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Hemodynamic, Hormonal, and Renal Effects of Intracerebroventricular Adrenomedullin in Conscious Sheep¹

Department of Medicine, Christchurch School of Medicine, Christchurch 8001, New Zealand; Department of Medicine, School of Medicine, Developmental Biology and Cancer Research Group, School of Biological Sciences, University of Auckland, Auckland 1, New Zealand, and Department of Medicine, Tulane University, New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Dr. C. J. Charles, Department of Medicine, Christchurch School of Medicine, P.O. Box 4345, Christchurch, New Zealand. E-mail: endolab5{at}chmeds.ac.nz

	Abstract

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Adrenomedullin, the recently described vasodilator that exhibits potent hypotensive actions when administered systemically, is also found in the central nervous system, suggesting a role for adrenomedullin as a neurohormone. However, only a limited number of studies have examined the central effects of adrenomedullin. Therefore, we have examined the integrative hemodynamic, renal, and hormonal effects of intracerebroventricular (ICV) adrenomedullin in conscious sheep. Eight surgically prepared sheep received ICV infusions of adrenomedullin at two doses (2 ng/kg·min followed immediately by 20 ng/kg·min each for 90 min) in a vehicle-controlled study. Water deprivation for 48 h before control infusion resulted in sheep drinking 2617 ± 583 ml in the 90-min period following reintroduction of water. On the adrenomedullin day, drinking was halved to 1392 ± 361 ml (P < 0.05). Adrenomedullin had no significant effect on urinary volume and sodium excretion. Plasma adrenomedullin levels remained unchanged during control infusions but were elevated by the end of ICV adrenomedullin infusions (P < 0.001). Plasma ANP levels were also increased approximately 50% (P < 0.05). Plasma levels of both ACTH and cortisol were also increased 3- to 4-fold in response to ICV adrenomedullin (P < 0.05). There was no significant difference in arterial pressure, heart rate, or cardiac output between study days. In conclusion, adrenomedullin within the central nervous system may have at least two roles: modulation of the hypothalamo-pituitary-adrenal axis and protection against fluid overload.

	Introduction

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ADRENOMEDULLIN is a recently discovered vasodilator peptide first isolated from human pheochromocytoma cells and subsequently found to be distributed in a wide variety of tissues including the adrenal medulla, lung, and kidney (1). In man, it is a 52-amino acid peptide possessing a ring structure with a disulfide bridge and a carboxy-terminal amide that shows moderate sequence similarity to calcitonin gene-related peptide (CGRP) and amylin (1). Systemic administration of adrenomedullin results in a variety of biological effects including reduction of arterial pressure, increased cardiac output, and relative suppression of aldosterone secretion (2). Adrenomedullin is also found in the central nervous system (CNS) and adrenomedullin-like immunoreactive material has been described in human cerebrospinal fluid (3). Satoh et al. (4) reported tissue immunoreactive adrenomedullin levels in the human brain tissue, with highest concentrations reported in the pituitary followed by thalamus, hypothalamus, and other regions. Within the hypothalamus, adrenomedullin-immunoreactive neurons have been reported in the paraventricular and supraoptic nuclei of the rat with adrenomedullin found to costain in some neurons with oxytocin and vasopressin (5). Immunoreactive adrenomedullin cells have been reported in human and porcine anterior pituitary. The distribution of these cells was different from that of GH, PRL, and ACTH (6). Receptors for adrenomedullin are also found throughout the CNS (7, 8) and in mouse (9) and rat astrocytes (10). The presence of adrenomedullin and its receptors in the CNS suggests a role for adrenomedullin as a neurotransmitter, neuromodulator or neurohormone. However, only a limited number of studies have examined the biological effects of central (brain) administration of adrenomedullin, and findings have been inconsistent. For example, Murphy and Samson reported intracerebroventricular (ICV) adrenomedullin reduces drinking responses (11) and salt appetite (12) in rats. Takahashi et al. (13) reported that ICV and intracisternal adrenomedullin in anesthetized rats increased arterial pressure and abdominal sympathetic discharge. In contrast, ICV administration of adrenomedullin in sheep has been reported to have no significant hemodynamic or hormonal effects (14). We lack detailed information regarding the integrative hemodynamic, renal, and endocrine actions of centrally administered adrenomedullin in conscious animals. Accordingly, we have used ICV infusions of adrenomedullin in normal (water-deprived) conscious sheep under carefully controlled conditions.

	Materials and Methods

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The study protocol was approved by the Animal Ethics Committee of the Christchurch School of Medicine. Eight Coopworth ewes (Lincoln University Farm, Christchurch, New Zealand) were housed in an air-conditioned light-controlled room and received a standard diet of sheep nuts and chaff, providing a daily intake of 70 mmol sodium and 150 mmol potassium. Catheterization of the lateral cerebral ventricle was performed under general anesthesia (induced by 17 mg/kg thiopentone sodium and maintained by a mixture of halothane, nitrous oxide, and oxygen). Correct positioning of the ICV catheter was subsequently confirmed at postmortem in all sheep. A carotid artery was cannulated (16G Angiocath, Becton Dickinson, Sandy, UT), for direct measurement of mean arterial pressure (MAP) and heart rate, and two polyethylene catheters were placed in the jugular veins for blood sampling and measurement of right atrial pressure (RAP). A Swan-Ganz thermodilution catheter (American Edwards, Santa Ana, CA) was placed in the pulmonary artery via the jugular vein for the measurement of cardiac output. A Foley catheter (14G) was placed via the urethra in the urinary bladder. The animals were allowed to recover for at least 7 days before experiments commenced, during which time there was free access to drinking water up until 48 h before experimentation.

Each animal was studied on two occasions at least 5 days apart. On one day they received ICV adrenomedullin in 0.9% saline, and on the other (control) the same volume of ICV saline (vehicle) alone. In four animals, adrenomedullin was infused before control, and the order was reversed in the other four animals. Adrenomedullin was infused via the lateral cerebral ventricle at two doses 2 ng/kg·min for 90 min (low dose), followed immediately by 20 ng/kg·min for 90 min (high dose) both in a volume of 2.1 ml per hour, commencing at 1000 h.

Commencing 45 min before infusions, MAP and RAP were measured continuously using Statham pressure transducers (Spectramed Medical Products, Singapore) and an Astromed chart recorder (Astromed Inc., W. Warwick, RI). These recordings were continued for 90 min post infusion. Cardiac output (thermodilution) was measured at 90-min intervals. Heart rate and blood pressure recordings were manually integrated over 5-min periods at 45-min intervals for the duration of the experiment.

Venous blood was drawn at 45-min intervals starting 45 min before infusions and up to 90 min after infusions. Blood was taken into chilled EDTA tubes and centrifuged, and the plasma stored at -80 C. Plasma samples were assayed according to previously reported methods as follows: atrial natriuretic peptide (ANP) [coefficients of variation (CVs) = 4.4%; 14.6%, intraassay and interassay, respectively] (15), brain natriuretic peptide (BNP) (CVs = 7.3%; 19%) (16), aldosterone (CVs = 4.4%; 8.9%) (17), PRA (CVs = 4.3%; 9.0%) (18), ACTH (CVs = 9.9%; 10%) (19), arginine vasopressin (AVP) (CVs = 3.5%; 10%) (20), and cortisol (CVs = 7.6%; 8.6%) (21). Plasma adrenomedullin levels were measured by RIA following extraction as previously described in abstract form (22). Briefly, plasma samples (2 ml) were mixed with an equal volume of P-ATC buffer (0.05 M phosphate buffer, pH 7.4, 0.1% alkali-treated casein, 0.1% Triton X-100, 0.1% sodium-EDTA, 0.2% sodium azide) before extraction on SepPak C18 cartridges. Adrenomedullin was eluted with 2 ml 80% isopropanol/0.013 M HCl into a tube precoated with P-ATC, dried down, and reconstituted in P-ATC. The extract was neutralized with 0.1 M NaOH before RIA using a locally raised antisera to human adrenomedullin (1–52). Detection limit in the assay was 1.8 pmol/liter, and the IC₅₀ was 20 pmol/liter. Intra and interassay CVs were 3.2% and 8%, respectively. Recovery of adrenomedullin spiked into sheep plasma was determined for each assay and ranged from 34–68%. For each hormone, all samples from each animal were measured in the same assay to reduce interassay variability. Samples were also drawn into lithium heparin for determination of plasma sodium, potassium, and creatinine by standard methods.

Urine collections were made at 90-min intervals (starting 90 min before infusions) for measurements of volume, sodium, potassium, and creatinine. Water intake was measured 30 min after the start of the high dose infusion and thereafter at the end of infusion and 90 min post infusion. The animals were water deprived for 48 h before the high dose infusion of adrenomedullin or vehicle being administered.

Human adrenomedullin-52 was synthesized on methylbenzhydrylamine resin using standard solid-phase procedures and cleaved with hydrogen fluoride/anisole (23). The sequence containing a disulfide bridge was cyclized by titration with I₂ in 90% acetic acid/water solutions. Crude material was purified by gel filtration on Sephadex columns in 50% acetic acid followed by gradient elution on C18 silica using acetonitrile/0.1% trifluoroacetic acid eluants. Homogeneity of the final product was assessed by TLC, analytical HPLC, amino acid analysis, and matrix-assisted laser-desorption-ionization mass spectrometry. Purity was greater than 98%.

Statistics
Results are expressed as mean ± SEM except for plasma AVP results, for which levels between sheep varied markedly in a nonparametric fashion (baseline range = 2.7–139 pmol/liter). Therefore, plasma AVP levels were log transformed and results are expressed as geometric means ± SEM. Baseline hemodynamic and hormonal values represent the mean of two recordings respectively made within 1 h immediately preinfusion. Two way ANOVA (ANOVA) with time as a repeated measure was used to determine time and treatment differences between adrenomedullin and control arms of the study. Significance was assumed when P < 0.05. Where significant differences were identified by ANOVA, a priori Fisher’s protected least square difference (LSD) tests were used to identify time-points significantly different from time-matched control.

	Results

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Experiments were completed without mishap, and data collection was complete. During vehicle control infusions, water deprivation for 48 h resulted in the sheep drinking 2617 ± 583 ml over 90 min (Fig. 1). On the day adrenomedullin was infused, the volume taken was reduced approximately 50% to 1392 ± 361 ml in the corresponding period (P < 0.05). Despite this reduction in water intake in response to ICV adrenomedullin, urinary output tended to be higher on the adrenomedullin day, although there was no statistical difference between study days (Fig. 1). Likewise, there was no difference in urinary sodium (Fig. 1), potassium, or creatinine excretion rates (Table 1) between the two study days. Baseline plasma sodium levels (Table 1) were elevated compared with laboratory water-replete control values [144 ± 0.6 mmol/liter (n = 20)]. Plasma sodium levels were reduced similarly across the time-course of both experimental days with levels falling following the reintroduction of water. There was no significant difference between study days. There was no significant difference in plasma potassium, creatinine, or albumin levels (Table 1).

View larger version (25K): [in this window] [in a new window]   Figure 1. Urine volume, sodium excretion, and drinking response to consecutive 90 min ICV infusions of adrenomedullin (solid bars) at doses of 2 ng/kg·min and 20 ng/kg·min and vehicle control (open bars) in 8 sheep. Sheep were water deprived for 48 h before time-point 1.5 h. Values shown are mean ± SEM. Water intake was reduced in response to adrenomedullin compared with vehicle (*, P < 0.05).

View larger version (23K): [in this window] [in a new window]   Figure 2. Plasma adrenomedullin and atrial (ANP) and brain (BNP) natriuretic peptide levels during consecutive 90 min ICV infusions of adrenomedullin (filled circles) and vehicle control (open circles) in eight sheep. Values shown are mean ± SEM. Plasma ANP (P < 0.05) and adrenomedullin (P < 0.001) levels were significantly increased in response to adrenomedullin. Individual time points significantly different from time-matched control (Fisher’s protected LSD from two-way ANOVA) are indicated by *, P < 0.05 and , P < 0.01.

View larger version (25K): [in this window] [in a new window]   Figure 3. PRA, aldosterone, cortisol, ACTH, and AVP levels in response to ICV infusions of adrenomedullin (filled circles) and vehicle control (open circles) in eight sheep. Values shown are mean ± SEM (except for AVP, which are geometric mean ± SEM). Plasma ACTH (P < 0.05) and cortisol (P < 0.05) levels were both significantly raised in response to adrenomedullin. Individual time points significantly different from time-matched control (Fisher’s protected LSD from two-way ANOVA) are indicated by *, P < 0.05 and , P < 0.01.

View larger version (20K): [in this window] [in a new window]   Figure 4. Hemodynamic response to ICV infusions of adrenomedullin (filled circles) and vehicle control (open circles) in eight sheep. Values shown are mean ± SEM.

	Discussion

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Peripheral actions of vasoactive peptides such as angiotensin II and the natriuretic peptides are often mirrored by complementary CNS actions (24). This may also be true of some of the actions of adrenomedullin. Thus, the renal actions of adrenomedullin to induce natriuresis and diuresis appear to be complemented by significant CNS-mediated behavioral actions. ICV adrenomedullin has previously been reported to inhibit water drinking and salt appetite in rats (11, 12). Inhibition of the drinking response to dehydration was confirmed in the present study performed in sheep. Notwithstanding the marked reduction in water intake, urine volume and sodium excretion tended to increase with ICV adrenomedullin infusion. The sheep were clearly volume-depleted at baseline as evidenced by elevated plasma sodium and AVP levels. Both plasma sodium and AVP levels were reduced following reintroduction of the drinking water; however, there was no difference between adrenomedullin and control days in this regard. Therefore, the precise mechanism underlying the observed urinary effects are not clear but might relate in part to the increase in plasma levels of ANP in particular, and perhaps also adrenomedullin. Interestingly, Yokoi et al. (25) reported that ICV adrenomedullin inhibits both hyperosmolar and hypovolemic-induced AVP in conscious rats. In the present study, we saw no evidence of suppression of plasma AVP levels; however, a different experimental design (continuous water deprivation) may have given different results.

It is unclear whether adrenomedullin can cross the blood brain barrier; hence, the mechanism for the increase in plasma adrenomedullin levels remains uncertain. It is possible that there exist neural or other pathways whereby central manipulations of adrenomedullin may modulate systemic secretion of the peptide, as has been postulated for other vasoactive peptides such as ANP (26). Similarly, the mechanism of the rise in plasma ANP with ICV adrenomedullin infusion remains unclear. In this regard, it is of note that interactions between adrenomedullin and ANP have been reported previously with both an increment in circulating levels of ANP in sheep infused with adrenomedullin (27) and suppression of ANP gene expression in cultured rat cardiomyocytes (28). Clearly, interactions between adrenomedullin and the natriuretic peptides require further investigation.

As stated above, there have been contrasting findings to date with respect to hemodynamic actions of centrally administered adrenomedullin. Early studies performed in anesthetized rats reported that both adrenomedullin (13) and the fragment adrenomedullin (13–52) (29) administered in doses up to 3 nmol/kg induced prolonged dose-dependent increases in arterial pressure associated with marked increases in either abdominal or renal sympathetic outflow. Similarly, in conscious rats, ICV administration of 1 nmol/kg adrenomedullin increased blood pressure heart rate and renal sympathetic nerve activity (30). However, a number of studies published subsequently, including the present study, have found no evidence for hemodynamic actions of ICV adrenomedullin. Murphy and Samson (11) found that ICV adrenomedullin (400 and 800 pmol/kg), despite antidrinking activity, had no effect on blood pressure or heart rate. Similarly, in the present study, 330 pmol/kg adrenomedullin (infused ICV over a 3-h period), a dose that inhibited drinking responses, had no significant effect on arterial pressure or any other hemodynamic parameter measured. Parkes and May (14) likewise reported no hemodynamic action in response to a similar dose of adrenomedullin given by ICV infusion in conscious sheep. Thus, it is possible that the doses used in the latter studies were below a threshold for hemodynamic actions.

ICV infusion of adrenomedullin in the present study induced statistically significant and sustained 3- to 4-fold increments in plasma levels of both ACTH and cortisol. These effects on ACTH and cortisol are in contrast to those observed in other studies. Parkes and May (14) found no significant effects of ICV adrenomedullin on plasma ACTH or cortisol, although the small sample size (n = 5) and absence of time-matched control (vehicle) data may be pertinent. The same author reported that iv adrenomedullin suppressed endogenous plasma levels of ACTH and cortisol (14). Likewise, studies with cultured dispersed rat anterior pituitary cells showed that adrenomedullin dose dependently inhibited both basal and CRH-stimulated ACTH release (31). These contrasting findings suggest that effects of adrenomedullin on the hypothalamo-pituitary-adrenal axis may vary according to the site of action. It seems unlikely that the small increase in plasma adrenomedullin levels would have contributed to the changes in plasma ACTH and cortisol given the different time-course of these effects. Thus, adrenomedullin may affect the HPA axis at the level of the hypothalamus, which is probably accessible by ICV administration, to increase CRH levels, which in turn augment ACTH and cortisol secretion. In the present study, there was no significant effect of adrenomedullin on plasma AVP levels, another known secretagogue for ACTH. As CRH levels (which are rarely raised in peripheral blood) were not determined in the present study, it remains to be seen if these are direct effects at the hypothalamus. By contrast, at the level of the pituitary, current evidence from in vitro and iv studies is that adrenomedullin acts to inhibit ACTH release.

In conclusion, our studies in healthy, conscious sheep demonstrate that ICV adrenomedullin inhibits thirst yet maintains urinary volume and sodium excretion, induces subtle but significant increases in plasma ANP and adrenomedullin levels, and stimulates 3- to 4-fold increases in plasma ACTH and cortisol levels. Based on the findings of this and previous studies, adrenomedullin within the CNS may have at least two roles, namely modulation of activity of the HPA axis and protection against fluid overload, including inhibition of thirst and salt appetite, an increase in circulating ANP, and diuretic and natriuretic actions. Better definition of these possible actions of adrenomedullin within the CNS awaits the development of a specific blocker of adrenomedullin secretion or action.

	Acknowledgments

 
We would like to thank Laurel Watt for assistance with animal experiments and staff of the Christchurch Endocrine Laboratory for hormone assays.

	Footnotes

 
¹ This work was supported by grants from the National Heart Foundation and Health Research Council of New Zealand.

Received September 3, 1997.

	References

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Charles, C. J. Articles by Nicholls, M. G. Search for Related Content PubMed PubMed Citation Articles by Charles, C. J. Articles by Nicholls, M. G.