Failure

M. T. Rademaker, BSc; C. J. Charles, PhD; L. K. Lewis, MSc; T. G. Yandle, PhD; G. J. S. Cooper, DPhil; D. H. Coy, PhD, FRACP; A. M. Richards, PhD, MD, FRACP; ; M. G. Nicholls, MD, FRACP

From the Department of Medicine, The Christchurch School of Medicine (M.T.R., C.J.C., L.K.L., T.G.Y., A.M.R., M.G.N.), and Developmental Biology and Cancer Research Group, School of Biological Sciences, University of Auckland (G.J.S.C.), New Zealand; and the Department of Medicine, Tulane University, New Orleans, La (D.H.C.).

Correspondence to M.T. Rademaker, Department of Medicine, The Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand.

	Abstract

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Background Adrenomedullin is a recently discovered endogenous peptide with hypotensive and natriuretic actions in normal animals. Circulating and ventricular adrenomedullin are elevated in congestive heart failure, suggesting a possible role in the pathophysiology of this disease. No studies have previously examined the effects of adrenomedullin in heart failure.

Methods and Results Eight sheep with pacing-induced heart failure received human adrenomedullin(1-52) at 10 and 100 ng · kg^-1 · min^-1 IV for 90 minutes each. Compared with vehicle control data, adrenomedullin increased plasma cAMP (high dose, P<.05) in association with dose-dependent falls in calculated peripheral resistance (13 mm Hg · L^-1 · min^-1, P<.001), mean arterial pressure (9 mm Hg, P<.001), and left atrial pressure (5 mm Hg, P<.001) and increases in cardiac output (0.5 L/min, P<.001). Adrenomedullin increased urine sodium (threefold, P<.05), creatinine (P<.05) and cAMP excretion (P<.01), creatinine clearance (P<.05), and renal production of cAMP (P<.05), whereas urine output was maintained during infusion and raised after infusion (P<.05). Adrenomedullin reduced plasma aldosterone levels (P<.05), whereas plasma atrial and brain natriuretic peptide concentrations were unchanged during infusion and rose after infusion (P<.01 and P<.05, respectively). Plasma catecholamine, cortisol, renin, calcium, and glucose concentrations were not significantly altered.

Conclusions Adrenomedullin reduced ventricular preload and afterload and improved cardiac output in sheep with congestive heart failure. Despite the clear fall in arterial pressure, adrenomedullin increased creatinine clearance and sodium excretion and maintained urine output. These results imply an important pathophysiological role for adrenomedullin in the regulation of pressure and volume in heart failure and raise the possibility of a new therapeutic approach to this disease.

Key Words: heart failure • hemodynamics • hormones • pharmacokinetics • vasodilation

	Introduction

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Human ADM, discovered in 1993, is a 52–amino-acid peptide showing structural homology with calcitonin gene–related peptide and amylin in terms of the six-residue ring structure (formed by a single disulfide bridge) and C-terminal amidation.¹ Although originally isolated from human pheochromocytoma cells,¹ immunoreactive ADM has subsequently been detected in a wide variety of tissues, including adrenal medulla, heart, brain, lung, kidney, and gastrointestinal organs.^{1 2} More recently, rat³ and porcine⁴ ADM have been sequenced and indicate that the structure is well conserved across species. The biological activity of ADM has been investigated to a limited extent both in vitro and in vivo. It has been reported to inhibit endothelin 1 and Ang II release from isolated rat aortic arteries,⁵ aldosterone secretion from rat adrenal zona glomerulosa cells,⁶ ACTH from rat anterior pituitary cells,⁷ catecholamine secretion from the adrenal medulla,⁸ and the mitogenesis and proliferation of VSMCs.^{9 10} In the intact normal animal, ADM administration has been shown to reduce peripheral resistance and arterial pressure (with blunting of any baroreceptor-mediated rise in heart rate), increase CO, and induce diuresis and natriuresis.^{11 12 13 14}

Plasma ADM levels are typically in the lower picomolar range in normal humans, and concentrations are reported to increase during exercise.¹⁵ This observation, together with its biological effects, suggests that the peptide may play an important role in pressure and volume homeostasis. Furthermore, circulating levels are reported to be elevated in hypertension, congestive heart failure, and chronic renal failure in proportion to the severity of the disease.¹⁴ Kohno et al¹⁶ observed that plasma ADM levels correlated positively with plasma creatinine concentrations and inversely with GFR in hypertensive patients. In human congestive heart failure, plasma ADM relates inversely with left ventricular ejection fraction and positively with left ventricular end-diastolic pressure¹⁷ and pathophysiologically important hormone systems, including the cardiac natriuretic peptides and renin.^{17 18}

The source of ADM in plasma is unclear. Nishikimi et al¹⁹ observed no significant increase in the concentration of the peptide in venous drainage from various organs (including the adrenals) compared with arterial levels. However, Sugo et al^{20 21} reported secretion of ADM from both endothelial cells and VSMCs (with VSMCs expressing ADM mRNA at levels 40-fold higher than in the adrenal medulla). Together with the discovery of specific receptors on vascular smooth muscle,²² these findings raise the possibility that the peptide may function as a paracrine and/or autocrine factor as well as a circulating hormone. Although immunohistochemical staining for ADM in the normal canine heart has been reported to be more intense in the myocardium of the atria than in the ventricles,²³ Jougasaki et al²⁴ detected staining for ADM to be greater in ventricles from patients with congestive heart failure than in normal human ventricles, with little change in atrial levels. Furthermore, this group has shown a significant step-up in the plasma concentration of ADM between the aorta and anterior interventricular vein, which drains the ventricle,¹⁷ indicating the possibility that the failing ventricle contributes to the increased plasma concentration of ADM in patients with congestive heart failure.

In view of the possible involvement of ADM in the pathophysiology of heart failure and because its known biological actions are likely to prove advantageous in states of cardiac compromise, we have investigated, for the first time, the combined hemodynamic, endocrine, and renal effects of ADM in an animal model of congestive heart failure.

	Methods

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Surgical Preparation
Eight Coopworth ewes (body weight, 41 to 55 kg) were instrumented as previously described²⁵ via a left lateral thoracotomy. Under general anesthesia (induced by thiopentone 17 mg/kg and maintained with halothane and nitrous oxide), two polyvinyl chloride catheters were inserted in the left atrium for blood sampling and LAP determination; a Konigsberg (P 6.0) high-fidelity pressure-tip transducer was inserted into the aorta for measurement of MAP; an electromagnetic flow probe was placed around the ascending aorta to measure CO; a 7F Swan-Ganz catheter was inserted into the pulmonary artery for infusions; and a 7F His-bundle electrode was stitched subepicardially to the wall of the left ventricle for subsequent left ventricular pacing by an external pacemaker.

All leads were externalized through individual incisions in the neck. An indwelling bladder catheter was inserted via the urethra for subsequent urine collections. The animals were allowed to recover for at least 14 days before the study protocol was begun. During the experiments, the animals were held in metabolic cages, had free access to water, and ate a diet of chaff and sheep pellets (containing 40 mmol/d sodium and 200 mmol/d potassium) supplemented with a further 40 mmol of sodium administered orally with an applicator each morning as NaCl tablets.

Study Protocol
Heart failure was induced by 7 days of rapid left ventricular pacing at 225 bpm²⁵ and maintained by continuous pacing for the duration of the study. On days 8 and 10 of pacing, the sheep received, in random order, a vehicle control (Hemaccel; Behring) and human ADM-52. The investigator was not blinded to the order of treatment. ADM was infused at two doses (10 ng · kg^-1 · min^-1 for 90 minutes followed immediately by 100 ng · kg^-1 · min^-1 for 90 minutes). All infusions were administered in a total volume of 43 mL via the pulmonary artery catheter, commencing at 10 AM. Hemodynamic recordings (MAP, LAP, CO, and CTPR) were performed at 15-minute intervals from the hour before infusion (baseline) and then twice every 45 minutes to 3 hours after cessation of infusion. All measurements were made with the sheep standing quietly in the metabolic cage. The left atrial catheter was connected to a Statham P50 strain-gauge transducer positioned at the level of the atria (approximately one third of the distance from the base of the chest to the back) and linked to a hemodynamic monitor (Mennen-Greatbatch Ltd; M17294) for pressure determination relative to atmospheric pressure. The Konigsberg pressure transducer was connected to a preamplifier before display by the monitor. Hemodynamic measurements were determined by on-line computer-assisted analysis by methods previously described.²⁶

Blood samples were drawn from the left atrium at 45-minute intervals starting 45 minutes before infusion to 3 hours after infusion. The blood was taken into chilled EDTA tubes, immediately centrifuged at 4°C, and stored at -80°C before assay for ADM, cAMP (Commercial Kit, Biotrak, Amersham), ANP,²⁷ BNP,²⁸ PRA, aldosterone, cortisol,²⁵ and catecholamines.²⁹ Additional ADM samples were taken 22 minutes after the initiation of each infusion and at 2, 4, 6, 8, 10, 15, and 30 minutes after cessation of the high-dose infusion to determine the plasma half-life of the peptide. All samples from each animal were measured in the same assay to avoid interassay variability. Hematocrit was measured with every blood sample taken. Samples for analysis of plasma sodium, potassium, creatinine, calcium, and glucose concentrations were drawn into heparin tubes at 90-minute intervals starting immediately before infusion.

Plasma ADM concentrations were measured by radioimmunoassay.³⁰ The detection limit of the assay was 1.8 pmol/L, and the IC₅₀ was 20 pmol/L. Intra-assay and interassay coefficients of variation were 3.2% and 8%, respectively, over the range of 1 to 20 pmol/L.

The MCR of ADM was calculated by two methods. In the first method, MCR=infusion rate of ADM/(plateau-baseline ADM plasma concentration). The second used a two-compartment open model (using measured ADM levels).

Urine collections were made at 90-minute intervals starting 90 minutes before infusion for measurements of sodium, potassium, creatinine, and cAMP excretion. Renal production of cAMP was calculated by (urine cAMP concentrationxurine volume)- (plasma cAMP concentrationxcreatinine clearance).

Human ADM-52 was synthesized as previously described.³⁰ Purity as assessed by mass spectrometry was >98%.

The study protocol was approved by the Animal Ethics Committee of the Christchurch School of Medicine.

Statistics
Results are expressed as mean±SEM. Baseline hemodynamic and hormone values represent the mean of the four and two measurements, respectively, made within the hour immediately before infusion. Statistical analysis was performed by repeated-measures ANOVA with the BMDP P2V package. Baseline data before vehicle and ADM were compared. Treatment and time differences between vehicle and ADM were determined by a two-way ANOVA. Significance was assumed when P<.05. Where significant differences were identified by ANOVA, Fisher's protected least significant difference tests were used to identify time points significantly different from control.

	Results

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There were no significant differences in pretreatment baseline data for any variable between vehicle and ADM infusion days. After 7 days of rapid left ventricular pacing, all sheep exhibited the hemodynamic and hormonal hallmarks of established heart failure.²⁵ MAP and CO were reduced, whereas CTPR, LAP, and plasma norepinephrine, epinephrine, renin, aldosterone, and cardiac natriuretic peptide levels were elevated.

Compared with vehicle control data, plasma ADM levels were significantly increased during both the LD (control, 1.2±0.1 pmol/L; ADM, 13.6±2.2 pmol/L; P<.01) and HD (control, 1.3±0.1 pmol/L; ADM, 202±32 pmol/L; P<.001) infusions (Fig 1). The MCR of ADM calculated from the simple formula quoted previously was 1.24±0.08 L/min (n=5), and with the two-compartment model, it was 1.73±0.38 L/min. The half-life of infused ADM in sheep with heart failure was 6.8 minutes for the first phase and 51.9 minutes for the second phase.

View larger version (23K): [in this window] [in a new window]   Figure 1. Plasma ADM and cAMP responses to infusions of ADM (10 and 100 ng · kg-1 · min-1 for 90 minutes each) and a vehicle control in eight sheep with pacing-induced heart failure. Data are mean±SEM. Baseline data points represent mean of two samples taken in the 90 minutes preceding treatment. Significant differences between vehicle and ADM are shown by *P<.05, P<.001.

Plasma cAMP levels were unchanged during LD ADM infusion but were significantly increased during HD (control, 29±2 nmol/L; HD ADM, 40±5 nmol/L; P<.05) (Fig 1). Levels still tended to be elevated compared with control data at 3 hours after infusion (P=NS).

ADM dose-dependently reduced MAP (LD ADM, 4 mm Hg, P<.01; HD ADM, 9 mm Hg; P<.001), CTPR (LD, 5 mm Hg · L^-1 · min^-1, P<.001; HD, 13 mm Hg · L^-1 · min^-1, P<.001), and LAP (LD, 3.3 mm Hg, P<.001; HD, 5.1 mm Hg, P<.001) and increased CO (LD, 0.15 L/min, P<.01; HD, 0.51 L/min, P<.001) (Fig 2). MAP, CTPR, and CO all gradually returned to control levels over the 90 minutes after cessation of infusion, whereas LAP was still significantly reduced at 3 hours after infusion (P<.001). Hematocrit was similar on vehicle and ADM infusion days (Table).

View larger version (25K): [in this window] [in a new window]   Figure 2. MAP, LAP, CO, and CTPR during infusions of ADM (10 and 100 ng · kg-1 · min-1 for 90 minutes each) and a vehicle control in eight sheep with pacing-induced heart failure. Data are mean±SEM. Baseline data points represent mean of four samples taken in the 90 minutes preceding treatment. Significant differences between vehicle and ADM at end of each dose are shown by P<.001.

View this table: [in this window] [in a new window]   Table 1. Effects of Intravenous ADM in Eight Sheep With Heart Failure

Water intake was significantly increased during the ADM infusion period compared with vehicle control (control, 110±61 mL/h; HD ADM, 323±98 mL/h; P<.05), whereas urine volume was unchanged during the infusion and significantly increased over the 3 hours after infusion (control, 43±11 mL/h; ADM, 97±38 mL/h; P<.05) (Fig 3). Urine sodium excretion rose threefold during the 90-minute HD ADM infusion (control, 0.7±0.4 mmol/h; ADM, 2.1±1.1 mmol/h; P<.05) and increased further over the 3-hour postinfusion period (control, 1.0±0.8 mmol/h; ADM, 6.2±3.5 mmol/h; P<.05) (Fig 3). ADM slightly but significantly increased urine creatinine excretion (P<.05, Fig 3) and creatinine clearance (P<.05, Table) relative to control data. Urine cAMP excretion was also increased both during (control, 171±43 mmol/h; HD ADM, 257±51 mmol/h; P=.001) and after ADM infusion (Fig 3), as was the calculated renal production of cAMP (P<.05, Table). Urine potassium excretion was not altered significantly by ADM (Table).

View larger version (27K): [in this window] [in a new window]   Figure 3. Renal response to infusions of ADM (10 and 100 ng · kg-1 · min-1 for 90 minutes each) and a vehicle control in eight sheep with pacing-induced heart failure. Data are mean±SEM. Significant differences between vehicle and ADM are shown by *P<.05, **P<.01, P<.001.

No significant changes were observed in plasma norepinephrine (Fig 4), epinephrine, or cortisol levels during ADM infusion compared with control data (Table). PRA tended to be elevated during the ADM infusions compared with vehicle control, but conventional levels of statistical significance were not achieved (control, 1.65±0.41 nmol · L^-1 · h^-1; HD ADM, 2.23±0.52 nmol · L^-1 · h^-1; P=NS) (Fig 4). In contrast, aldosterone levels were reduced both during (control, 2328±825 pmol/L; HD ADM, 1485±319 pmol/L; P<.05) and after ADM administration (Fig 4). Plasma ANP and BNP concentrations were unchanged during the infusion but rose significantly after infusion (ANP at 3 hours after infusion: control, 143±13 pmol/L; ADM, 178±18 pmol/L; P<.01) (BNP: control, 52±6 pmol/L; ADM, 63±8 pmol/L; P<.05) (Fig 4). Plasma calcium, glucose (Table), sodium, potassium, and creatinine concentrations were unaltered (data not shown).

View larger version (26K): [in this window] [in a new window]   Figure 4. Plasma norepinephrine, renin activity, aldosterone, ANP, and BNP responses to infusions of ADM (10 and 100 ng · kg-1 · min-1 for 90 minutes each) and a vehicle control in eight sheep with pacing-induced heart failure. Data are mean±SEM. Baseline data points represent mean of two samples taken in the 90 minutes preceding treatment. Significant differences between vehicle and ADM are shown by *P<.05, **P<.01, P<.001.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present vehicle-controlled study examines for the first time the combined hemodynamic, endocrine, and renal effects of ADM in sheep with pacing-induced heart failure. Under these experimental conditions, intravenous ADM induced a significant rise in plasma cAMP levels (during HD) in association with dose-dependent falls in peripheral resistance, arterial pressure, and left atrial pressure and increases in CO. ADM maintained urine volume and increased urine sodium, creatinine, and cAMP excretion. Creatinine clearance and renal production of cAMP were elevated compared with control data. Water intake was augmented during infusion of ADM. Plasma aldosterone levels were reduced, whereas ANP and BNP concentrations were maintained during the ADM infusion period and rose after infusion. No significant changes were observed in plasma catecholamines, cortisol, renin, calcium, and glucose levels.

Because the amino acid structure of ovine ADM has yet to be determined, the human form of ADM was infused in the present study. However, there appears to be a high degree of sequence homology for ADM between the species studied thus far, namely, human,³¹ rat,³ and pig.⁴ Furthermore, it has been reported that there is little, if any, difference in the hypotensive activity of rat and human ADM in the rat.³² During administration of ADM in the present study, plasma levels of the peptide peaked at 202±32 pmol/L 90 minutes into the HD infusion period. We found the MCR of ADM to be 1.24 to 1.73 L/min, whereas the half-life of the peptide was 6.8 minutes for the first phase and 51.9 minutes for the second.

Ishiyama et al³³ used a bolus injection of ADM and reported a biphasic disappearance of the peptide in anesthetized spontaneously hypertensive rats to be 1.05±0.04 and 18.1±1.4 minutes for the first and second phases, respectively. Differences in experimental protocols, particularly bolus injection compared with infusion of the peptide, and differences in the animal species studied might account for the discrepant plasma half-lives from the present study and that of Ishiyama et al.³³

ADM has been shown to have specific receptors coupled with adenylate cyclase expressed on endothelial and vascular smooth muscles and to dose-dependently increase intracellular cAMP.^{22 34} In the present study, plasma levels of cAMP, one of the proposed second messengers for ADM, were significantly increased during the HD ADM infusion but remained unchanged during the lower dose. Despite this, significant hemodynamic and renal effects were observed during the LD infusion. It is possible that at this LD, ADM stimulated cAMP sufficiently at the tissue level to induce a biological response but insufficiently to induce a measurable rise in circulating concentrations. In addition, there is evidence that alternative signal transduction pathways for ADM may exist, namely, the stimulation of nitric oxide³⁵ and decrease of intracellular calcium.³⁶ A contribution of these alternative cell signaling mechanisms to the observed effects of ADM cannot be discounted.

Administration of ADM in sheep with heart failure induced significant and dose-dependent falls in left ventricular preload and arterial pressure and increases in CO. The concomitant decrease in peripheral resistance suggests a direct affect of ADM on arterial tone, although inhibitory actions of the peptide on the vasoconstrictor actions of endothelin 1 and Ang II may have played a contributory role.⁵ The hemodynamic response is consistent with previous reports in a variety of normal animals, including the sheep, rat, dog, cat, and rabbit,^{11 12 14} showing a clear correlation between fall in arterial pressure and fall in calculated peripheral resistance. Also consistent with previous observations in normal animals,^{11 12 14} we noted a relatively sustained hypotensive effect of ADM in sheep with heart failure, with arterial pressure gradually returning to control levels over the 90 minutes after infusion. Ishiyama et al³³ compared the hemodynamic effects of ADM in normotensive and spontaneously hypertensive rats and found that, although the fall in blood pressure was greater in the hypertensive animals, the percentage change was similar in the two groups. A previous study by our group using identical doses of ADM in normal sheep showed a maximum reduction in MAP of 13 mm Hg from baseline levels,¹¹ whereas in the present study in sheep with heart failure, a fall of 9 mm Hg was achieved. These results demonstrate a similar percentage reduction in blood pressure in both normal and heart-failure sheep (14% and 12%, respectively). It is unlikely that a reduction in plasma volume contributed to the hemodynamic changes induced by ADM in the present study, because there was no increase in either urine output or hematocrit levels during the period of peptide infusion. However, it must be noted that LAP was still significantly reduced over the 3 hours after infusion, at which time a significant diuresis did occur. The vigorous rise in CO observed during the present study (due at least in part to the fall in left ventricular afterload) has previously been demonstrated in normal animals in response to ADM administration.^{11 12} In addition, results from ADM studies in the isolated perfused rat heart³⁷ and in normal sheep¹² suggest that ADM has a direct positive inotropic action, and this might have contributed to the observed augmentation in CO in the present study.

The renal effects of ADM, previously reported in normal animals, include reduced renal vascular resistance and increased renal blood flow (via preglomerular and postglomerular arteriolar vasodilation),³⁸ GFR, medullary blood flow, urine volume, and urine sodium and cAMP excretion.^{13 14 38} Majid et al,¹³ however, observed a natriuresis and diuresis in dogs in response to ADM in the absence of change in filtered load, implying that this peptide can directly inhibit tubular sodium resorption. For the first time in heart failure, we have shown that ADM administration significantly increased urine sodium excretion and maintained urine output despite the marked fall in blood pressure (and therefore renal perfusion pressure). These effects occurred in conjunction with significant increases in the renal production of cAMP and urine cAMP excretion. Our study was not designed to dissect the mechanisms underlying the observed changes in urine sodium excretion, but they may well reflect an increase in GFR (as indicated by the rise in endogenous creatinine clearance) and reduced tubular resorption.¹³ Whatever the mechanisms, the ability of ADM to increase urine sodium excretion and GFR and maintain urine output in the face of low levels of renal perfusion pressure is remarkable and of potential therapeutic importance in clinical cardiac failure.

Intravenous ADM has been reported to increase PRA in normal sheep^{11 39} and is thought to represent reflex activation secondary to the fall in blood pressure through stimulation of the afferent arteriolar baroreceptor rather than a direct effect of ADM on renin secretion. Although ADM tended to increase PRA in the present study, this rise was not significant. Indeed, one might have expected an exaggerated increase in renin release in response to the fall in blood pressure in these sheep with heart failure, because Eide et al⁴⁰ have shown that the combination of low renal arterial pressure and high sympathetic activity, as seen in heart failure, potentiates renin release. The lack of a significant compensatory increase in PRA raises the possibility of an inhibitory effect of ADM on renin release. In this regard, Lainchbury et al³⁰ also reported no significant change in plasma renin concentrations after ADM administration to normal human subjects, despite a substantial fall in arterial pressure.

Despite the tendency for PRA to rise, plasma aldosterone levels were reduced both during and after ADM infusion. This suggests suppression of Ang II–induced aldosterone secretion and is consistent with previous studies demonstrating that ADM dose-dependently inhibited Ang II–induced secretion of aldosterone from dispersed rat zona glomerulosa cells⁶ and reduced plasma aldosterone levels in normal sheep.¹¹ ADM has also been shown to inhibit ACTH release from rat anterior pituitary cells⁷ and catecholamine secretion from the adrenal medulla.⁸ In agreement with these data is the failure of plasma cortisol, norepinephrine, and epinephrine levels to rise in response to the ADM-induced fall in blood pressure in the present study. The possible inhibitory effects of ADM on the renin-angiotensin-aldosterone and sympathetic nervous systems may have contributed to its hypotensive and natriuretic/diuretic actions.

Surprisingly, plasma ANP and BNP concentrations were unaltered during the ADM infusion period, despite the significant fall in LAP and MAP (indicating reduced stimulus for secretion and release of these peptides⁴¹ ), but increased during the postinfusion period. These results contrast sharply with previous studies demonstrating a close correlation between falls in LAP and plasma ANP and BNP levels after administration of vasodilator agents such as renin and ACE inhibitors in paced sheep⁴² and nitroglycerin in patients with congestive heart failure.⁴³ We presume that ADM can either directly stimulate secretion of ANP and BNP or alter their clearance from the circulation to account for the observed discrepancy between maintained plasma levels of the two cardiac peptides and the well-defined falls in LAP and MAP during the infusion period. The increase in plasma ANP and BNP concentrations seen after infusion may be due to a "resetting" of the stretch receptors in the heart as preload and afterload rise toward preinfusion levels, resulting in an increase in secretion and/or release. The natriuretic/diuretic and aldosterone inhibitory actions of ANP and BNP⁴¹ may have contributed to the renal response after ADM infusion when natriuretic peptide levels were elevated.

ADM administration induced a significant increase in water intake during the infusion period. This increase in drinking is likely to be in response to the marked fall in MAP that occurred at this time, rather than a direct central action of ADM on thirst, because intracerebroventricular ADM has previously been reported to antagonize Ang II–induced drinking in the rat,⁴⁴ where no concurrent effect on blood pressure occurred.

In that ADM shows structural homology with amylin,¹ which has been shown to alter plasma calcium and glucose concentrations, we measured both plasma calcium and glucose levels in the present study. No significant changes were observed, although this does not rule out a modulatory role for ADM in different circumstances, because we have previously noted a reduction in total plasma calcium in normal sheep receiving identical doses of ADM.¹¹

In summary, we have shown that ADM reduced left ventricular preload and afterload and improved CO in sheep with congestive heart failure. Despite a marked decline in arterial pressure, GFR and urine sodium excretion increased, and urine output was maintained. Circulating levels of norepinephrine, epinephrine, and renin were not stimulated in face of the fall in blood pressure, and aldosterone levels were suppressed. Plasma ANP and BNP concentrations were maintained despite brisk falls in atrial and left ventricular pressures. These data suggest that ADM might play a protective role as heart failure develops through diverse actions on blood vessels, heart, kidney, and endocrine organs. Clarification of this possibility must await additional studies and, in particular, the development of specific blockers of ADM secretion or action. From a therapeutic viewpoint, any agent that is a vasodilator, has positive inotropic activity, is natriuretic, suppresses aldosterone secretion and perhaps sympathetic activity and renin production, and augments (or maintains) circulating levels of cardiac natriuretic peptides is of major interest. In that ADM also has demonstrable antimitogenic and antiproliferative activity,^{9 10} manipulations that augment production of this peptide or inhibit its breakdown might find a place in the management of patients with cardiac failure.

	Selected Abbreviations and Acronyms

 

ADM = adrenomedullin Ang II = angiotensin II ANP = atrial natriuretic peptide BNP = brain natriuretic peptide CO = cardiac output CTPR = calculated total peripheral resistance, =MAP/CO GFR = glomerular filtration rate HD = high-dose LAP = left atrial pressure LD = low-dose MAP = mean arterial pressure MCR = metabolic clearance rate PRA = plasma renin activity VSMC = vascular smooth muscle cell

	Acknowledgments

 
This study was supported by grants from the National Heart Foundation of New Zealand and the Health Research Council of New Zealand. We are grateful to the staff of the Christchurch School of Medicine Animal Laboratory for care of the animals and to the staff of the Endocrine, Steroid, and Biochemistry Laboratories for hormone and biochemical assays. Special thanks to Mary Smith, who developed the adrenomedullin assay, and Dr Evan Begg, who determined the pharmacokinetics of adrenomedullin in this study.

Received December 23, 1996; revision received March 28, 1997; accepted April 8, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun. 1993;192:553-560.[Medline] [Order article via Infotrieve]

2. Ichiki Y, Kitamura K, Kangawa K, Kawamoto M, Matsuo H, Eto T. Distribution and characterization of immunoreactive adrenomedullin in human tissue and plasma. FEBS Lett. 1994;338:6-10.[Medline] [Order article via Infotrieve]

3. Sakata J, Shimokubo T, Kitamura K, Nakamura S, Kangawa K. Molecular cloning and biological activities of rat adrenomedullin, a hypotensive peptide. Biochem Biophys Res Commun. 1993;195:921-927.[Medline] [Order article via Infotrieve]

4. Kitamura K, Kangawa K, Kojima M, Ichiki Y, Matsuo H, Eto T. Complete amino acid sequence of porcine adrenomedullin and cloning of cDNA encoding its precursor. FEBS Lett. 1994;338:306-310.[Medline] [Order article via Infotrieve]

5. Tian Q, Zhao D, Tan DY, Zhao YT, Li QH, Qiu JX, Song LW, Gong CN, Yang J, Lippton H, Hyman AL, Tang J, Chang JK. Vasodilator effect of human adrenomedullin(13-52) on hypertensive rats. Can J Physiol Pharmacol. 1995;73:1065-1069.[Medline] [Order article via Infotrieve]

6. Yamaguchi T, Baba K, Doi Y, Yano K. Effect of adrenomedullin on aldosterone secretion by dispersed rat adrenal zona glomerulosa cells. Life Sci. 1995;56:379-387.[Medline] [Order article via Infotrieve]

7. Samson WK, Murphy T, Schell DA. A novel vasoactive peptide, adrenomedullin, inhibits pituitary adrenocorticotropin release. Endocrinology. 1995;136:2349-2352.[Abstract]

8. Katoh F, Kitamura K, Niina H, Yamamoto R, Washime H, Kangawa K, Yamaoto Y, Kobayashi H, Eto T, Wada A. Proadrenomedullin N-terminal 20 peptide (PAMP), an endogenous anticholinergic peptide: its exocytotic secretion and inhibition of catecholamine secretion in adrenal medulla. J Neurochem. 1995;64:459-461.[Medline] [Order article via Infotrieve]

9. Chini EN, Choi E, Grande JP, Burnett JC, Dousa TP. Adrenomedullin suppresses mitogenesis in rat mesangial cells via cAMP pathway. Biochem Biophys Res Commun. 1995;215:868-873.[Medline] [Order article via Infotrieve]

10. Kano H, Kohno M, Yasunari K, Yokokawa K, Horio T, Ikeda M, Minami M, Hanehira T, Takeda T, Yoshikawa J. Adrenomedullin as a novel antiproliferative factor of vascular smooth muscle cells. J Hypertens. 1996;14:209-213.[Medline] [Order article via Infotrieve]

11. Charles CJ, Rademaker MT, Richards AM, Cooper GJS, Coy DH, Jing N, Nicholls MG. Hemodynamic, hormonal and renal effects of adrenomedullin in conscious sheep. Am J Physiol. In press.

12. Parkes DG. Cardiovascular actions of adrenomedullin in conscious sheep. Am J Physiol. 1995;268:H2574-H2578.[Abstract/Free Full Text]

13. Majid DSA, Kadowitz PJ, Coy DH, Navar LG. Renal responses to intra-arterial administration of adrenomedullin in dogs. Am J Physiol. 1996;270:F200-F205.[Abstract/Free Full Text]

14. Richards AM, Nicholls MG, Lewis L, Lainchbury JG. Adrenomedullin. Clin Sci. 1996;91:3-16.[Medline] [Order article via Infotrieve]

15. Tanaka M, Kitamura K, Ishizaka Y, Ishiyama Y, Kato J, Kangawa K, Eto T. Plasma adrenomedullin in various diseases and exercise-induced change in adrenomedullin in healthy subjects. Intern Med. 1995;34:728-733.[Medline] [Order article via Infotrieve]

16. Kohno M, Hanehira T, Kano H, Horio T, Yokokawa K, Ikeda M, Minami M, Yasunari K, Yoshikawa J. Plasma adrenomedullin concentrations in essential hypertension. Hypertension. 1996;27:102-107.[Abstract/Free Full Text]

17. Jougasaki M, Rodeheffer RJ, Redfield MM, Yamamoto K, Wei C-M, McKinley LJ, Burnett JC. Cardiac secretion of adrenomedullin in human heart failure. J Clin Invest. 1996;97:2370-2376.[Medline] [Order article via Infotrieve]

18. Kato J, Kobayashi K, Etoh T, Tanaka M, Kitamura K, Imamura T, Koiwaya Y, Kangawa K, Eto T. Plasma adrenomedullin concentration in patients with heart failure. J Clin Endocrinol Metab. 1996;81:180-183.[Abstract]

19. Nishikimi T, Kitamura K, Saito Y, Shimada K, Ishimitsu T, Tamiya M, Kangawa K, Matsuo H, Eto T, Omae T, Matsuoka K. Clinical studies for the sites of production and clearance of circulating adrenomedullin in human subjects. Hypertension. 1994;24:600-604.[Abstract/Free Full Text]

20. Sugo S, Minamino N, Kangawa K, Miyamoto K, Kitamura K, Sakata J, Eto T, Matsuo H. Endothelial cells actively synthesize and secrete adrenomedullin. Biochem Biophys Res Commun. 1994;201:1160-1166.[Medline] [Order article via Infotrieve]

21. Sugo S, Minamino N, Shoji H, Kangawa K, Kitamura K, Eto T, Matsuo H. Production and secretion of adrenomedullin from vascular smooth muscle cells: augmented production by tumor necrosis factor-. Biochem Biophys Res Commun. 1994;203:719-726.[Medline] [Order article via Infotrieve]

22. Eguchi S, Hirata Y, Kano H, Sato K, Watanabe Y, Watanabe TX, Nakajima K, Sakakibara S, Murumo F. Specific receptors for adrenomedullin in cultured rat vascular smooth muscle cells. FEBS Lett. 1994;340:226-230.[Medline] [Order article via Infotrieve]

23. Jougasaki M, Wei C-M, Heublein DM, Sandberg SM, Burnett JC. Immunohistochemical localization of adrenomedullin in canine heart and aorta. Peptides. 1995;16:773-775.[Medline] [Order article via Infotrieve]

24. Jougasaki M, Wei C-M, McKinley LJ, Burnett JC. Elevation of circulating and ventricular adrenomedullin in human congestive heart failure. Circulation. 1995;92:286-289.[Abstract/Free Full Text]

25. Fitzpatrick MA, Nicholls MG, Espiner EA, Ikram H, Yandle TG, Bagshaw P, Collyer G, A'Court G. Neurohumoral changes during the onset and offset of ovine heart failure: role of ANP. Am J Physiol. 1989;256:H1052-H1059.[Abstract/Free Full Text]

26. Fitzpatrick MA, Rademaker MT, Frampton CM, Charles CJ, Yandle TG, Espiner EA, Ikram H. Hemodynamic and hormonal effects of renin inhibition in ovine heart failure. Am J Physiol. 1990;258:H1625-H1631.[Abstract/Free Full Text]

27. Charles CJ, Espiner EA, Cameron VA, Richards AM. Hemodynamic, renal, and endocrine actions of ANF in sheep: effect of 24-h, low-dose infusions. Am J Physiol. 1990;258:R1279-R1285.[Abstract/Free Full Text]

28. Yandle TG, Aitken GD, Fisher SF, Rademaker MT, Espiner EA, Nicholls MG. Ovine brain natriuretic peptide: identity measurement and regulation. J Hypertens. 1994;12:50S. Abstract.

29. Goldstein DS, Feuerstein G, Izzo JL, Kopin IJ, Keiser HR. Validity and reliability of liquid chromatography with electrochemical detection for measuring plasma levels of norepinephrine and epinephrine in man. Life Sci. 1981;28:267-275.

30. Lainchbury JG, Cooper GJS, Coy DH, Jiang N-Y, Lewis LK, Yandle TG, Richards AM, Nicholls MG. Adrenomedullin: a hypotensive hormone in man. Clin Sci. In press.

31. Kitamura K, Sakata K, Kangawa K, Kojima M, Matsuo H, Eto T. Cloning and characterization of cDNA encoding a precursor for human adrenomedullin. Biochem Biophys Res Commun. 1993;194:720-725.[Medline] [Order article via Infotrieve]

32. Itahara Y, Watanabe TX, Inui T, Chino N, Kimura T, Sakakibara S. Analysis of hypotensive mechanisms of human and rat adrenomedullin in anesthetized rat. Jpn J Pharmacol. 1994;64:145. Abstract.

33. Ishiyama Y, Kitamura K, Ichiki Y, Sakata J, Kida O, Kangawa K, Eto T. Haemodynamic responses to rat adrenomedullin in anaesthetized spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 1995;22:614-618.[Medline] [Order article via Infotrieve]

34. Ishizaka Y, Ishizaka Y, Tanaka M, Kitamura K, Kangawa K, Minamino N, Matsuo H, Eto T. Adrenomedullin stimulates cyclic AMP formation in rat vascular smooth muscle cells. Biochem Biophys Res Commun. 1994;200:642-646.[Medline] [Order article via Infotrieve]

35. Miura K, Ebara T, Okumura M, Matsura T, Kim S, Yukimura T, Iwao H. Attenuation of adrenomedullin-induced renal vasodilation by N^G-nitro L-arginine but not glibenclamide. Br J Pharmacol. 1995;115:917-924.[Medline] [Order article via Infotrieve]

36. Seguchi H, Nishimura J, Kobayashi S, Kumazawa J, Kanaide H. Autocrine regulation of the renal arterial tone by adrenomedullin. Biochem Biophys Res Commun. 1995;215:619-625.[Medline] [Order article via Infotrieve]

37. Szokodi I, Kinnunen P, Ruskoaho H. Inotropic effect of adrenomedullin in the isolated perfused rat heart. Acta Physiol Scand. 1996;156:151-152.[Medline] [Order article via Infotrieve]

38. Hirata Y, Hayakawa H, Suzuki Y, Suzuki E, Ikenouchi H, Kohmoto O, Kimura K, Eto T, Kangawa K, Matsuo H, Omata M. Mechanisms of adrenomedullin-induced vasodilation in the rat kidney. Hypertension. 1995;25:790-795.[Abstract/Free Full Text]

39. Parkes DG, May CN. ACTH-suppressive and vasodilator actions of adrenomedullin in conscious sheep. J Neuroendocrinol. 1995;7:923-929.[Medline] [Order article via Infotrieve]

40. Eide I, Loyning E, Kiil F. Potentiation of renin release by combining renal arterial constriction and ß-adrenergic stimulation. Scand J Clin Lab Invest. 1974;34:301-310.[Medline] [Order article via Infotrieve]

41. Espiner EA. Physiology of natriuretic peptides. J Intern Med. 1994;235:527-541.[Medline] [Order article via Infotrieve]

42. Fitzpatrick MA, Rademaker MT, Charles CJ, Yandle TG, Espiner EA, Ikram H, Nussberger J. Comparison of the effect of renin inhibition and angiotensin-converting enzyme inhibition in ovine heart failure. J Cardiovasc Pharmacol. 1992;19:169-175.[Medline] [Order article via Infotrieve]

43. Webster MWI, Sharpe N, Coxon R, Murphy J, Hannan S, Nicholls MG, Espiner EA. Effect of reducing atrial pressure on atrial natriuretic peptide and vasoactive hormones in congestive heart failure secondary to ischemic and nonischemic dilated cardiomyopathy. Am J Cardiol. 1989;63:217-221.[Medline] [Order article via Infotrieve]

44. Murphy TC, Samson WK. The novel vasoactive hormone, adrenomedullin, inhibits water drinking in the rat. Endocrinology. 1995;136:2459-2463.[Abstract]

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