1 Department of Veterinary Biomedical Sciences, University of Missouri- Columbia, Columbia, Missouri 65211; and 2 Department of Health and Kinesiology, Texas A & M University, College Station, Texas 77843
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ABSTRACT |
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Previous research
has shown that skeletal muscle blood flow, at rest and during muscular
contractions, is elevated in the hyperthyroid state. We hypothesized
that reduced vascular contractile and enhanced endothelium-dependent
relaxation responses contribute to these observations. To test these
hypotheses, male rats were administered triiodothyronine (Hyper,
n = 27; 300 µg/kg) for 6-12 wk.
Compared with euthyroid control rats (Eut,
n = 27), Hyper exhibited left
ventricular hypertrophy (Eut, 2.01 ± 0.04 mg/g body wt; Hyper, 2.70 ± 0.06; P < 0.0005) and greater
oxidative enzyme activity in several skeletal muscles (all
P < 0.0005). Vascular rings,
2-3 mm in axial length, were prepared from abdominal aortas, and
responses to vasoactive agents were determined in vitro. Compared with
Eut, vascular rings with intact endothelium from Hyper exhibited
reductions in contractile responses to norepinephrine (NE) across a
range of NE concentrations (P < 0.05). Maximal tension developed in response to NE was reduced ~30%
in hyperthyroidism (Eut, 3.8 ± 0.2 g; Hyper, 2.6 ± 0.4;
P < 0.01). Contractile responses to
NE were not different between Eut and Hyper in rings denuded of
endothelium. Maximal vasorelaxation responses to acetylcholine (ACh),
after precontraction with NE
(107 M), were enhanced in
the hyperthyroid state (Eut, 65.1 ± 4.8%; Hyper, 84.0 ± 7.1;
P < 0.05). Enhanced vasorelaxation
to ACh was also observed when precontraction was induced by
prostaglandin F2
. These
findings indicate that vascular contractile and relaxation responses
are altered in male hyperthyroid rats.
blood flow; smooth muscle; endothelium; norepinephrine; acetylcholine
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INTRODUCTION |
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CARDIOVASCULAR FUNCTION is significantly altered in the hyperthyroid state. Hyperthyroidism is characterized by increased cardiac output and a reduction in total peripheral resistance (11, 22). These changes are associated with increased peripheral tissue blood flow. For example, skeletal muscle blood flow has been reported to be elevated in hyperthyroid humans and animal models of hyperthyroidism. Greater skeletal muscle blood flow has been found both at rest (12, 13, 18) and during muscle contractions (12, 13). We recently extended those observations by demonstrating that blood flows to a variety of hindlimb skeletal muscles were 50-150% greater in hyperthyroid rats compared with their euthyroid counterparts during treadmill running (20). Hindlimb muscle vascular resistance during exercise was 33% lower in hyperthyroid animals compared with euthyroid control animals.
Reduced vascular resistance in skeletal muscle could be accounted for by increased vascularity and/or alterations in vascular control mechanisms favoring greater vasodilation. Hyperthyroidism has been found to be associated with greater capillary numbers in muscles of humans (3) and rats (2). Increased capillary density may be accompanied by an increase in the number of resistance arterial vessels in parallel, which could reduce vascular resistance. Reduced contractile responses of blood vessels isolated from hyperthyroid rats have also been reported (10, 14, 27). These alterations in vascular control could contribute to a reduction in vascular resistance.
Endurance exercise-trained rats are characterized by greater skeletal muscle blood flows during exercise compared with those of their sedentary counterparts (1, 23). Training-induced enhancement of muscle blood flow, while less in magnitude, is qualitatively similar to that associated with hyperthyroidism. We (7) and others (4, 16, 33) have found that exercise training is associated with alterations in vascular control that could enhance muscle blood flow. Those studies, conducted in arterial vessels isolated from sedentary and exercise-trained rats, revealed reduced contractile responses to norepinephrine (NE; see Ref. 7) and enhanced responses to vasorelaxing agents acting via the endothelium (4, 7, 16, 33). Thus the purpose of this study was to test the hypotheses that hyperthyroidism is similarly associated with reduced responses to contractile agents and that endothelium-dependent vasorelaxation is enhanced in the hyperthyroid state.
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METHODS |
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Animals
Male Sprague-Dawley rats (175-200 g) were obtained from the breeder (Sasco) and were housed two per cage in a room with controlled temperature (20-21°C) and light (12:12-h light-dark cycle). Each rat was randomly assigned to one of two groups, euthyroid control (Eut) or hyperthyroid (Hyper). Rats in the Eut group were slightly food restricted (by ~20% of normal bulk food intake) to match their body weights with those of Hyper rats. The latter consumed food ad libitum.Treatment
Hyper rats were rendered hyperthyroid with triiodothyronine (T3, sodium salt; in 0.50 mM NaOH), as done previously by us (20) and others (2, 9, 15). T3 was injected intraperitoneally at a dose of 300 µg/kg. T3 was administered on alternate days over a 6- to 12-wk period.Assessment of Treatment Efficacy
Establishment of a hyperthyroid state was confirmed by determining left ventricular weight and muscle oxidative capacity. Oxidative enzymatic capacity was estimated by determining citrate synthase activity using the colorimetric assay of Srere (28). Citrate synthase activity was determined in homogenates of the following muscles/muscle sections: soleus, red section of vastus lateralis, white section of vastus lateralis, and plantaris. These muscles were selected to represent skeletal muscle composed primarily of slow oxidative fibers (soleus), fast oxidative/glycolytic fibers (red section of vastus lateralis), and fast glycolytic fibers (white section of vastus lateralis; cf. Ref. 6). The plantaris was chosen as a muscle of mixed fiber type composition.Vascular Ring Preparation
On experimental days, rats were anesthetized with pentobarbital sodium (65 mg/kg). Rats were then killed by decapitation, and the abdominal aorta (i.e., aorta distal to renal arteries) was carefully dissected from each rat and immediately placed in chilled (4°C) Krebs bicarbonate buffer solution (see below). Fat and connective tissue were carefully cleaned from abdominal aortic segments, without damaging the vascular wall, with the aid of a stereomicroscope (Zeiss). A total of four vascular rings, 2-3 mm in axial length, were cut from each aortic segment. Outside diameter, inside diameter, and axial length of each vascular ring were determined at this time during vascular ring preparation using a calibrated micrometer eyepiece mounted on the stereomicroscope. Endothelial denudation of two of the four vascular rings prepared from each rat was accomplished by gentle rubbing of the luminal surface with fine-tipped forceps. Relaxation of <5% to acetylcholine (ACh; 10Length-Tension Relationship
Abdominal aortic rings were set to individual optima of their length-developed tension relationships, as described previously (7, 8). Briefly, two stainless steel wires (0.406 mm diameter) were passed through the lumen of each vascular ring. One wire was connected to a force transducer (Grass FT03), permitting measurement of isometric force. Force was continuously recorded using a computerized data acquisition system (MacLab). The other wire was connected to a micrometer microdrive (Stoelting), allowing the ring to be stretched in known increments. The vascular ring was then submerged in Krebs bicarbonate buffer solution (see below) contained in a 20-ml tissue bath. The buffer solution was equilibrated, at 37°C, with a 95% O2-5% CO2 gas mixture.Multiple exposures to 60 mM KCl at increasing stretch (5-10% increments) permitted vascular rings to be set to individual optima of their length-developed tension relationships. Buffer solution was replaced after each exposure to KCl so that this contractile agent could be washed out before changing stretch and reassessing developed tension in response to 60 mM KCl. Once optimal stretch was ascertained for all rings, a 1-h stabilization period was allowed before further experimentation. All vascular rings were studied at optimal stretch.
Pharmacological Studies
Series I. These experiments were designed to characterize fundamental vascular contractile and relaxation responses in the euthyroid and hyperthyroid states. These experiments were conducted using vascular rings prepared from 14 Eut and 13 Hyper rats.Concentration-dependent contractile responses of vascular rings to KCl
and NE were determined by cumulative addition of KCl (10-100 mM)
and NE (109 to
10
4 M) to tissue baths, as
done previously (7, 8). Recovery periods of ~15 and 60 min for KCl
and NE, respectively, were allowed so that resting tension could be
reattained by all vascular rings after administration of each agent.
Buffer solution was changed at 5- to 10-min intervals during all
recovery periods.
After KCl and NE studies, concentration-dependent relaxation responses
to the endothelium-dependent agent ACh and the endothelium-independent agent sodium nitroprusside (SNP) were determined. Cumulative addition of ACh (109 to
10
4 M) and SNP
(10
10 to
10
5 M) to tissue baths was
performed as done previously (7, 8). Before administration of ACh and
SNP, vascular rings were precontracted with NE
(10
7 M). Developed tension
in response to this concentration of NE was similar for rings from Eut
and Hyper rats. Recovery periods of ~30 min each were allowed after
determination of concentration-dependent relaxation responses to ACh
and SNP, permitting reattainment of resting tension by all vascular
rings.
Series II. Experimental results from
Series I indicated that
hyperthyroidism alters vascular responses to NE and ACh.
Series II experiments were designed to
assess the roles of
1-adrenergic receptors and
endothelium-derived nitric oxide (EDNO) in altered responses to NE and
ACh, respectively. These experiments were conducted using vascular
rings prepared from eight Eut and nine Hyper rats.
To assess the role of
1-adrenergic receptors in
reduced contractile responses to NE, concentration-dependent
contractile responses of vascular rings to the
1-adrenoceptor-specific agent phenylephrine (PE) were determined by cumulative addition of PE (10
8 to
10
4 M) to tissue baths, as
done previously (7). After a recovery period of ~60 min, permitting
reattainment of resting tension by all vascular rings, studies were
conducted to examine the role of EDNO in enhanced responses to ACh.
Vascular rings were precontracted with NE
(10
7 M), and vasorelaxation
responses to ACh (10
4 M)
were determined. After a recovery period of ~30 min, one of the two
vascular rings with intact endothelium from each rat studied was
incubated for 20 min in
NG-nitro-L-arginine
methyl ester (L-NAME; 300 µM), a competitive inhibitor of
the formation of EDNO (21). All vascular rings were then precontracted
with NE (10
7 M), and
relaxation responses to ACh
(10
4 M) again were
determined. Responses of vascular rings incubated in L-NAME
were used to assess the role of EDNO in mediating the endothelium-dependent response to ACh, as done previously (7). The
response to ACh in the untreated vascular ring with intact endothelium
from each rat was used as a time control, ensuring that any alteration
in the response to ACh after L-NAME treatment was due to
inhibition of EDNO formation. Finally, vascular rings were administered
L-arginine (L-Arg; 3 mM) in an attempt to
reverse competitive inhibition of EDNO formation effected by
L-NAME.
Series III. These experiments were conducted to determine whether the altered vasorelaxation response to ACh in hyperthyroidism (Series I) was specific to precontraction with NE or could be generalized to precontraction with other contractile agents, as done previously (7). Vascular rings prepared from five Eut and five Hyper rats were used in these experiments.
Vascular rings were precontracted with prostaglandin
F2
(PGF2
; 3 × 10
5 M). Developed tension
in response to this concentration of
PGF2
was similar for rings from
Eut and Hyper rats. ACh
(10
9 to
10
4 M) was then added to
tissue baths in a cumulative fashion to determine
concentration-dependent responses to this endothelium-dependent agent.
Solutions and Drugs
Krebs bicarbonate buffer solution contained (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 to opposeConcentrated stock solutions of vasoactive agents were prepared in distilled water. Stock solutions were serially diluted with distilled water, and appropriate aliquots were added to tissue baths to achieve desired concentrations. All vasoactive agents were purchased from Sigma Chemical.
Statistical Analysis
Data are presented as means ± SE. Data for contractile agents (KCl, NE, and PE) are expressed in grams of developed tension. Developed tension is that tension exhibited in response to a contractile agent above resting tension due to stretch of the vascular ring. Data for vasorelaxing agents (ACh and SNP) are expressed as relative relaxation from precontracted levels. Vasorelaxation data were included in analyses only if maximal responses were >20%. This criterion was considered to be indicative of preservation of functional endothelium during vascular ring preparation. Before statistical analysis, data for appropriate vascular rings from an animal were averaged; thus one animal counted as one observation.Left ventricular weight-to-body weight ratios, citrate synthase activities, and vascular ring characteristics were compared between Eut and Hyper using unpaired t-tests (30). Two-way ANOVA, with repeated measures on one factor, was used to compare contractile and relaxation responses of Eut and Hyper vascular rings across the entire range of agent concentrations tested (30). To determine differences between Eut and Hyper at various vasoactive agent concentrations, planned contrasts were performed using unpaired t-tests with the Bonferroni correction for multiple comparisons (31).
Maximal reponses to vasoactive agents (irrespective of agent concentration at which they occurred), as well as EC50/IC50 values, were compared between Eut and Hyper using unpaired t-tests (30). Agent concentration inducing 50% of the maximal contractile response was designated EC50; conversely, agent concentration inducing 50% of the maximal vasorelaxation response was designated IC50. EC50/IC50 values were derived using nonlinear regression analysis (GraphPad). EC50/IC50 values were subjected to logarithmic transformation before statistical analysis. For all analyses, P < 0.05 was considered significant.
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RESULTS |
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Treatment Efficacy
Administration of T3 was effective in inducing hyperthyroidism in Hyper rats. Citrate synthase activities were greater (all P < 0.0005) in muscles from Hyper than in those from Eut, including the soleus (Eut, 29.0 ± 1.0 µmol · minVascular Ring Characteristics
Characteristics of rings prepared from abdominal aortic segments are presented in Table 1. Outside diameter, inside diameter, and axial length of rings did not differ between Eut and Hyper. Additionally, stretch necessary for optimal tension development and resting tension exhibited at optimal stretch were similar for the two groups (Table 1). Values for ring characteristics in Table 1 were pooled from Series I, II, and III, since there were no differences among series for any variable in either Eut or Hyper.
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Pharmacological Studies
Series I. This series of experiments examined dose-dependent contractile responses to KCl and NE and dose-dependent vasorelaxation responses to ACh and SNP.Figure 1 illustrates responses of Eut and Hyper vascular rings to KCl. Across the entire range of KCl concentrations tested, contractile responses were similar for the two groups. Maximal contractile responses (irrespective of KCl concentration at which they occurred) were, however, 25% lower in Hyper rings (P < 0.05; Table 2). Sensitivities to KCl, as indicated by EC50 values, were similar between groups (Table 2).
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Contractile responses to NE in rings with intact endothelium are shown in Fig. 2A. Responses across the entire range of NE concentrations were reduced in vascular rings from Hyper animals (P < 0.05). Furthermore, maximal responses to NE were ~30% lower in rings from Hyper rats (P < 0.01; Table 2). Responses to NE were not significantly reduced for Hyper compared with Eut rats in vascular rings denuded of endothelium (Fig. 2B and Table 2). EC50 values indicated that thyroid status did not affect sensitivity to NE, either in endothelium-intact or denuded rings (Table 2).
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Vasorelaxation responses to the endothelium-dependent agent ACh are
illustrated in Fig.
3A.
Although responses across the entire range of ACh concentrations were
similar between groups, maximal relaxation to ACh was enhanced in
vascular rings with intact endothelium from Hyper rats compared with
those from Eut rats (P < 0.05; Table
2). Sensitivity to ACh, as indicated by IC50 values, was not different
between groups (Table 2). Denuded rings exhibited minimal relaxation to
ACh (104 M; Eut,
0.4 ± 1.0%, n = 14; Hyper, 0.8 ± 0.8, n=12).
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Figure 3B shows vasorelaxation
responses to the endothelium-independent agent SNP. Vascular rings from
both Eut and Hyper rats exhibited complete relaxation at
107 M SNP. Hyperthyroidism
did not affect either sensitivity or maximal response to SNP (Table 2).
Series II. Contractile responses to
the 1-specific adrenergic agent
PE are illustrated in Fig. 4,
A and
B. Responses across the entire range
of PE concentrations were similar between groups, whether endothelium
was present (Fig. 4A) or absent
(Fig. 4B). Maximal responses to PE
were, however, lower in both endothelium-intact and denuded vascular
rings from Hyper animals (P < 0.05;
Table 2). In addition, sensitivity to PE was greater in hyperthyroidism (P < 0.05; Table 2). Rings from
Hyper rats in this experimental series also exhibited lower maximal
responses to the nonspecific adrenergic agent NE
(P < 0.01; Table 2), reproducing the
findings of Series I.
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Also reproducing findings from Series
I, maximal relaxation to ACh
(104 M) was greater in
rings from Hyper animals (Eut, 61.1 ± 6.9%, n = 7; Hyper, 90.7 ± 9.6, n = 9;
P < 0.05). For each animal studied (i.e., 2 vascular rings with intact endothelium), serial responses to
ACh (10
4 M) of one ring
were determined in the absence of L-NAME and
L-Arg to establish reproducibility of the relaxation
response to ACh. In both Eut (49.3 ± 8.7% and 44.4 ± 5.7, n = 6; NS) and Hyper (86.4 ± 8.2% and 79.7 ± 14.7, n = 7; NS) rings, vasorelaxation to ACh was reproducible. In the other
ring with intact endothelium, effects of L-NAME and
subsequent addition of L-Arg on relaxation responses to ACh
(10
4 M) were determined.
Results are shown in Fig. 5. In vascular rings from both Eut and Hyper rats, inhibition of EDNO formation with
L-NAME markedly reduced relaxation responses to ACh.
Administration of L-Arg partially restored these responses.
The magnitude of reduction of responses to ACh with L-NAME
and restoration with L-Arg did not differ between groups.
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Series III. Concentration-dependent
vasorelaxation responses to ACh after precontraction with
PGF2 (3 × 10
5 M), rather than NE, are
illustrated in Fig. 6. Relaxation responses of vascular rings from Hyper rats were greater than those of rings from
Eut rats across the entire range of ACh concentrations tested (P < 0.05). Maximal response and
sensitivity to ACh after precontraction with
PGF2
were also greater in
hyperthyroidism (P < 0.05; Table 2).
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DISCUSSION |
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The key new finding of this study is that ACh-induced, endothelium-dependent relaxation of the abdominal aorta is enhanced in male Hyper rats. In addition, we have confirmed that contractile responses to NE are reduced in the hyperthyroid state in the presence of functional endothelium. Thus hyperthyroidism appears to induce adaptations in the vascular endothelium. These adaptations, if present throughout the peripheral arterial vasculature, are consistent with reduced vascular resistance characteristic of this disease state. Importantly, vascular rings prepared from Eut and Hyper animals were studied under identical conditions of size and stretch, precontraction, and milieu. Thus differences between groups can be attributed to alterations in vascular reactivity induced by hyperthyroidism.
Contractile Responses
Hyperthyroidism was associated with reduced contractile responses to NE. Experiments were conducted to determine whether reduced contractile responses to NE were due to modulation of the vascular smooth muscle contractile response to NE by endothelium (via endothelialWe found that maximal responses to KCl (Series
I; Fig. 1) and PE (Series
II; Fig. 4, A and
B), an
1-adrenoceptor-specific agonist, were reduced in hyperthyroidism, suggesting that
hyperthyroidism also induces adaptations in vascular smooth muscle.
These findings are consistent with those of most (10, 14, 27), although not all (26), previous studies. A reduced maximal response to PE may
involve mechanisms at the adrenergic receptor level. Reduced
1-adrenoceptor number (14) and
lower
1-adrenoceptor-operated calcium channel influx of calcium (32) in Hyper rat aortic tissue have
been reported. Because maximal responses were achieved at high
concentrations of KCl and PE, the physiological significance of reduced
maximal responses is unknown.
Vasorelaxation Responses
A key finding of this study is that vasorelaxation in response to ACh is enhanced in the hyperthyroid state. This feature of hyperthyroidism involves adaptations specfic to the endothelium, as suggested by two lines of evidence. First, the vasorelaxation response to ACh was abolished in denuded vascular rings from Hyper animals. Second, vasorelaxation responses to SNP were identical in the euthyroid and hyperthyroid states. Because this inorganic nitrate donates nitric oxide directly to vascular smooth muscle (cf. Ref. 21), this finding indicates that the smooth muscle response to EDNO is not altered by thyroid status. Thus the enhanced response to ACh is not due to an enhanced response of vascular smooth muscle to EDNO.It is also noteworthy that vascular rings from Hyper rats exhibited
enhanced responses to ACh when either NE or
PGF2 was used to accomplish
precontraction. These two agents induce contraction of vascular smooth
muscle via different intracellular pathways (cf. Ref. 29). In spite of
this difference, ACh-induced vasorelaxation was enhanced in
hyperthyroidism in both cases. It is also important to note that, at
the concentrations of NE and
PGF2
used, developed tension
was similar for vascular rings from Eut and Hyper animals. Thus
relaxation was not greater in hyperthyroidism because absolute tension
(from which the relative relaxation response was calculated) was lower
in the hyperthyroid state.
The similarities between adaptations in endothelium-dependent
vasorelaxation with hyperthyroidism and endurance exercise training are
interesting. We have previously reported that abdominal aortic rings
from exercise-trained rats exhibit enhanced relaxation responses to ACh
after either NE- or
PGF2-induced contraction (7). In that study, SNP-induced vasorelaxation was identical between rats
subjected to exercise training and their sedentary counterparts. Common
features of the hyperthyroid and exercise-trained states are increased
cardiac output and peripheral tissue blood flow. In hyperthyroidism,
increased blood flow through the abdominal aorta would be continuously
present (cf. Ref. 22). Exercise training increases cardiac output and
abdominal aortic blood flow, but in an episodic manner (i.e., for the
duration of training sessions, typically 1-2 h/day; cf. Ref. 7).
Furthermore, it was recently reported that chronically elevated aortic
blood flow, achieved by aortocaval fistula, led to increased expression
of aortic endothelial nitric oxide synthase (24). Conversely, we have
shown that a chronic low-flow condition, hypothyroidism, is associated
with blunted endothelium-dependent vasorelaxation (8). Thus it is
tempting to speculate that chronically altered blood flow induces
adaptations in the vascular endothelium that result in changes in the
potential for endothelium-dependent vasorelaxation (cf. Ref. 19). It
should be noted, however, that endurance exercise training and
hyperthyroidism are dissimilar in many respects. They may act via
different mechanisms to produce augmented endothelium-dependent vasorelaxation observed in this study and in studies involving exercise
training (4, 7, 16, 33). For example, thyroid hormones may have direct
effects on gene expression in the vascular wall that account for
enhanced endothelium-dependent vasorelaxation.
Our data do not permit precise identification of the endothelium-derived factor(s) responsible for enhanced endothelium-dependent vasorelaxation in hyperthyroidism. Inhibition of formation of EDNO eliminated much of the vasorelaxation response to ACh, in both the euthyroid and hyperthyroid states (Fig. 5). Nonetheless, relaxation of ~20% in magnitude was exhibited by vascular rings from Hyper animals, even with EDNO formation inhibited. This residual relaxation approximates the augmentation in maximal response to ACh observed in hyperthyroidism (Table 2). We (unpublished observations) and others (17) have found that prostaglandins (e.g., prostaglandin I2) do not contribute to endothelium-dependent relaxation of rat abdominal aorta. A candidate to account for residual vasorelaxation is endothelium-derived hyperpolarizing factor (EDHF; cf. Ref. 5). Previous work has shown that EDHF plays a role in endothelium-dependent vasorelaxation of conduit-type arterial vessels in the rat (25). Further experiments are required to establish whether EDHF contributes to endothelium-dependent vasorelaxation in hyperthyroidism.
Physiological Importance
The results of this study indicate that, in male rats, hyperthyroidism is associated with a reduced vascular contractile response to NE and enhanced ACh-induced, endothelium-dependent vasorelaxation. These changes in vascular control are consistent with previous work demonstrating greater muscle blood flow in the hyperthyroid state, both at rest (12, 13, 18) and during muscle contractions/exercise (12, 13, 20). These observations suggest that alterations in contractile and relaxation responses observed in the abdominal aorta in this study may also occur in resistance segments of the vascular tree. Studies of resistance arterial vessels more proximal to skeletal muscle are required to test this hypothesis. ![]() |
ACKNOWLEDGEMENTS |
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The valuable technical assistance of Tammy Knox and Tammy Strawn is gratefully acknowledged. Expert animal care was provided by Joe Sansone.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grant HL-36088 (to M. H. Laughlin), a grant from the University of Missouri Committee on Research (to R. M. McAllister), and a postdoctoral fellowship from the American Heart Association, Missouri Affiliate (to R. M. McAllister).
Address for reprint requests: R. M. McAllister, Dept. of Anatomy & Physiology, 228, Vet. Med. Sci. Bldg., Kansas State Univ., Manhattan, KS 66506-5602.
Received 28 July 1997; accepted in final form 6 February 1998.
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