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Hemodynamic, Renal, and Hormonal Effects of Ghrelin Infusion in Patients with Chronic Heart Failure

Department of Internal Medicine (N.Nag., K.M., H.O., W.S., N.Nak.), National Cardiovascular Center, Department of Internal Medicine (M.U.), Osaka Seamen’s Insurance Hospital, Department of Biochemistry (M.K., K.K.), National Cardiovascular Center Research Institute, and Department of Physiology (H.M.), National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

Address all correspondence and requests for reprints to: Noritoshi Nagaya, M.D., Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail: nagayann{at}hsp.ncvc.go.jp

Abstract

Ghrelin is a novel GH-releasing peptide that may also induce vasodilation and a positive energy balance through GH-independent mechanisms. However, the hemodynamic, renal, and hormonal effects of ghrelin in patients with chronic heart failure (CHF) remain unknown. Accordingly, 12 patients with CHF were given an iv infusion of human ghrelin (0.1 µg/kg·min) or placebo. Ghrelin significantly decreased mean arterial pressure (-9 mm Hg, P < 0.05) without a significant change in heart rate. Ghrelin significantly increased cardiac index (+25%, P < 0.05) and stroke volume index (+30%, P < 0.05), although it did not significantly alter mean pulmonary arterial pressure or pulmonary capillary wedge pressure. Infusion of ghrelin induced a marked increase in serum GH level (15-fold), associated with slight increases in circulating epinephrine, ACTH, cortisol, and PRL. Infusion of ghrelin did not significantly alter urine volume, urinary sodium excretion, or creatinine clearance. These hemodynamic, renal and hormonal parameters remained unchanged during placebo infusion. In summary, iv infusion of ghrelin, a potent GH-releasing peptide, had beneficial hemodynamic effects in patients with CHF in the absence of renal effects.

GHRELIN IS A novel GH-releasing peptide, isolated from the rat stomach, which is identified as an endogenous ligand for GH secretagogues receptor (GHS-R) (1). Human ghrelin is a 28-amino acid peptide containing an n-octanoyl modification at serine 3 and is homologous to rat ghrelin apart from two amino acids. Injection of human ghrelin dose dependently stimulates GH release in healthy humans (2). Earlier studies have shown that GH and its mediator, IGF-1, induce myocardial growth and increase myocardial contractility (3, 4, 5, 6). Thus, ghrelin may improve myocardial structure and function in chronic heart failure (CHF) via its GH-releasing effects. On the other hand, GHS-R mRNA is detected not only in the hypothalamus and pituitary but also in the heart and vessels (7, 8). Stimulation of GHS-R by hexarelin, a synthetic GHS, has been shown to prevent cardiac damage after ischemia-reperfusion in hypophysectomized rats (9). These results suggest direct cardiovascular effects of ghrelin. Interestingly, iv injection of ghrelin induces vasodilation and increases cardiac output in healthy humans (8). These findings raise the possibility that administration of ghrelin may be beneficial in patients with CHF. The purpose of this study was to investigate the hemodynamic, renal, and hormonal effects of short-term iv infusion of human ghrelin in patients with CHF.

Subjects and Methods

Patients

The study included 12 patients with clinically overt CHF (8 men, 4 women, mean age = 61 ± 3 yr). The patients randomly received either ghrelin (ghrelin group, n = 6) or placebo (placebo group, n = 6). Patients with one or both of the following conditions were excluded: 1) chronic renal impairment (serum creatinine level 2.0 mg/dl), and/or 2) systolic blood pressure < 100 mm Hg. Baseline characteristics for each group are given in Table 1. There was no significant difference in demographics, the etiology of CHF, disease period, clinical status, hemodynamics, exercise capacity, or medication use between the ghrelin group and the placebo group. The study was approved by the ethical committee of the National Cardiovascular Center, and all patients gave written informed consent.

Human ghrelin was obtained from the Peptide Institute Inc. (Osaka, Japan). The homogeneity of human ghrelin was confirmed by reverse-phase HPLC and amino acid analysis. Ghrelin was dissolved in distilled water with 4% D-mannitol and was sterilized by passage through a 0.22-µm filter (Millipore Corp., Bedford, MA). Ghrelin was stored as 1-ml volumes (each containing 300 µg ghrelin) at -80 C until the time of preparation for administration.

Study protocol

This study was conducted in a double-blind, randomized, placebo-controlled fashion. All cardiovascular drugs were withdrawn at least 24 h before beginning the study procedure. A 7.5-French Swan-Ganz catheter (TOO21H-7.5F, Baxter Co., Irvine, CA) was positioned in the pulmonary artery through a jugular vein, as reported previously (10). One 22-gauge cannula was inserted into a radial artery for hemodynamic measurements and blood sampling. Another 22-gauge cannula was inserted into a forearm vein for infusion of 0.9% saline, with or without ghrelin. A bladder catheter was inserted for urine sampling. After an equilibration period of 30 min, saline was infused at a rate of 0.5 ml/min for 60 min. Baseline measurements were obtained during this period. Then, ghrelin (0.1 µg/kg·min) or saline was iv administered at a rate of 0.5 ml/min for 60 min, followed by 60-min saline infusion (Fig. 1). Mean arterial pressure, mean pulmonary arterial pressure, and pulmonary capillary wedge pressure were measured at 15-min intervals during the protocol. Cardiac output was measured by the thermodilution method at 30-min intervals. Cardiac index was derived by correcting cardiac output for body surface area. Stroke volume index was obtained by dividing cardiac index by heart rate. Systemic vascular resistance and pulmonary vascular resistance were calculated using standard formulas. Blood samples were taken at 30-min intervals before, during, and after infusion of ghrelin or placebo. Urine samples were collected for 60 min each before, during, and after the infusion.

View larger version (19K): [in this window] [in a new window]   Figure 1. Experimental protocol. After a 60-min baseline period, ghrelin (0.10 µg/kg·min) or placebo was iv administered at a rate of 0.5 ml/min for 60 min, followed by a 60-min post infusion period.

The blood was immediately transferred into a chilled glass tube containing disodium EDTA (1 g/liter) and aprotinin (500 U/ml) and centrifuged immediately at 4 C. The plasma samples were frozen and stored at -80 C and then were extracted before RIA. Briefly, Sep-Pak C18 cartridges (Waters Corp., Milford, MA) were preconditioned with 5 ml each of chloroform, methanol, 60% acetonitrile containing 0.1% trifluoroacetic acid (TFA), and saline. Plasma (1000 µl) was diluted with 1000 µl saline and then loaded onto a Sep-Pak C18 cartridge. After the column was washed with 5 ml each of saline and 5% acetonitrile containing 0.1% TFA, the absorbed materials were eluted with 3 ml 60% acetonitrile containing 0.1% TFA. The eluate was then lyophilized.

RIA for plasma ghrelin was performed as described previously (11). In brief, a polyclonal antibody was raised against the C-terminal fragment [13–28] of rat ghrelin in a rabbit. A maleimide activated mariculture keyhole limpet hemocyanin-[Cys 0]-ghrelin [13–28] conjugate was used for immunization. [Tyr 0]-rat ghrelin [13–28] was radioiodinated by the lactoperoxidase method. A monoiodinated ligand was purified by RP-HPLC on a µBondasphere C18 column (3.9 x 150 mm, Waters Corp.). The tracer was stable for 3 months when stored at -20 C in 0.1% BSA. The RIA incubation mixture consisted of 100 µl standard ghrelin or unknown sample, normal rabbit serum, and 200 µl antiserum at a dilution of 1:10,000. After a 12-h incubation at 4 C, 100 µl of ¹²⁵I-labeled ligand (15,000 cpm) were added to the mixture. After 36-h incubation at 4 C, 100 µl goat antirabbit IgG antiserum were added. Free and bound tracers were separated by centrifugation at 3,000 rpm for 30 min after incubation for 24 h at 4 C. After aspiration of supernatant, radioactivity in the pellet was quantified using a counter (ARC-600, Aloka, Tokyo, Japan). The minimum detectable dose of ghrelin was less than 6 fmol/tube. The antiserum exhibited 100% cross-reactivity with rat or human ghrelin [13–28]. No significant cross-reactivity with other peptides was observed.

Other biochemical measurements

Serum GH was measured using an immunoradiometric assay kit (Ab Bead HGH Eiken, Eiken Chemical Co., Ltd., Tokyo, Japan). Serum IGF-1 was determined using an immunoradiometric assay kit (Somatomedin CII Bayer, Bayer Corp. Medical Ltd., Tokyo, Japan). Serum FSH, LH, PRL, and TSH were measured using immunoradiometric assay kits (SPAC-S FSH, LH, PRL, and TSH, Daiichi Radioisotope Laboratories, Ltd., Tokyo, Japan). Plasma ACTH was measured by an immunoradiometric assay (ACTH IRMA Mitsubishi, Mitsubishi Chemical Co., Tokyo, Japan). Serum cortisol was measured by enzyme immunoassay (AIA-PACK CORT, Tosoh Co., Yamaguchi, Japan) Plasma norepinephrine and epinephrine were measured by high-performance liquid chromatography combined with the trihydroxyindole fluorometric procedure (HLC8030, Tosoh Co.). PRA and aldosterone were measured using RIA kits (RENIN RIABEAD; ALDOSTERONE RIAKIT II, DAINABOT Co., Tokyo, Japan). Serum sodium level was measured by flame photometry.

Urine sampling

Urine volume was expressed as urinary flow rate (ml/min). Urinary sodium was measured by flame photometry. Urinary sodium excretion was calculated with standard formulas. Endogenous creatinine clearance was calculated based on a standard formula as an index of glomerular filtration rate.

Statistical analysis

All data were expressed as mean ± SEM unless otherwise indicated. Comparisons of parameters between the two groups were made by Fisher’s exact test or unpaired t test. Comparisons of the time course of parameters between the two groups were made by two-way ANOVA for repeated measures, followed by Scheffé’s multiple comparison test. A P value < 0.05 was considered statistically significant.

Results

All subjects tolerated this study protocol, although ghrelin caused a slight feeling of being warm and sleepiness in two subjects. Clinically significant systemic hypotension was not observed in any patients. No arrhythmias were noted during ghrelin infusion.

Hemodynamic response to ghrelin

Iv infusion of ghrelin significantly decreased mean arterial pressure in patients with CHF (-9 mm Hg, P < 0.05, Fig. 2). Nevertheless, no significant increase in heart rate was observed during ghrelin infusion. The hypotensive effect of ghrelin lasted for 60 min after the end of ghrelin infusion. There was no significant difference in mean pulmonary arterial pressure. Infusion of ghrelin tended to decrease pulmonary capillary wedge pressure, although these changes did not reach statistical significance. At the end of ghrelin infusion, cardiac index significantly rose compared with baseline values (+25%, P < 0.05, Fig. 3), and stroke volume index rose markedly (+30%, P < 0.05). Ghrelin significantly decreased systemic vascular resistance (-28%, P < 0.05). These hemodynamic parameters remained unchanged during placebo infusion.

View larger version (21K): [in this window] [in a new window]   Figure 2. Changes in heart rate (HR), mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), and pulmonary capillary wedge pressure (PCWP) during infusion of ghrelin or placebo. Data are mean ± SEM. *, P < 0.05 vs. value at time 0; , P < 0.05 vs. placebo.

View larger version (19K): [in this window] [in a new window]   Figure 3. Changes in cardiac index (CI), stroke volume index (SVI), systemic vascular resistance (SVR), and pulmonary vascular resistance (PVR) during infusion of ghrelin or placebo. Data are mean ± SEM. *, P < 0.05 vs. value at time 0; , P < 0.05 vs. placebo.

At the end of iv infusion of ghrelin, plasma ghrelin level increased about 43-fold compared with baseline values (Fig. 4). Ghrelin elicited a marked increase in serum GH (15 times baseline value). The elevation of GH level lasted longer than 60 min after the end of ghrelin infusion. Infusion of ghrelin significantly increased plasma epinephrine but not norepinephrine. No significant change in serum IGF-1 was observed throughout the study protocol (Table 2). Ghrelin slightly increased circulating levels of PRL, ACTH, and cortisol, whereas it did not significantly alter FSH, LH, or TSH. Ghrelin did not significantly alter PRA or aldosterone. These hormonal parameters also remained unchanged during placebo infusion.

View larger version (19K): [in this window] [in a new window]   Figure 4. Changes in circulating levels of ghrelin, GH, epinephrine (EPI), and norepinephrine (NOR) during infusion of ghrelin or placebo. Data are mean ± SEM. *, P < 0.05 vs. value at time 0; , P < 0.05 vs. placebo.

Infusion of ghrelin did not significantly change urine volume (Fig. 5). Ghrelin also did not alter urinary sodium excretion or creatinine clearance.

View larger version (26K): [in this window] [in a new window]   Figure 5. Changes in urine volume (UV), urinary sodium excretion (UNaV), and creatinine clearance (Ccr) during infusion of ghrelin or placebo. Data are mean ± SEM.

This is the first placebo-controlled clinical study to examine hemodynamic, renal, and hormonal effects of iv infusion of ghrelin in patients with CHF. In this study, we demonstrated that 1) infusion of ghrelin significantly decreased mean arterial pressure without a significant change in heart rate in patients with CHF, and 2) ghrelin markedly increased cardiac index and stroke volume index. We also demonstrated that 3) infusion of ghrelin markedly increased serum GH and slightly induced the secretion of epinephrine, ACTH, cortisol, and PRL, and 4) it did not alter urine volume, urinary sodium excretion, or creatinine clearance.

Ghrelin is a novel GH-releasing peptide, isolated from the stomach, which acts through an independent mechanism from that of hypothalamic GHRH. To our knowledge, GHRH has no direct cardiovascular effects because the GHRH receptor is restricted to specific tissues including pituitary membranes (12). In contrast, ghrelin peptide and its specific receptor, GHS-R, are detected in a variety of tissues including the heart and blood vessels (7, 8, 11, 13). In the present study, ghrelin significantly decreased mean arterial pressure and systemic vascular resistance in patients with CHF, as previously shown in healthy humans (8). Recently, we found that a decrease in systemic vascular resistance by ghrelin was observed not only in normal rats, but also in spontaneous dwarf rats, a GH-deficient rat model that carries a disrupted GH gene (13A ). One-hour infusion of ghrelin did not significantly increase circulating IGF-1, which has been shown to cause vasodilation through a direct stimulatory effect on nitric oxide synthesis (14). These findings indicate that ghrelin has a GH/IGF-1-independent vasodilatory effect. Surprisingly, the hypotensive effect of ghrelin was not associated with an increase in heart rate or plasma norepinephrine. It is interesting to speculate that ghrelin may inhibit activation of the sympathetic nervous system during hypotension, which may be beneficial in treating patients with CHF. Infusion of ghrelin tended to decrease pulmonary capillary wedge pressure in patients with CHF, although these changes did not reach statistical significance. Further studies are necessary to elucidate whether ghrelin has venous dilator effects.

In the present study, infusion of ghrelin improved cardiac performance in patients with CHF, as indicated by significant increases in cardiac index and stroke volume index. The decrease in systemic vascular resistance by ghrelin suggests that the improved cardiac function may be due to arterial vasodilation and reduction of cardiac afterload. Another possible explanation for the increase in cardiac index would be an increase in plasma epinephrine by ghrelin. Infusion of hexarelin, a synthetic GHS, has been shown to increase left ventricular ejection fraction in humans (15). In addition, stimulation of GHS-R by hexarelin has been shown to prevent cardiac damage after ischemia-reperfusion in hypophysectomized rats (9). Thus, it is interesting to speculate that ghrelin has some direct actions on the myocardium. Further studies will be needed to examine potential mechanisms responsible for improved cardiac performance during ghrelin infusion.

The GH-releasing effects of ghrelin have been shown to be more potent than that of GHRH (2). The present study also demonstrated that infusion of ghrelin markedly increased serum GH level in patients with CHF. The release of GH by ghrelin is thought to be mediated by GHS-R, mainly present at the pituitary level (1, 7). Taken together, this molecule may reach and act on the anterior pituitary via the blood circulation. GH and its mediator, IGF-1, are anabolic hormones that are essential for skeletal and myocardial growth and metabolic homeostasis (3, 4). GH supplementation has been shown to cause beneficial effects on left ventricular myocardial structure and function in some patients with CHF (16), although neutral results of randomized trials have also been reported (17). Thus, infusion of ghrelin may have beneficial effects in patients with CHF, at least in part through GH-dependent mechanisms.

Interestingly, infusion of ghrelin significantly increased plasma epinephrine, although it did not alter plasma norepinephrine level. GHS-R has been shown to exist in the adrenal (13). Thus, the epinephrine-releasing effect of ghrelin may be due to direct effects on the adrenal, although the mechanisms of the epinephrine release need to be determined in another study. Ghrelin also increased circulating ACTH, cortisol, and PRL in patients with CHF, consistent with earlier studies (2, 8). GHS-R, a specific receptor for ghrelin, has been shown to exist abundantly in the hypothalamus and pituitary (7), suggesting that this releasing activity may depend on central nervous system-mediated mechanisms. Further studies are necessary to elucidate the mechanisms responsible for these hormonal effects of ghrelin.

A recent study has demonstrated that ghrelin immunoreactivity is intense in the kidney, where the GHS-R and prepro-ghrelin genes are expressed (18). These findings suggest endocrine and/or paracrine roles of ghrelin in the kidney. However, diuretic and natriuretic effects of ghrelin were not observed in the present study. Further studies are necessary to investigate the pathophysiological roles of ghrelin in the kidney.

A considerable amount of ghrelin is known to circulate in the plasma of healthy volunteers. Nevertheless, exogenously administered ghrelin at a pharmacological level (43 times baseline value) increased cardiac performance together with stimulation of GH in patients with CHF. In addition, ghrelin has recently been shown to cause a positive energy balance by stimulating food intake (19) and inducing adiposity (20). Thus, it would be interesting to examine long-term effects of ghrelin in cachectic patients with CHF.

In conclusion, iv infusion of ghrelin, a potent GH-releasing peptide, had beneficial hemodynamic effects in patients with CHF in the absence of renal effects.

Acknowledgments

We thank Kazuyuki Ueno and Masahiko Shibakawa for preparing ghrelin. We also thank Yumi Takara and Toshino Yukimoto for their technical assistance.

Footnotes

This work was supported by the Research Grant for Cardiovascular Disease (12C-2 and 13C-1) from the Ministry of Health, Labor and Welfare, the Uehara Memorial Foundation, and the Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research (OPSR) of Japan.

Abbreviations: CHF, Chronic heart failure; GHS-R, GH secretagogues receptor; TFA, trifluoroacetic acid.

Received May 23, 2001.

Accepted September 4, 2001.

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