Vol. 280, Issue 1, H76-H82, January 2001
Melatonin potentiates contractile responses to serotonin in
isolated porcine coronary arteries
Qiong
Yang1,
Elizabeth
Scalbert2,
Philippe
Delagrange2,
Paul M.
Vanhoutte2, and
Stephen T.
O'Rourke1
1 Department of Pharmaceutical Sciences, North Dakota State
University, Fargo, North Dakota 58105; and 2 Institut de
Recherches Internationales Servier, 92415 Courbevoie Cedex,
France
 |
ABSTRACT |
The present study was designed to
determine the effects of melatonin on coronary vasomotor tone. Porcine
coronary arteries were suspended in organ chambers for isometric
tension recording. Melatonin (10
10-105 M)
itself caused neither contraction nor relaxation of the tissues. Serotonin (109-105 M) caused
concentration-dependent contractions of coronary arteries, and in the
presence of melatonin (107 M) the maximal response to
serotonin was increased in rings with but not without endothelium. In
contrast, melatonin had no effect on contractions produced by the
thromboxane A2 analog U-46619 (1010-107 M). The melatonin-receptor
antagonist S-20928 (106 M) abolished the potentiating
effect of melatonin on serotonin-induced contractions in
endothelium-intact coronary arteries, as did treatment with
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (105 M),
methylene blue (105 M), or
NG-nitro-L-arginine (3 × 105 M). In tissues contracted with U-46619, serotonin
caused endothelium-dependent relaxations that were inhibited by
melatonin (107 M). Melatonin also inhibited coronary
artery relaxation induced by sodium nitroprusside
(109-105 M) but not by isoproterenol
(109-105 M). These results support the
hypothesis that melatonin, by inhibiting the action of nitric oxide on
coronary vascular smooth muscle, selectively potentiates the
vasoconstrictor response to serotonin in coronary arteries with endothelium.
nitric oxide; sodium nitroprusside; vasoconstriction; vascular
smooth muscle
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INTRODUCTION |
THE PINEAL HORMONE
MELATONIN contributes to the regulation of circadian rhythms
(46). The daily rhythm in circulating melatonin levels
parallels the day-night cycle, with plasma melatonin concentration ([melatonin]) rising during the night and falling toward morning (7). Within the cardiovascular system, circadian
variations in several hemodynamic parameters including heart rate,
cardiac output, and arterial blood pressure are well documented
(35, 53). Moreover, the onset of certain acute
cardiovascular events such as stroke, myocardial infarction,
and sudden cardiac death displays a marked circadian pattern, with most
such ischemic episodes occurring during the early morning hours
(26, 37, 57). The role, if any, of melatonin in these
phenomena is not yet defined.
The possibility that melatonin may be involved in cardiovascular
regulation was first suggested by animal studies in which removal of
the pineal gland resulted in hypertension (25, 59), an
effect that was reversed by the administration of exogenous melatonin
(22). In humans, oral administration of melatonin lowers
blood pressure in normotensive individuals (1, 8), and
melatonin levels are decreased in patients suffering from stroke
(17), migraine (6), and coronary heart
disease (5). The recent finding that receptors for
melatonin are present in the arteries of several species (44,
55) including humans (45) indicates that the
hormone may be directly involved in the local control of blood vessel
diameter. Indeed, a functional role for melatonin in the vasculature is
supported by evidence from several studies demonstrating that melatonin
causes vasoconstriction in certain arteries (15, 19, 49,
56) and potentiation of contractile responses in others
(29, 49, 55). If similar responses were to occur in
epicardial coronary arteries, the resultant vasospasm might initiate or
exacerbate episodes of myocardial ischemia (33). Because
little is known about the actions of melatonin in the coronary
circulation, the present study was designed to determine the effect(s)
of melatonin on the responsiveness of isolated coronary arteries.
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METHODS |
Tissue preparation.
Porcine hearts were obtained from a local abattoir and immediately
immersed in cold physiological salt solution before transfer to the
laboratory. The left anterior descending coronary artery was dissected
free from the surrounding myocardium, cleaned of adherent fat and
connective tissue, and cut into rings 4-5 mm in length; 4-8
coronary arterial rings were prepared from each heart. In some rings
the endothelium was removed by gently rubbing the intimal surface with
a fine forceps (14). The absence or presence of
endothelial cells was confirmed by the absence or presence of
relaxation to the endothelium-dependent vasodilator bradykinin
(107 M).
The rings were suspended in water-jacketed organ chambers filled with
25 ml of physiological salt solution. The solution was aerated with a
mixture of 95% O2-5% CO2, and the temperature
was maintained at 37°C throughout the experiment. Each ring was
suspended by two fine stainless steel wire clips passed through the
lumen; one clip was anchored inside the organ bath and the other was connected to a force transducer (model FT03, Grass Instruments, Quincy,
MA). Isometric tension was measured and recorded on a Grass polygraph.
The tissues were stretched progressively to the optimal point of their
length-tension relationship by using KCl (20 mM) to generate a standard
contractile response (10). After this procedure, the
preparations were allowed to equilibrate at their optimal length for at
least 30 min before being exposed to other vasoactive substances.
Experimental protocols.
For contractile responses, concentration-response curves to melatonin
(1010-105 M), serotonin
(109-105 M), and
9,11-dideoxy-11
,9-epoxymethano-PGF2
(U-46619, 1010-107 M) were obtained in resting
coronary arterial rings with and without endothelium. The
concentration-response curves to serotonin and U-46619 were obtained in
the absence and presence of melatonin (107 M), which was
added to the organ chamber immediately before the addition of the
contractile agonist. This [melatonin] was selected because in
preliminary experiments it produced the greatest potentiating effect on
contractile responses in isolated pig coronary arteries, which is in
agreement with previous studies in other blood vessels (29,
49). Potentiation was also observed with lower [melatonin] in
this preparation, but the results were inconsistent. [Melatonin] > 107 M had no further effect, which is in agreement with
previous findings (29, 49).
In some experiments the preparations were incubated with the
melatonin-receptor antagonist
N-[2-napth-1-yl-ethyl]-cyclobutyl carboxamide (S-20928,
106 M) (58) for 30 min before exposure to
melatonin. In a separate series of experiments, concentration-response
curves to serotonin in the absence and presence of melatonin were
obtained in the presence of the soluble guanylyl cyclase inhibitors
methylene blue (105 M) (32) and
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 105
M) (18) or the inhibitor of nitric oxide (NO) synthases
(NOS), NG-nitro-L-arginine
(L-NNA, 3 × 105 M) (36).
In these experiments, the inhibitors were added to the organ chamber 20 min before exposure to serotonin and remained in contact with the
tissues throughout the remainder of the experiment.
Relaxation of coronary arteries was studied in rings contracted with
U-46619 (1-3 × 109 M). After the
U-46619-induced contraction had reached a stable plateau, increasing
concentrations of the following drugs were added to the bath solution:
melatonin (1010-105 M), sodium
nitroprusside (109-105 M), isoproterenol
(109-105 M), or serotonin
(109-105 M). The experiments with serotonin
were performed in the presence of the 5-HT2-receptor
antagonist ketanserin (106 M) to inhibit the direct
contractile effect of serotonin on coronary smooth muscle
(43). Concentration-response curves to sodium nitroprusside, serotonin, and isoproterenol were obtained in the absence and presence of melatonin (107 M), which was
added to the organ bath immediately before exposure to the vasodilator.
After completion of each concentration-response curve, papaverine
(104 M) was added to the preparations to ensure maximal
relaxation of the tissues.
In all experiments concentration-response curves were obtained by
increasing the drug concentration in the organ chamber in a cumulative
manner by approximately threefold, after the response to the previous
concentration had been allowed to reach its maximum (52).
Control and treated rings from the same animal were studied in
parallel. Only one concentration-response curve was obtained in each
blood vessel ring.
Data analysis.
Contractile responses were normalized by expressing them as a
percentage of the contraction evoked by KCl (60 mM), which was added to
the organ chamber at the conclusion of the experiment. Relaxations were
expressed as a percentage of the initial increase in isometric tension
induced by U-46619. The data were quantified by determining both the
maximal effect (Emax) and the concentration of
the agonist necessary to produce 50% of its own maximal response (EC50). The EC50 values were converted to
negative logarithms and expressed as 
log molar EC50.
Results are expressed as means ± SE, and n refers to
the number of animals from which blood vessels were taken. Values were
compared by Student's t-test for paired or unpaired
observations and were considered to be significantly different when
P < 0.05.
Drugs and solutions.
The following drugs used in this study were obtained from Sigma
Chemical (St. Louis, MO): bradykinin, dl-isoproterenol
hydrochloride, melatonin, methylene blue, L-NNA, papaverine
hydrochloride, serotonin creatinine sulfate, and sodium nitroprusside.
Ketanserin tartrate was obtained from Janssen Pharmaceutica (Beerse,
Belgium); ODQ was from Tocris Cookson (Ballwin, MO); S-20928 was from
Institut de Recherches Internationales Servier (Courbevoie, France);
and U-46619 was from Upjohn (Kalamazoo, MI). Drug solutions
were prepared daily, kept on ice, and protected from light until used.
All drugs were dissolved initially in distilled water with the
exception of melatonin, which was dissolved in ethanol, and ODQ and
S-20928, which were dissolved in DMSO before further dilution in
distilled water. Drugs were added to the organ chambers in volumes not
greater than 0.2 ml. Drug concentrations are reported as final molar
concentrations in the organ chamber. The composition of the
physiological salt solution was as follows (in mM): 118.3 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 25.0 NaHCO3, and 11.1 glucose.
| |
RESULTS |
Direct effect of melatonin.
Melatonin (1010-105 M) itself had no direct
contractile effect on quiescent coronary arteries, nor did the hormone
cause relaxation of tissues contracted with the thromboxane
A2 analog U-46619 (data not shown). The results were
similar in coronary arteries with and without endothelium.
Effect of melatonin on coronary vasoconstrictors.
Concentration-response curves to the coronary vasoconstrictors
serotonin and U-46619 were obtained in the absence and presence of
melatonin (107 M). In rings with endothelium, the maximal
contractile response to serotonin was increased in the presence of
melatonin (107 M) (Fig.
1A), whereas the
concentration-response curve for U-46619 was unaffected under these
same conditions (Fig. 2). Removal of the
endothelium shifted the concentration-response curve for serotonin to
the left and abolished the potentiating effect of melatonin on
serotonin-induced contractions (Fig. 1B). In the presence of the melatonin-receptor antagonist S-20928 (106 M),
melatonin had no potentiating effect on the concentration-response curve for serotonin in coronary arteries with intact endothelium (Fig.
3). The antagonist itself did not affect
the concentration-response curve for serotonin (data not shown).
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Fig. 1.
Log concentration-response curves for serotonin in
contracting isolated porcine coronary arteries with endothelium
(A) or without endothelium (B). Responses to
serotonin were obtained in the absence ( ) and presence
( ) of 107 M melatonin. Data are expressed
as a percentage of the contraction evoked by 60 mM KCl, which averaged
20.5 ± 2.3 g (with endothelium) and 16.4 ± 4.2 g
(without endothelium) in the absence of melatonin and did not differ
significantly in rings treated with melatonin. Each point represents
the mean ± SE; n = 6; *P < 0.05 (statistically significant) from untreated control preparations.
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Fig. 2.
Log concentration-response curves for
9,11-dideoxy-11,9-epoxymethano-PGF2 (U-46619) in
contracting isolated porcine coronary arteries with endothelium in the
absence () and presence () of
107 M melatonin. Data are expressed as a percentage of
the contraction evoked by 60 mM KCl, which averaged 28.7 ± 2.5 g in the absence of melatonin and did not differ significantly
in rings treated with melatonin. Each point represents the mean ± SE; n = 6.
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Fig. 3.
Log concentration-response curves for serotonin in
contracting isolated porcine coronary arteries with endothelium.
Responses to serotonin were obtained in untreated control rings
(), rings treated with 107 M melatonin
(), and rings treated with 107 M
melatonin plus 106 M
N-[2-napth-1-yl-ethyl]-cyclobutyl carboxamide (S-20928,
 ). Data are expressed as a percentage of the contraction evoked by
60 mM KCl, which averaged 19.0 ± 2.2 g in the absence of
melatonin and did not differ significantly in rings treated with
melatonin or S-20928. Each point represents the mean ± SE;
n = 5; *P < 0.05 between responses
obtained in the absence and presence of S-20928.
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Concentration-response curves to serotonin in the absence and presence
of melatonin (107 M) were also obtained in coronary
arteries with endothelium treated with L-NNA (3 × 105 M) or ODQ (105 M). Similar to the
results obtained in rings in which the endothelium had been removed,
the concentration-response curve for serotonin was shifted to the left
in the presence of either L-NNA or ODQ compared with the
responses obtained under control conditions (i.e., Fig. 1A),
and the potentiating effect of melatonin on serotonin-induced contractions was abolished (Fig. 4).
Likewise, melatonin had no potentiating effect on the
concentration-response curve for serotonin in arteries with endothelium
treated with methylene blue (105 M) (data not shown).
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Fig. 4.
Log concentration-response curves for serotonin in
contracting isolated porcine coronary arteries with endothelium treated
with 3 × 105 M
NG-nitro-L-arginine
(L-NNA, A) or 105 M
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, B).
Responses to serotonin were obtained in the absence ()
and presence () of 107 M melatonin. Data
are expressed as a percentage of the contraction evoked by 60 mM KCl,
which averaged 23.9 ± 3.3 g in the absence of melatonin and
did not differ significantly in rings treated with melatonin. Each
point represents the mean ± SE; n = 6.
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Effect of melatonin on coronary vasodilators.
In the presence of ketanserin (106 M), serotonin caused
concentration-dependent relaxations of coronary arteries with
endothelium contracted with U-46619 (Fig.
5). The endothelium-dependent relaxations to serotonin were reduced significantly in the presence of melatonin (107 M) (Fig. 5). In coronary arteries without
endothelium contracted with U-46619 (109 M), sodium
nitroprusside caused concentration-dependent relaxations that were also
inhibited by melatonin (107 M) (Fig.
6). The log molar EC50
values for sodium nitroprusside were 7.42 ± 0.19 versus 6.70 ± 0.27 (P < 0.05) in the absence and presence of
melatonin (107 M), respectively.
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Fig. 5.
Log concentration-response curves for serotonin in
producing relaxation of isolated porcine coronary arteries with
endothelium treated with 106 M ketanserin. Responses to
serotonin were obtained in the absence () and presence
() of 107 M melatonin. Data are expressed
as a percentage of the initial increase in tension induced by U-46619
(1-3 × 109 M). Each point represents the
means ± SE; n = 8; *P < 0.05 from untreated control preparations.
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Fig. 6.
Log concentration-response curves for sodium
nitroprusside in producing relaxation of isolated porcine coronary
arteries without endothelium in the absence () and
presence () of 107 M melatonin. Data are
expressed as a percentage of the initial increase in tension induced by
U-46619 (1-3 × 109 M). Each point represents
the mean ± SE; n = 5; *P < 0.05 from untreated control preparations.
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Isoproterenol caused concentration-dependent relaxations of coronary
arterial rings contracted with U-46619 (log molar
EC50 = 7.62 ± 0.20;
Emax = 99.5 ± 0.5). The addition of
melatonin (107 M) to the organ chamber had no significant
effect on the concentration-response curve for isoproterenol (log
molar EC50 = 7.53 ± 0.10;
Emax = 99.3 ± 0.7; n = 4).
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DISCUSSION |
Although considerable progress has been made regarding the
neurobiology of melatonin (50), its role in the
cardiovascular system is poorly understood. The discovery of receptors
for melatonin in mammalian blood vessels suggests that the hormone may
be involved in controlling vasomotor tone (44, 45, 55).
Indeed, melatonin either causes or potentiates vasoconstriction in
certain vascular beds. For example, in rat cerebral arteries, melatonin
causes vasoconstriction and reduces cerebral blood flow (9, 19, 56). In the caudal artery of the same species, melatonin does not directly cause contraction of the smooth muscle but it potentiates vasoconstrictor responses to norepinephrine and adrenergic nerve stimulation (29, 55). The results of the present study
demonstrate that the coronary circulation is also a site of action for
the vasoconstrictor-potentiating effect of melatonin, an effect that is
mediated by receptors sensitive to inhibition by the melatonin-receptor antagonist S-20928 (58).
A novel finding of this study is that the potentiating effect of
melatonin in coronary arteries is selective for contractions elicited
by serotonin, inasmuch as the contractile response to U-46619, a
thromboxane A2 analog, was unaffected by the hormone. Moreover, the effect of melatonin on contractions evoked by serotonin was observed only in coronary arteries with an intact endothelium. These results most likely relate to the role of the endothelium in
modulating serotonin-induced constriction of coronary arteries (10). Both U-46619 and serotonin act directly on vascular
smooth muscle cells to cause contraction, but serotonin, unlike U-46619 (12), also causes endothelium-dependent relaxation via the
release of NO (41, 54). In porcine coronary arteries,
these opposing effects of serotonin are mediated by different serotonin
receptor subtypes. The direct contractile effect of serotonin is
mediated by 5-HT2A receptors located on the smooth muscle
cells (13), whereas NO release is mediated by
5-HT1D-like receptors found on the coronary endothelial
cells (42). Thus, in coronary arteries with endothelium,
the direct contractile response to serotonin is suppressed by the
indirect inhibitory effect of NO on the smooth muscle (10,
12). Indeed, the ability of the endothelium to modify
serotonin-induced contractions in this preparation is evident from the
increased responsiveness of rings without endothelium to serotonin
observed in this study and others (12). That the synergistic effect of melatonin on serotonin-induced contractions occurred only in coronary arteries with endothelium suggests that the
potentiating effect of the hormone may involve impairment of the NO
pathway (i.e., decreased synthesis or release of NO or inhibition of
its action on vascular smooth muscle). Such a mechanism would also
explain the lack of potentiating effect of melatonin on the response to
U-46619, because the thromboxane A2 analog does not release
endothelium-derived NO in coronary arteries (12).
The hypothesis that melatonin potentiates serotonin-induced
contractions by inhibiting the NO pathway is supported by those experiments in which the synergistic effect of melatonin was abolished in the presence of either ODQ or L-NNA. By inhibiting the
soluble form of guanylyl cyclase (18), ODQ inhibits the
action of NO at the level of the vascular smooth muscle, whereas the
NOS inhibitor L-NNA (36) prevents the
formation of NO in endothelial cells. Thus, in tissues treated with ODQ
or L-NNA, the inhibitory effect of endothelium-derived NO
on the contractile response to serotonin is negated. If the synergistic
effect of melatonin on serotonin-induced contractions is indeed due to
decreased vascular relaxation by NO, then, consistent with the
observations reported in this study, melatonin would not be expected to
have an effect in the presence of either of these inhibitors. Further
support for this hypothesis is provided by the experiments in which
melatonin inhibited endothelium-dependent relaxations to serotonin,
which are mediated solely by NO in porcine coronary arteries (41,
54). This effect of melatonin was not due to a nonspecific
inhibitory action of the hormone, because the response to
isoproterenol, which acts independently of NO, was unaffected by
exposure to melatonin.
There are several potential mechanisms by which melatonin could
interfere with the NO pathway and thus potentiate serotonin-induced contractions in coronary arteries. One possibility is that melatonin may inhibit NOS (3, 31, 40). Although an effect of
melatonin on NOS in coronary arteries cannot be ruled out under the
present experimental conditions, the inhibitory effect of melatonin on relaxations to sodium nitroprusside, which serves as an exogenous NO
donor and is not dependent on NOS (28),
suggests a site of action other than or in addition to inhibition of
NOS. Alternatively, melatonin could act by attenuating the action of NO
at the level of the vascular smooth muscle. NO relaxes vascular smooth
muscle by increasing intracellular cGMP levels (23, 38)
and by activating potassium channels in the cell membrane (2,
4). Recent evidence suggests that melatonin prevents increased
cGMP accumulation in several cell types (24, 31, 39, 51)
and that the hormone has potassium channel-blocking properties
(19, 20). Thus it is likely that melatonin may potentiate
serotonin-induced vasoconstriction by inhibiting the action of NO on
coronary vascular smooth muscle cells rather than by inhibiting the
release of NO from endothelial cells (20).
The results of the present study suggest that melatonin may play a role
in regulating coronary vasomotor tone. The [melatonin] in blood rises
during the night and falls to nearly undetectable levels during the
day. Circulating peak plasma [melatonin] generally ranges from
0.5-1 nM (27), concentrations that are lower than those used in this study. However, because of its high lipophilicity, tissue [melatonin] may exceed plasma [melatonin]. Moreover, several extrapineal sources of melatonin have now been identified, including mast cells, leukocytes, platelets, and, particularly relevant to the
present study, endothelial cells (16, 30). This further increases the potential for elevations in the local tissue
[melatonin]. Indeed, [melatonin] two to three orders of magnitude
higher than those typically found in blood have been reported in bile
and bone marrow (47, 48). Elevated levels of melatonin may
increase the sensitivity of the coronary arteries to serotonin, a
putative mediator in coronary vasospasm and unstable angina (21,
34), and thus contribute to episodes of myocardial ischemia.
Given the considerable interindividual variation in the pattern of
melatonin release, further studies will be needed to determine the
significance of this effect of melatonin in relation to the circadian
variations in melatonin levels and acute cardiac events.
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ACKNOWLEDGEMENTS |
This study was supported in part by a grant from the Institut de
Recherches Internationales Servier.
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FOOTNOTES |
Address for reprint requests and other correspondence: S. T. O'Rourke, Dept. of Pharmaceutical Sciences, North Dakota State Univ., Fargo, ND 58105 (E-mail:
Stephen_orouke{at}ndsu.nodak.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 20 December 1999; accepted in final form 4 August 2000.
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