Departments of Kinesiology and Anatomy and Physiology, Kansas State University, Manhattan, Kansas 66506
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ABSTRACT |
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We have previously reported that changes in thyroid status are
associated with significant alterations in skeletal muscle blood flow
during exercise and that changes in endothelium-dependent vasodilation
may contribute to these blood flow abnormalities. The purpose of this
study was to test the hypothesis that altered endothelium-dependent
vasoconstriction is also associated with changes in thyroid status. To
test this hypothesis, rats were rendered hypothyroid with
propylthiouracil (Hypo, n = 14) or hyperthyroid with
triiodothyronine (Hyper, n = 14) over ~3 mo.
Treatment efficacy was confirmed by altered (P < 0.05)
citrate synthase activity in several hindlimb skeletal muscles from
Hypo and Hyper, compared with that in muscles from euthyroid rats (Eut,
n = 12). Vascular rings were prepared from abdominal
aortae, and responses to several vasoactive agents were determined in
vitro. As found previously, maximal acetylcholine-induced
vasorelaxation was modulated by thyroid status (Eut, 47 ± 9;
Hypo, 28 ± 6; Hyper, 68 ± 5%; P < 0.05).
Contractile responses of vascular rings with intact endothelium to the
endothelium-derived constrictor endothelin-1 (ET-1), however, were
similar among groups across a range of ET-1 concentrations. In
addition, maximal responses [Eut, 3.75 ± 0.47; Hypo, 2.72 ± 0.25; Hyper, 3.22 ± 0.42 g; not significant (NS)] and
sensitivities (Eut, 8.12 ± 0.09; Hypo, 8.10 ± 0.06; Hyper,
8.28 ± 0.09 log M; NS) to ET-1 were similar among groups. If
these findings from the conduit-type abdominal aorta extend into
resistance vasculature, it appears that changes in
endothelium-dependent vasoconstriction do not contribute to skeletal
muscle blood flow abnormalities associated with thyroid disease states.
hypothyroidism; hyperthyroidism; acetylcholine; vasodilation; vasoconstriction
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INTRODUCTION |
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THYROID DISEASES ARE ESTIMATED to affect ~5% of the population (34). Two common thyroid diseases, hypo- and hyperthyroidism, are both characterized by exercise intolerance (20). Poor exercise tolerance in hypothyroidism appears to be multifactorial. One factor contributing to exercise intolerance in this disease is inadequate perfusion of active skeletal muscle. We have found that blood flows to hindlimb muscles of hypothyroid rats are reduced ~50% compared with those of euthyroid rats during treadmill running (21). Poor left ventricular function, also associated with hypothyroidism, undoubtedly makes an important contribution to inadequate skeletal muscle perfusion during exercise (26). In addition, alterations in vascular function may contribute to poor perfusion of muscle. Consistent with this possibility, we have reported (5) that hypothyroidism is associated with blunted endothelium-dependent relaxation of isolated arterial vessels. Conversely, left ventricular function (26), endothelium-dependent vasorelaxation (22, 28), and skeletal muscle blood flow during exercise (9, 23) are all augmented in hyperthyroidism. Enhanced perfusion of active muscle suggests that other factors (e.g., impaired thermoregulation) must account for exercise intolerance in this disease (20).
In addition to synthesizing relaxing factors (e.g., nitric oxide), the endothelium can synthesize substances that induce vascular smooth muscle contraction. The best characterized of these substances is endothelin-1 (ET-1), a 21-amino acid polypeptide with potent vasoconstrictor ability (36). Effects of thyroid diseases on endothelium-dependent vasoconstriction are unknown. Data are, however, available for hypertension, a disease having hemodynamic similarities with hypothyroidism (15, 20). Vascular smooth muscle contraction induced by ET-1 has been reported to be greater in hypertensive patients (11) and in a rodent model of hypertension (3) compared with normotensive controls. Thus hypothyroidism may be associated with inadequate perfusion of skeletal muscle during exercise for two reasons related to vascular function. First, blood flow to active muscle may be inadequate because of blunted endothelium-dependent vasodilation (5). Second, augmented vasoconstriction in response to ET-1 may reduce muscle blood flow. The second possibility is important to investigate, because it has been reported that ET-1 contributes to the control of resting skeletal muscle blood flow (12, 35) and that plasma ET-1 concentration increases with exercise (19). Hyperthyroidism, on the other hand, may be characterized by augmented muscle blood flow during exercise because of enhanced endothelium-dependent vasorelaxation (22, 28) and/or lesser ET-1-induced vasoconstriction.
This study was designed to test two hypotheses. First, we hypothesized that the vascular smooth muscle contractile response to ET-1 is augmented in hypothyroidism. Second, we hypothesized that hyperthyroidism is associated with a decreased contractile response to ET-1. In addition, we wished to determine which ET receptor subtype(s) mediates contraction of vascular smooth muscle induced by ET-1 in arterial vessels of euthyroid, hypothyroid, and hyperthyroid rats. Previous work had suggested that the ETA receptor subtype is primarily responsible for mediating the smooth muscle contractile response to ET-1 in normal vasculature (10, 35).
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METHODS |
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Experimental animals. Male Sprague-Dawley rats (Charles River) initially weighing 150-175 g were housed in a room with controlled temperature (20-21°C) and light (12:12-h light-dark). Rats were randomly assigned to one of three groups: euthyroid control (Eut), hypothyroid (Hypo), and hyperthyroid (Hyper). Eut were slightly food restricted (~90% of normal bulk food intake) to match their body weights with those of Hypo and Hyper. Rats in the latter two groups were allowed to consume food ad libitum.
Treatments. Hypothyroidism was induced by ~3-mo treatment with propylthiouracil (Sigma-Aldrich) in the drinking water (0.04 g/100 ml), as done previously (5, 21). Hyperthyroidism was induced by intraperitoneal injections of triiodothyronine (T3, sodium salt, Sigma-Aldrich; 300 µg/kg) on alternate days over ~3 mo, as done previously (8, 14, 22, 23). These treatments and other experimental procedures were approved by the Kansas State University Institutional Animal Care and Use Committee.
Determination of treatment efficacy. Effectiveness of propylthiouracil and T3 treatments was assessed by determination of left ventricular weight and by estimation of skeletal muscle oxidative capacity, as done previously (5, 8, 14, 21- 23). Oxidative capacity was estimated by determination of citrate synthase activity in several hindlimb muscles. These muscles included the vastus lateralis (red section), vastus lateralis (white section), and soleus, which are composed primarily of fast oxidative glycolytic, fast glycolytic, and slow oxidative muscle fibers, respectively (4). Citrate synthase activity was determined spectrophotometrically by the method of Srere (31).
Preparation of arterial vascular rings.
Pentobarbital sodium (65 mg/kg) administered intraperitoneally was used
to anesthetize rats. They were then killed by decapitation, and
abdominal aortae distal to the renal arteries were quickly dissected.
These segments were placed in Krebs bicarbonate buffer solution (4°C;
see Solutions and drugs for composition), and fat and
connective tissue were carefully removed. Each abdominal aortic segment
was cut into three rings ~3 mm in axial length. Axial length, as well
as passive outside and inside diameters, were determined with a
calibrated micrometer eyepiece (JML Optical) mounted on the
stereomicroscope (Nikon) used during preparation of vascular rings.
Wall thickness was calculated as the difference between outside and
inside diameters divided by 2. Endothelial denudation of one of the
three vascular rings from each aortic segment was achieved by gently
rubbing the luminal surface with fine-tipped forceps. Adequate
denudation was indicated by relaxation of <5% to acetylcholine
(104 M; see Solutions and drugs) after
precontraction of a denuded vascular ring by norepinephrine (NE,
10
7 M).
Length-tension relationship. Aortic vascular rings were adjusted to optima of their individual length-developed tension relationships, as done previously (5, 22). In brief, two fine stainless steel wires were passed through the lumen of each vascular ring. One wire was connected to an isometric force transducer (Harvard Apparatus); the other wire was connected to a micrometer microdrive (Stoelting). Isometric force was continuously monitored by means of a computerized data acquisition system (MacLab). Each vascular ring/wire combination was submerged in Krebs bicarbonate buffer solution (37°C) contained in a 20-ml tissue bath.
Repeated exposures to 60 mM of KCl at increasing length permitted vascular rings to be adjusted to optima of their individual length-developed tension relationships. Length was changed by stretching rings in 5-10% (of passive outside diameter) increments with the micrometer microdrives. After each exposure to and determination of developed tension in response to 60 mM KCl, the buffer solution was replaced to allow for washout of the contractile effect of KCl before further stretching and assessing developed tension in response to 60 mM KCl at a greater length. Upon attainment of optimal stretch, a 1-h period of stabilization was allowed.Pharmacological studies.
After the stabilization period, concentration-dependent contractile
responses to NE were determined (108-10
4 M,
in one-half log increments), as done previously (5,
22). Concentration was increased by cumulative addition of
NE to tissue baths. A recovery period of 90-120 min, during which
buffer solution was changed at 5- to 10-min intervals, was allowed to
reattain resting tension in all vascular rings.
Solutions and drugs.
Krebs bicarbonate buffer solution consisted of (in mM): 131.5 NaCl, 5.0 KCl, 1.2 NaH2PO4, 1.2 MgCl2, 2.5 CaCl2, 11.2 glucose, 13.5 NaHCO3, 0.003 propranolol, and 0.025 EDTA. Propranolol was included in the buffer
solution to antagonize 2-adrenoreceptor-mediated vasorelaxation. Upon equilibration with a 95% O2-5%
CO2 gas mixture, the buffer solution was of pH 7.4.
Statistical analysis.
All data are presented as means ± SE. Responses to contractile
agents (NE, ET-1) are expressed in grams of developed tension, meaning
the increase in isometric tension above resting level (that caused by
stretch of vascular ring) in response to either NE or ET-1. Responses
to vasorelaxing agents (acetylcholine, sodium nitroprusside) are
expressed in relative terms, i.e., as a percentage of developed tension
induced by the precontracting agent NE. Vasorelaxation of vascular
rings with intact endothelium was required to be 10% for inclusion
in the data set. Relaxation of a vascular ring with intact endothelium
of <10% was considered to indicate endothelial damage incurred during
ring preparation. Data for appropriate vascular rings from an
experimental animal were averaged before statistical analysis.
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RESULTS |
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Treatment efficacy.
Propylthiouracil treatment successfully induced hypothyroidism. Citrate
synthase activity, an estimate of oxidative capacity, was decreased in
hindlimb skeletal muscles from Hypo compared with those from Eut (Fig.
1). The magnitude of reduction in citrate synthase activity ranged from ~30% in the vastus lateralis muscle (white section) to nearly 60% (P < 0.05) in the
soleus. Conversely, citrate synthase activity was increased in muscles
from Hyper compared with those from Eut, with the magnitude of
augmentation ranging from slightly less than 10% in the vastus
lateralis (white section) to nearly 50% (P < 0.05) in
the red section of the same muscle (Fig. 1). These findings demonstrate
that hyperthyroidism was induced by T3 treatment. In
addition, Hyper exhibited left ventricular hypertrophy, as indicated by
greater left ventricular weight-to-body weight ratio (Eut 1.86 ± 0.04, Hyper 2.36 ± 0.07 mg/g; P < 0.05). Hypo
did not exhibit altered left ventricular size [1.78 ± 0.05 mg/g;
not significant (NS) vs. Eut]. Final body weights were 493 ± 8, 297 ± 8, and 532 ± 13 g for Eut, Hypo, and Hyper rats,
respectively.
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Vascular ring characteristics.
Table 1 presents the characteristics of
rings prepared from abdominal aortae of Eut, Hypo, and Hyper rats.
Vascular rings from rats of different groups were of similar
dimensions. Vascular rings from Hypo, compared with those from Eut and
Hyper, were of slightly smaller outside diameter and exhibited less
resting tension at optimal stretch (Table 1). Calculated wall
thickness, however, was similar among groups (Eut 0.23 ± 0.02, Hypo 0.21 ± 0.02, Hyper 0.24 ± 0.02 mm; NS).
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Contractile responses to NE.
Sensitivity to NE was reduced (P < 0.05) in Hypo
(7.19 ± 0.09, log M units) compared with both Eut (7.66 ± 0.07) and Hyper (7.63 ± 0.09). Maximal responses to NE tended
(P = 0.054) to be reduced in Hypo (3.37 ± 0.30 g) and Hyper (3.19 ± 0.34 g) compared with Eut
(4.38 ± 0.42 g).
Vasorelaxation responses.
Relaxation responses to maximally effective doses of the
endothelium-dependent agent acetylcholine and the
endothelium-independent agent sodium nitroprusside are shown in Fig.
2. Contractile responses to NE
(107 M), given to precontract vascular rings before
administration of acetylcholine or sodium nitroprusside, did not differ
among groups (data not shown). Endothelium-dependent vasorelaxation in
rings with intact endothelium was modulated by thyroid status (P < 0.05 among groups), whereas
endothelium-independent vasorelaxation in the same rings was similar
among groups (Fig. 2).
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Contractile responses to ET-1.
Figure 3A illustrates
contractile responses to ET-1 of vascular rings with intact endothelium
from Eut, Hypo, and Hyper. Across the range of ET-1 concentrations
tested, contractile responses were similar among groups. In addition,
maximal responses to ET-1, irrespective of the ET-1 concentration at
which they occurred, were similar among groups (Eut 3.75 ± 0.47, Hypo 2.72 ± 0.25, Hyper 3.22 ± 0.42 g; NS).
Sensitivities to ET-1, as indicated by EC50 values (log
M), were also similar among groups (Eut 8.12 ± 0.09, Hypo
8.10 ± 0.06, Hyper 8.28 ± 0.09; NS). Maximal responses to
ET-1 were correlated with those to NE in all groups (Eut,
r = 0.92; Hypo, r = 0.94; Hyper,
r = 0.93; P < 0.05 for all).
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ET receptor subtypes and contractile responses to ET-1.
Table 2 presents maximal responses and
sensitivities to ET-1 under control conditions and in the presence of
either ETA receptor blockade with BQ-123 or ETB
receptor blockade with BQ-788. ETA receptor blockade
reduced sensitivity to ET-1 in Eut, Hypo, and Hyper. ETB
receptor blockade, however, reduced sensitivity to ET-1 only in Hyper.
ET receptor blockade generally did not alter maximal responses to ET-1.
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DISCUSSION |
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The key new finding of this study is that changes in thyroid status are not associated with alterations in the vascular smooth muscle response to ET-1. Thus our hypothesis that hypothyroidism is associated with an increased contractile response to ET-1 was not confirmed. In addition, our hypothesis that a decreased vascular smooth muscle contractile response to ET-1 is characteristic of hyperthyroidism was not confirmed. Our findings suggest that altered responses to ET-1 do not contribute to the significant skeletal muscle blood flow abnormalities associated with thyroid diseases. This conclusion is necessarily tentative, because responses observed in a conduit vessel such as the abdominal aorta may not reflect those in resistance vessels (5, 22).
Animal models of thyroid diseases. As we (5, 21) and others (14) previously reported, propylthiouracil treatment reduced skeletal muscle oxidative capacity. This feature is a hallmark of hypothyroidism (20). Conversely, T3 treatment increased muscle oxidative capacity, as both we (22, 23) and others (14) previously demonstrated. Hyper rats also exhibited left ventricular hypertrophy, as we (22, 23) and other investigators (8) observed in the past. These findings validate our animal models of hypo- and hyperthyroidism.
Importantly, vascular rings prepared from abdominal aortae of Hypo exhibited several characteristics that we had previously observed, including reduced sensitivity to NE, blunted endothelium-dependent relaxation, and unaltered endothelium-independent relaxation (5). Vascular rings from Hyper also exhibited characteristics previously reported, including a tendency toward reduced maximal response to NE, enhanced endothelium-dependent relaxation, and unchanged endothelium-independent relaxation (22).Contractile responses to ET-1. Contrary to our hypotheses, the vascular smooth muscle contractile response to ET-1 was generally not altered by either hypo- or hyperthyroidism. Indeed, the only statistically significant finding was that the maximal response to ET-1 was reduced in denuded vascular rings from Hypo rats, an alteration directionally opposite to what we had hypothesized would occur. Other data are not available concerning effects of thyroid diseases on the response to ET-1. Hypertension, a disease with hemodynamic similarities to hypothyroidism, has been examined. Systemic vascular resistance is increased in hypothyroidism (20), and hypertension can also be characterized by elevated systemic vascular resistance (15). Haynes et al. (11) reported that constrictor responses of dorsal hand veins to local infusion of ET-1 in hypertensive patients were twice those of normotensive control subjects. Furthermore, venoconstriction to ET-1 was highly correlated with mean arterial pressure in their hypertensive patients, suggesting that an enhanced contractile response to ET-1 contributes to the etiology of hypertension. An approximately twofold greater pressor response to ET-1 infusion was reported for perfused mesenteric vascular beds of spontaneously hypertensive rats compared with normotensive control animals (3). On the other hand, investigators studying DOCA-salt hypertensive rats reported unchanged vascular responses to ET-1 (6). It is important to note, however, that these differing findings may be accounted for by the different rodent models of hypertension used in these studies. Nonetheless, although it is an attractive hypothesis that ET-1 plays a role in the development and/or maintenance of hypertension, research findings are equivocal regarding this notion (1).
Maximal responses to NE were also not significantly augmented in Hypo (see RESULTS). Because NE and ET-1 utilize common intracellular signaling pathways (30), an unchanged response to ET-1 in hypothyroidism may be internally consistent. Indeed, maximal responses to NE and ET-1 were highly correlated in all experimental groups (see RESULTS). Interestingly, Criscione et al. (3) found increased pressor responses to NE in the mesenteric vascular beds of their spontaneously hypertensive rats, whereas Haynes et al. (11) reported that venoconstrictor responses to NE were not different in their hypertensive patients compared with normotensive controls. Experiments examining intracellular signaling pathways are required to reconcile these differences. An alternate hypothesis invoking a role for ET-1 in blood flow abnormalities associated with thyroid diseases is that ET-1 formation in the endothelium is altered. Endothelium-derived nitric oxide has been reported to suppress ET-1 formation in both isolated arterial vessels (2, 24) and cultured endothelial cells (16). We have previously reported (5) that endothelium-dependent vasorelaxation is blunted in hypothyroidism and that this impairment appears to be localized to the endothelium. Because generation of nitric oxide in the endothelium therefore appears to be decreased in hypothyroidism, there could be a lesser inhibitory influence on endothelial ET-1 formation. If plasma ET-1 concentration reflects endothelial ET-1 formation, it appears that thyroid disease has minimal effects on ET-1 formation. Hypothyroidism has not been found to be associated with altered plasma ET-1 concentration in human (18) and animal studies (17, 27). Plasma ET-1 levels were found to be elevated in hyperthyroid patients (18) and in rats (27). This alteration is puzzling because it is inconsistent with the hemodynamic profile of hyperthyroidism (20). Furthermore, as is apparent in Fig. 3, the magnitude of elevation (<100%) in ET-1 concentration observed in these studies would not be predicted to increase the contractile response to ET-1 perceptibly. Thus we believe that altered ET-1 formation is unlikely to contribute to skeletal muscle blood flow abnormalities found in thyroid diseases.ET receptor subtypes and contractile responses to ET-1. A secondary purpose of this study was to determine which ET receptor subtype(s) is responsible for mediating the vascular smooth muscle contractile response to ET-1 in thyroid disease states. Although some investigators have reported that both ETA and ETB receptors mediate the constrictor response to ET-1 in normal vasculature (29, 33), other studies have suggested that only the ETA receptor participates to any significant degree (10, 35). In addition, there are reports of endothelial ETB receptors that, when activated by ET-1, lead to the release of nitric oxide and/or vasodilatory prostaglandins that may buffer the ET-1-induced constriction mediated by ET receptors on vascular smooth muscle (7, 13, 35).
Our findings indicate that it is the ETA receptor subtype that is primarily responsible for the constrictor response to ET-1 in rodent conduit-type vessels. The ETA-selective receptor antagonist BQ-123 reduced sensitivity to ET-1 in vascular rings from all experimental groups; in contrast, the ETB-selective receptor antagonist BQ-788 reduced sensitivity to ET-1 only in Hyper. Furthermore, the shift in sensitivity with BQ-788 in Hyper was about one-half log unit of ET-1 concentration, compared with about one whole log unit with BQ-123. It appears that thyroid status does not affect the relative importance of ETA and ETB receptor subtypes in mediating vascular smooth muscle contraction, because sensitivity to ET-1 was reduced similarly in all experimental groups with BQ-123. Consistent with the competitive nature of these ET receptor antagonists, maximal responses to ET-1 were not affected by either BQ-123 or BQ-788. Our data do not indicate that endothelial ETB receptors are present in rat abdominal aortae. Vascular rings without endothelium exhibited similar responses to ET-1 to those with intact endothelium (see RESULTS and Fig. 3, B vs. A). An enhanced response to ET-1 would be predicted if endothelial ETB receptors were absent because of denudation. Furthermore, the ETB-selective receptor antagonist BQ-788 had minimal impact on responses to ET-1. The presence/absence of ETB receptors on the endothelium may be vessel type (conduit vs. resistance), location, and/or species specific.Physiological relevance. Skeletal muscle blood flow during exercise is significantly modified by thyroid status. Previous work has suggested that alterations in endothelium-dependent vasorelaxation contribute to blood flow abnormalities associated with thyroid diseases. The results of the present study indicate that altered endothelium-dependent vascular smooth muscle contraction at the conduit vessel level, on the other hand, does not contribute to abnormal skeletal muscle blood flow in thyroid disease states. Further studies at the level of resistance vasculature are required to confirm this notion.
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ACKNOWLEDGEMENTS |
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The authors gratefully acknowledge the provision of equipment essential for this research by Drs. Lisa Freeman and Timothy Musch.
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FOOTNOTES |
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This research was supported by National Institutes of Health Grant HL-57226 and a grant from the Dean's Fund, College of Veterinary Medicine, Kansas State University.
Address for reprint requests and other correspondence: R. M. McAllister, Dept. of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506 (E-mail: mcallist{at}vet.ksu.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. §1734 solely to indicate this fact.
Received 9 August 1999; accepted in final form 7 March 2000.
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