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Department of Pharmacology (V.L., G.R., F.S., A.T., V.D.G.C., M.B., E.E.M., F.B.), and Institute of Pharmacological Sciences (G.R.), University of Milan, 20129 Milan, Italy; and Europeptides (R.D.), Argenteuil 95100, France
Address all correspondence and requests for reprints to: Prof. Ferruccio Berti, Department of Pharmacology, Via Vanvitelli 32, 20129 Milan, Italy. E-mail: Ferruccio.Berti{at}unimi.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have shown that heart preparations from rats rendered GHD by passive immunization against GHRH are more sensitive to postischemic ventricular dysfunction than those from control rats (5). In these animals, in vivo GH replacement was effective in improving ischemic damage, and its effects were similar to those of hexarelin under identical experimental conditions (6).
Hexarelin is a highly effective GH secretagogue (GHS) (7), and its cardiac effects are likely mediated by GH (6). However, previous studies indicated that the GH-secreting activity of hexarelin was largely impaired in the GHD rat model (8). Like other GHSs, hexarelin requires the presence of endogenous GHRH for maximal stimulation of GH secretion (8, 9), because passive immunization against GHRH blunts hexarelin-induced GH secretion (10). Alternatively, hexarelin activity in the heart may be only partially dependent on GH or even independent of GH. In fact, the recent demonstrations of specific binding sites for GHS-like compounds in the heart (11, 12) suggest that hexarelin may have direct cardiac effects.
To address this issue, we compared the effects of hexarelin with those of GH on the mechanical and metabolic alterations induced by low-flow ischemia and reperfusion in isolated hearts obtained from hypophysectomized rats treated for 1 week with hexarelin, GH, or saline. To study the specificity of hexarelin on cardiac function, we compared its effects with those of EP 51389, a synthetic tripeptide with strong GH-releasing activity (11, 13). The structure of EP 51389 is distinct from that of hexarelin; and therefore, it is unable to displace hexarelin from its cardiac binding sites (11). In the hypophysectomized rats, hexarelin or EP 51389 cannot stimulate the release of pituitary GH; therefore, the cardiac effects of these peptides must be GH-independent.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All experimental protocols were approved by the Review Committee of the Department of Pharmacology and met the Italian guidelines for use of laboratory animals, which conform with the European Communities Directive of November 1986 (86/609/EEC).
GH assay
Plasma GH concentrations were measured using a double-antibody
RIA (15). Results were expressed as ng/ml, relative to the National
Institutes of Health standard rat GH RP-2, the potency of which was 2
U/mg. The minimum detectable value of rat GH was 1 µg/liter;
intraassay variability was 6%. To avoid possible interassay
variations, all samples were assayed in a single RIA. Reagents for GH
RIA were a kind gift of the National Hormone and Pituitary
Program, NIDDK, NICHHD, USDA.
IGF-I assay in plasma and heart
Plasma samples were cryoprecipitated in 87.5% ethanol and
12.5% HCl 2N, as previously described by Brewer et al.
(16). Hearts were weighed and frozen in liquid nitrogen. Single hearts
were subsequently pulverized, and IGF-I was extracted using 1 mol/liter
ice-cold acetic acid (5 ml/g tissue), as previously described by
D’Ercole et al. (17). After centrifugation at 600 x
g for 10 min, the supernatants were frozen at -20 C,
lyophylized, and reconstituted with assay buffer (2 ml/g fresh weight).
Total IGF-I plasma levels and heart IGF-I concentrations were
determined using a commercially available RIA kit (Amersham Pharmacia Biotech Italia, Milan, Italy). The sensitivity of the
assay was 50 pg/ml; intraassay variability was less than 10%. To avoid
possible interassay variations, all samples were assayed in a single
RIA.
Perfused heart preparations
The isolated hearts were perfused, retrograde fashion, through
the aorta with gassed Krebs Henseleit solution (37 C), as previously
described by Berti et al. (18). The perfusion rate was
adjusted to yield a coronary perfusion pressure (CPP) of 55–60 mm Hg
with a flow rate of 12 ml/min. LV pressure (LVP) was measured by
inserting a small latex balloon into the ventricular cavity and filling
it with saline until LV end-diastolic pressure (LVEDP) stabilized in
the range of 5 mm Hg. The preparations were electrically paced at a
frequency of 300 beats/min with rectangular pulses (1 msec duration;
voltage, 10% above threshold) by a Grass stimulator (model S-88, Grass
Instruments, Quincy, MA).
The hearts of the experimental groups of hypophysectomized and intact rats were allowed to stabilize for 20 min and subsequently exposed to the low-flow ischemia and reperfusion protocol (see below).
Ischemia was induced by reducing the coronary flow to 2 ml/min (CPP, 4–6 mm Hg) for a period of 40 min. At the end of this period, reperfusion was resumed at the preischemic flow rate of 12 ml/min for another period of 20 min. In this study, CPP and LVP were monitored with Statham transducers (HP-1280C) connected to a dynograph (HP-7754A; Hewlett-Packard Co., Waltham, MA). LVEDP (which is an index of stiffness and difficulty in relaxation of cardiac cells) and postischemic LV-developed pressure (LVDP, which measures the strength of contractility of cardiac myocytes, calculated as the peak LVP minus LVEDP) were also evaluated. Furthermore, the reactivity of the coronary vasculature to angiotensin II was evaluated to assess the integrity of endothelium-dependent relaxant mechanisms. Angiotensin II (1 µg; Sigma Chemical Co., St. Louis, MO) was injected as a bolus into the perfusion system at the beginning of each experiment.
Creatine kinase (CK) in heart perfusate
CK activity, a biochemical marker of myocardial cell lesions,
was determined in heart perfusates, which were collected in an
iced-cooled beaker before flow reduction and during the 20 min of
reperfusion. CK activity was evaluated according to the method of
Bergmeyer et al. (19) using a commercial kit (Roche Molecular Biochemicals, Milan, Italy). Total CK was determined
spectrophotometrically (Lambda 16, Perkin-Elmer Italia, Monza, Italy) and expressed as U/20 min·g wet
tissue.
6-Keto-PGF1
in heart perfusate
Because prostacyclin (PGI2) generation plays an
important role in maintaining flow within vessels and protecting the
heart against ischemia, PGI2 release in the heart
perfusates was measured by assaying the levels of its stable
metabolite, 6-Keto-PGF1. Heart perfusates were collected
during the 5 min immediately preceding flow reduction and during the
first 10 min of reperfusion. The concentrations of
6-Keto-PGF1 were evaluated according to the enzyme
immunoassay method described by Pradelles et al. (20) using
a commercially available kit (detection limit 3 pg/ml; Amersham Pharmacia Biotech) and are expressed in ng/min.
Statistical analysis
Data were analyzed for statistical significance by one-way ANOVA
followed by the Tukey-Kramer test for multiple comparisons. A value of
P < 0.05 was considered significant. The area under
the curve (AUC) was assessed following the trapezoid method.
Drugs
Hexarelin
[His-D-2-Me-Trp-Ala-Trp-D-Phe-Lys-NH2]
and biosynthetic human GH (Genotropin) were kind gifts
from Pharmacia & Upjohn, Inc. (Stockholm, Sweden). EP
51389
[Aib-D-2-Me-Trp-D-2-Me-Trp-NH2]
was synthetized by Europeptides.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). No treatment altered the heart/body
weight ratio in hypophysectomized rats, indicating that proportional
changes in body and heart weight had occurred (Table 1). Plasma GH
concentrations were below the detection limit of the assay in all
hypophysectomized rats (data not shown).
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and 3). As a consequence, electrical
pacing was not reestablished, and cardiac rhythm disturbances were
associated with a severe impairment of heart contractility. Moreover,
upon reperfusion, CPP values were significantly increased (58.7 ±
5.2 mm Hg over the preischemic values; P < 0.01),
denoting severe coronary vasoconstriction caused, in part, by heart
stiffness (Fig. 2). Treatment of
hypophysectomized rats with hexarelin notably protected the isolated
hearts from ischemia-reperfusion damage, such that CPP values were in
the range of those determined in preparations from intact rats (
Figs. 1–3). At the end of the ischemic and reperfusion periods, LVEDP values
were, respectively, 31.3 ± 2.5 mm Hg (P < 0.01)
and 13.1 ± 1.7 mm Hg (P < 0.05); and CPP values
of hypophysectomized rats were not statistically different from those
of intact rats (Fig. 2). Similar results were obtained with heart
preparations from hypophysectomized rats given GH. In this case, LVEDP,
CPP (Fig. 2), and LVDP (Fig. 3) values
were not statistically different from those obtained from hearts of
hypophysectomized rats given hexarelin. In contrast, heart preparations
from hypophysectomized rats given EP 51389 generated LVEDP values,
recorded during ischemia (peak 62.5 ± 2.9 mm Hg) and at the end
of reperfusion (50.7 ± 3.4 mm Hg), that were consistently greater
than the corresponding preischemic values (Fig. 2). Dysrhythmia was
present during reperfusion. At the end of the reperfusion period, these
hearts recovered only 35% of their preischemic contractility values.
In line with these results, the CPP values were elevated to values
higher than basal values, i.e. 47.5 ± 3.2 mm Hg
(P < 0.01) at the end of reperfusion.
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). Treatment with GH or hexarelin
reduced, by almost 50% (P < 0.05), the amount of CK
released by the hearts of hypophysectomized rats during reperfusion. In
contrast, heart preparations from hypophysectomized rats given EP 51389
generated CK activity in amounts similar to those released by hearts
from saline-injected hypophysectomized rats (Fig. 4).
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). The
rate of 6-Keto-PGF1 production in hearts from
hypophysectomized rats was reduced by 55% and 54% in the preischemic
and reperfusion periods, respectively. Treatment with GH or hexarelin
prevented this fall in the rate of 6-Keto-PGF1a production
during the preischemic period. At reperfusion, the rate of formation of
the eicosanoid in hearts from hexarelin- or GH-treated
hypophysectomized rats was diminished only by 16% and 22%,
respectively, and was not significantly different from that of intact
rats. In contrast, in hearts from hypophysectomized rats given EP
51389, the rate of formation of 6-Keto-PGF1 was still
reduced by 47% and 49% in the preischemic and reperfusion periods,
respectively (Fig. 5).
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), which
was 3.7-fold higher (P < 0.01) than that recorded in
hearts from intact rats (16.2 ± 2.5 mm Hg). Treatment with GH or
hexarelin significantly reduced, by almost 50%, the effect of
angiotensin II in hypophysectomized rats. In contrast, EP 51389 failed
to protect the vascular endothelium from the ischemic damage. In fact,
in heart preparations from rats treated with EP 51389, the rise in CPP
values (46.5 ± 2.4 mm Hg) was 2.9-fold higher (P
< 0.01) than that measured in preparations from intact rats (Fig. 6).
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).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, hexarelin had a strong protective activity against
ischemia and reperfusion-induced myocardial damage, very similar to
that observed for GH. Hexarelin pretreatment effectively reduced the
ventricular contracture of the perfused heart during ischemia, and it
reduced CK activity in the heart outflow at reperfusion. These events
were paralleled by a more efficient recovery of LVDP, a prompt
compliance of the heart to follow the external electrical pacing, and a
reduction of the CPP. The protective effect of hexarelin was also
demonstrated by maintenance of 6-Keto-PGF1 production,
as well as restoration of the coronary vessel reactivity to angiotensin
II.
In the heart, PGI2 production is a critical cytoprotective mechanism for resisting the damage caused by ischemia. In fact, PGI2-mimetics (25, 26) or PGI2 releasers (27) are known to improve heart mechanics in ischemic hearts by reducing ventricular contracture (heart rigidity) and calcium ion overload within cardiac myocytes. Moreover, stabilization of cardiac lysosomes, provided by a normal generation of PGI2 in cardiac tissues, may represent another possible link with the beneficial effects disclosed by hexarelin in the present experiments. Cardiac lysosomes contain several acid hydrolases, including proteases and phospholipases. If these enzymes are released into the cell cytoplasm, they may contribute to the degradation of structural proteins and membrane phospholipids. During ischemia, leakage of lysosomal enzymes is reported to occur before the irreversible damage of myocardium (28). PGI2 has been reported to be a potent stabilizer of lysosomes in the isolated cat liver (29) and in ischemic myocardium of intact animals (30).
The mechanism by which hexarelin exerts its beneficial effects on cardiac function in hypophysectomized rats is obviously independent of GH. Data obtained with the tripeptide EP 51389 are consistent with this view. This molecule is as effective as hexarelin in stimulating GH secretion in the rat (11, 13), but it is far less effective in protecting the heart from ischemia (this study). The messenger RNA (mRNA) encoding a receptor specific for peptidyl and nonpeptidyl GHS has recently been cloned (31), and it has been reported that it is expressed in several peripheral organs of the male rat, including the heart (32, 33). Interestingly, EP 51389 effectively displaces hexarelin from its hypothalamic binding sites, and poorly from cardiac membranes (11), which suggested the presence of multiple receptor subtypes for GHS. More recently, evidence for GHS receptor subtypes in rat pituitary and heart, distinct from that previously cloned, was obtained using a photoactivable analog of hexarelin (12, 34).
A possible interpretation of our findings is that hexarelin, via stimulation of specific cardiac receptors, triggers cytoprotective mechanisms conferring resistance to ischemic insults.
The local generation and release of IGF-I may have contributed to the overall protective effect of hexarelin and GH. IGF-I has a positive inotropic effect in healthy male volunteers (35), increases force development in isolated rat papillary muscles (36), and increases free cytosolic Ca2+ concentrations in cultured cardiomyocytes (36). However, in our experiments, neither GH, hexarelin, nor EP 51389 had significant effects on IGF-1 titers in the heart. The cardioprotective effects of GH may have been mediated by an elevation of plasma IGF-I levels. In fact, it has been shown that IGF-I stimulates nitric oxide (NO) release from cultured endothelial cells, and NO is an important regulator of vascular function (37). In contrast, hexarelin did not stimulate plasma levels of IGF-I. The existence of a direct functional relationship between hexarelin and NO formation in cardiac endothelial cells is yet to be explored.
Our data showed that ablation of the pituitary gland also resulted in the hyperreactivity of coronary smooth muscle cells to angiotensin II, a phenomenon previously observed in rats with selective GHD (5). This finding, together with the clear-cut reduction of PGI2 generation, further emphasizes the involvement of the somatotropic axis in the mechanism(s) regulating the vascular tone.
It is well known that NO generation by endothelial cells plays a prominent role in the regulation of vascular tone and in the modulation of vasoconstrictor activity, whereas the contribution of PGI2 to this mechanism is rather poor (38). PGI2, released by the endothelium, is mainly directed toward the vascular lumen, so that its major activity would be the antiplatelet effect and not vasodilatation. This would imply that a dysfunction of NO production in the coronary vascular bed of the hypophysectomized rat should be considered for understanding the hyperreactivity to angiotensin II. Alterations of the vasopressor acetylcholine activity in perfused hearts obtained from rats with selective GHD already has been reported (5).
The mechanism(s) through which hexarelin and GH preserve the functional integrity of cardiac endothelial cell function and normalize PGI2 production in hypophysectomized rats is unknown. Whatever the mechanism(s) involved, it is intriguing that both hexarelin and GH were able to counteract the increased sensitivity of the coronary vasculature to vasoconstrictors in the hypopituitary state. This effect was not observed with EP 51389, which emphasizes the specificity of hexarelin action on the heart.
In conclusion, our findings demonstrate that short-term pretreatment with hexarelin counteracts ischemic damage in perfused hearts of hypophysectomized rats. This protective activity is likely exerted through specific cardiac receptors and is independent of its GH-releasing properties. These data suggest that the GHS may be of therapeutic value in the prevention of primary and, possibly, secondary myocardial ischemic events in humans.
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Acknowledgments |
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Footnotes |
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Received November 11, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A. Tivesten, E. Bollano, K. Caidahl, V. Kujacic, X. Y. Sun, T. Hedner, A. Hjalmarson, B.-A. Bengtsson, and J. Isgaard The Growth Hormone Secretagogue Hexarelin Improves Cardiac Function in Rats after Experimental Myocardial Infarction Endocrinology, January 1, 2000; 141(1): 60 - 66. [Abstract] [Full Text] [PDF]
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V. Bodart, M. Febbraio, A. Demers, N. McNicoll, P. Pohankova, A. Perreault, T. Sejlitz, E. Escher, R.L. Silverstein, D. Lamontagne, et al. CD36 Mediates the Cardiovascular Action of Growth Hormone-Releasing Peptides in the Heart Circ. Res., May 3, 2002; 90(8): 844 - 849. [Abstract] [Full Text] [PDF]
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