| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Joint Injury and Arthritis Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1
 |
ABSTRACT |
|---|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
The
ligaments of weight-bearing joints are known to become mechanically
inferior during pregnancy, and it has been postulated that this may be
due to changes in tissue perfusion. Calcitonin gene-related peptide
(CGRP) and epinephrine exert a tonic influence on the vasculature of
the medial collateral ligament (MCL), and the present study examined
whether these vasoactive influences were altered by pregnancy. Ligament
perfusion experiments were performed on primigravid New Zealand White
rabbits with the use of laser Doppler perfusion imaging. In pregnant
animals (day
29), MCL basal perfusion fell
significantly compared with control; however, values returned to normal
5 days postpartum. In normal joints, topical application of CGRP
resulted in a dose-dependent increase in MCL perfusion, whereas
epinephrine administration caused a dose-dependent fall in
blood flow. During pregnancy, the vasodilator effect of CGRP was
completely abolished, whereas adrenergic vasoconstriction was greater
than normal. Both responses returned postpartum. Pregnancy in the
rabbit produces hypoemia in the MCL, and this phenomenon may be
effected by a tempering of CGRP dilator responses and an augmentation
of 
-adrenoceptor-mediated vasoconstriction.
laser Doppler perfusion imaging; blood flow; neuropeptides; adrenergic system; knee joints
| |
INTRODUCTION |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
THERE IS GROWING EVIDENCE to suggest that pregnancy alters the stability of peripheral joints, possibly through a loss of ligament integrity (1, 6, 11, 14, 32). The mechanisms responsible for increased ligament laxity during pregnancy are unknown but may be related to the high levels of sex hormones associated with the pregnant state (18, 25, 37) or to the pregnancy-associated hormone relaxin (20, 35). An alternative explanation may lie in the fluctuation in peripheral blood flow that often accompanies normal pregnancy. Vasodilatation is known to occur in a number of tissues during pregnancy, including the heart, kidneys, liver, and adrenal glands (23, 34, 38). Because medial collateral ligament hyperemia has been correlated with a deterioration in ligament function (8), an alteration in ligament hemodynamics during pregnancy may be associated with disturbances in joint connective tissue mechanics.
The medial collateral ligament has a rich network of capillaries which
mainly occupies the superficial epiligamentous layer of the tissue (9).
In turn, these vessels are innervated by a significant number of
unmyelinated afferent neurons which have been shown to be
immunoreactive for the vasodilator neuropeptides substance P and
calcitonin gene-related peptide (CGRP) (27). The function of these
nerve fibers in knee joint ligaments is unclear but may be related to
the maintenance of joint homeostasis by regulation of tissue perfusion.
Ferrell et al. (15) showed that topical application of CGRP onto the
surface of the rabbit medial collateral ligament caused a
dose-dependent increase in ligament blood flow. Furthermore,
administration of the CGRP antagonist CGRP-(8
37) resulted in a
reduction in ligament blood flow, suggesting that the neuropeptide may
be released tonically in vivo, thereby contributing to the
physiological regulation of epiligamentous vessels. In addition to the
vasoactive effects of sensory neuropeptides, the vasculature of the
medial collateral ligament is also controlled by adrenergic mechanisms
(28). The constrictor response to epinephrine administration indicates
the presence of -adrenoceptors on ligament blood vessels, which in
conjunction with the dilator effects of CGRP may work antagonistically
to regulate ligament blood flow.
The purpose of the present study was to assess the effect of pregnancy on medial collateral ligament blood flow and to examine whether the vasoactive effects of CGRP and epinephrine were altered during pregnancy. A group of rabbits which were 5 days postterm were also used in the investigation to determine whether any observable changes in tissue vasoregulation persisted postparturition. Primigravid animals were used in the study to obviate any possible adaptation to multiple pregnancies.
| |
METHODS |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Twenty age-matched female New Zealand white rabbits (3.3-5.2 kg) were used in the present study, of which nine were primigravid animals (day 29 of pregnancy), four had recently given birth (day 5 postpartum), and seven were virgin animals and as such made up the normal control group. Animals were sedated with acepromazine maleate (0.2 ml iv) and then deeply anesthetized by intraperitoneal injection of urethan (1 g/kg). Animals were placed in dorsal recumbency, and their body temperature was maintained at ~37°C by a thermostatically controlled heating pad (American Pharmaseal). All experimental interventions had prior approval by the University of Calgary Animal Care Committee and were in complete accordance with the Canadian Council for Animal Care guidelines.
Surgical procedures. The right carotid artery was isolated in the neck and cannulated with a heparinized saline-filled cannula (Clay Adams PE-90, 0.86-mm ID) which was connected to a pressure transducer (Elcomatic EM752, Neilston, UK) to allow monitoring of systemic blood pressure. Pressure readings were recorded and analyzed on a computer using Codas software (Dataq Instruments). A longitudinal incision was then made in the medial aspect of the shaved knee joint, and the overlying skin was retracted to expose an area extending from the medial collateral ligament to the distal extremity of the patellar ligament. The superficial aponeurotic and fascial tissues were excised to remove any optical barrier to the ligament. Once the tissues were exposed, 37°C physiological saline (0.9% NaCl) was regularly superfused over the joint surface to prevent desiccation of the articular tissues.
Blood flow assessment. Ligament perfusion was measured by a laser Doppler perfusion imager (LDI) (Moor Instruments, Axminster, UK) using a standardized protocol (22) which has been validated for use in ligament blood flow studies (10). Briefly, a low-power (1 mW) He-Ne laser beam (633-nm wavelength) is scanned over the exposed surface of the joint and the backscattered Doppler broadened photons are collected by a photodetector which is incident within the scanner head. This information is then centrally processed to generate a two-dimensional, color-coded image of knee joint perfusion which is represented as a flux reading and assigned arbitrary perfusion units (PU). With the scanner head mounted in a stereotaxic frame and placed 19 cm above the exposed joint, a scan region was chosen that bounded the medial knee joint and typically took 20 s to complete. For testing perfusion to other articular structures, the hindlimb was internally rotated and a scan of the patellar ligament was performed. Measurements of the medial knee were taken during various experimental interventions (test) and related to control scans which were performed before the test scan. The hemodynamic changes effected by the experimental manipulations were of much longer duration than the scan time, and thus the possibility of missing any response was avoided. At the end of the experiment, the animal was killed by an overdose of pentobarbital sodium (360 mg intracardiac) and a final perfusion measurement (the "biological zero") obtained. Because the median sampling depth of a 633-nm laser is ~250 µm through highly absorptive skin (40) and medial collateral ligament blood vessels are mainly restricted to the superficial 180 µm of the tissue (9, 12), it is highly likely that the imager has sufficient penetrative power to assess ligamentous blood flow.
Experimental protocol.
After a suitable equilibration period, an initial basal perfusion
reading was made usually in both rabbit knees. CGRP
(10
13 to
109 mol) was then applied
topically to the ligament in a cumulative fashion, and a scan was taken
10 min after the application of each dose. This time point was chosen
because it corresponded to the maximal response of the neuropeptide.
The joint was then washed with saline and allowed to recover for 1 h
before progression to the epinephrine part of the experiment.
Epinephrine (1014 to
107 mol) was applied
topically to the joint, and a scan was taken 2 min after administration
of each of the doses, which were applied in a cumulative manner to
generate dose-response curves.
Image and data analysis. Using a standardized protocol (22), we analyzed images using Moor LDI software. An analysis region corresponding to the medial collateral ligament was chosen, and the mean flux reading for the area was noted. The biological zero was subtracted from each image before any calculations were carried out, and experimental responses were expressed as a percent change in perfusion from control.
Individual data points were presented as means ± SE for n observations. Statistical evaluation of the data was by either Student's t-test or one- or two-way ANOVA. A P value <0.05 was considered significant.| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
In first-time pregnant rabbits, basal perfusion of the medial collateral ligament was found to be significantly lower compared with age-matched virgin control animals (P < 0.03, unpaired 2-tailed Student's t-test; n = 13 and 15 for control and pregnant animals, respectively), with blood flow falling from 358.1 ± 41.3 PU in control rabbits to 233.3 ± 35.2 PU during gravidity (Fig. 1). At 5 days postpartum, ligamentous perfusion returned to control levels.
|
During pregnancy, mean arterial pressure appeared to fall slightly and then recover postpartum (Fig. 2), although this effect was not found to be statistically significant (P = 0.40, 1-way ANOVA; n = 6 for pregnant and control groups and n = 3 for postpartum group). It is unlikely that the pregnancy-induced hypoemia in the medial collateral ligament was due to the animal being hypotensive because perfusion to surrounding articular structures was unaltered during pregnancy. LDI-derived perfusion values derived from the patellar ligament of each group were not found to be significantly different from each other (P = 0.34; Fig. 1).
|
CGRP responses in normal and pregnant rabbits.
Topical application of CGRP
(1013 to
109 mol) onto medial
collateral ligaments of virgin animals caused an increase in tissue perfusion (Fig. 3). The vasodilatation was
found to be dose dependent (P < 0.0001, 1-way ANOVA; n = 7), with the
109 mol dose producing the
maximum increase in perfusion by 117.3 ± 26.0%. In primigravid
animals, this dilator effect of CGRP was completely abolished
(P = 0.2, 1-way ANOVA;
n = 7) and in some instances a
constrictor response to CGRP occurred. However, in postpartum animals
the vasoactive effects of CGRP returned
(P < 0.0001;
n = 8) although the magnitude of the
response was not as pronounced as in normal rabbits
(P < 0.01, 2-way ANOVA).
|
Epinephrine responses in normal and pregnant rabbits.
Epinephrine, when applied topically to the exposed surface of virgin
rabbit medial collateral ligaments, caused a dose-dependent (P < 0.0001 1-way ANOVA)
vasoconstriction of ligamentous blood vessels, culminating in a peak
reduction in perfusion of 54.8 ± 4.8% compared with control with
the 107 mol dose. Pregnancy
caused a leftward shift in the dose-response curve to epinephrine (Fig.
4), indicating an augmentation of the constrictor response. Two-way ANOVA revealed a highly significant difference between control responses and those found in the primigravid animal (P < 0.0001). Five
days postpartum, adrenergic vasoconstriction had returned toward
control levels; however, the responsiveness was not normal at this
early postpartum time point.
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Pregnancy is known to affect the metabolism and structural integrity of ligaments in the peripheral joints of humans (1, 6, 11, 14, 32), rats (18, 37), and rabbits (16, 19). The putative correlation between connective tissue function and blood flow prompted this investigation into whether the increased laxity of knee joint ligaments during pregnancy could be related to a rise in ligament perfusion. It was found that perfusion to the medial collateral ligament of preterm primigravid rabbits fell compared with age-matched virgin controls. Thus there is no evidence to suggest that pregnancy-related ligament laxity is due to an upregulation of ligament perfusion in this model. The hypoemic response to parity was pregnancy dependent because 5 days postpartum, ligament perfusion returned back toward control levels. It follows, therefore, that pregnancy affects the normal vasomotor control mechanisms of the medial collateral ligament only transiently. It could be argued, however, that because the rabbit knee is excluded from baroreflex vasomodulation (28), the observed changes in ligament basal blood flow were merely a consequence of pregnancy-related hypotension. Although systemic blood pressure did appear to show a slight reduction in the pregnant animal, it was not found to be statistically different from control rabbits and could not therefore be responsible for the conspicuous fall in ligament perfusion. Moreover, basal perfusion to the patellar ligament of the knee was unaffected by pregnancy, reaffirming the position that pregnancy-induced hypoemia of the medial collateral ligament was not the result of a fall in systemic blood pressure.
Previous studies have shown that rabbit knee ligament blood vessels are
richly innervated by CGRP containing primary afferent nerves (27) and
that this neuropeptide is released tonically to oppose sympathetic
vascular tone in this joint (15). The present study showed that, during
pregnancy, the dilator effects of CGRP were completely abolished even
at 109 mol, the highest
dose used. Postpartum, CGRP caused a dose-dependent increase in
ligamentous perfusion, although the magnitude of the response was not
quite as pronounced as normal. This finding suggests that during
pregnancy there may be a downregulation of CGRP receptor function or a
decreased expression of the receptors on medial collateral ligament
blood vessels. The fact that the response recovered almost completely
postpartum indicates that the loss of CGRP vasoactivity is a
pregnancy-dependent phenomenon. This suggests that during pregnancy the
CGRP receptors are merely latent and have the potential to be
"reactivated" once the inhibitory effects associated with
pregnancy have subsided. Stevenson et al. (39) found that systemic
levels of CGRP were significantly elevated during pregnancy but
returned to control levels postpartum. It is possible, therefore, that
an increased concentration of plasma CGRP during pregnancy could cause
downregulation of CGRP receptors in certain tissues. In another study,
pregnancy was shown to have a differential effect on CGRP-induced
smooth muscle relaxation in the rat. At
day
22 gestation, the normal relaxant effect of CGRP was abolished in the myometrium but maintained in the
aorta, implying that gestational loss of CGRP efficacy is tissue
specific (3). This result is very interesting because it could explain
why the medial collateral ligament becomes hypoemic during pregnancy
whereas perfusion to the patellar ligament is unaltered.
In addition to altered neuropeptide activity, topical administration of
epinephrine to pregnant rabbit medial collateral ligaments caused a
profound dose-dependent fall in tissue perfusion, the extent of which
was greater than that of control animals. Again, this effect only
lasted as long as the animal was pregnant, and constrictor responses
subsequently returned toward control levels in the postpartum period.
Possible reasons for increased epinephrine sensitivity include
upregulation and/or increased expression of -adrenoceptors
on the ligament vasculature. Alternatively, there could be a reduction
in 
-adrenoceptor population or function which would allow the
constrictor effects of the -adrenoceptors to prevail. Previous
studies on rat, human, and rabbit smooth muscle have shown that the
number of -adrenoceptors is greater in pregnant than in nonpregnant
animals (7, 33). This increase in potential -adrenergic binding
sites is thought to be mediated by elevated estrogen levels during
pregnancy because exogenously administered estradiol caused a similar
rise in the number of smooth muscle -adrenoceptors (33). In vitro
vascular reactivity studies have shown that pregnancy-induced changes
in adrenergic contractility may be variable depending on the vascular
bed being studied. -Adrenergic vasoconstriction is either attenuated
or unaffected by pregnancy in carotid, renal, and mesenteric arteries (2, 13), whereas blood vessels of the uterus and hindlimb are more
sensitive to sympathetic adrenergic activity (2, 13, 21,
30).
One possible limitation of this study is that pregnancy alters the pharmacokinetics of various anesthetics (17), and the resultant diverse sensitivity to these agents in the intrapartuant makes interpretation of perfusion changes problematic. This shortcoming aside, the combination of a decreased sensitivity to CGRP and upregulation of constrictor adrenergic responses during pregnancy could be contributing to the basal hypoemia observed in the collateral ligament at this time. This finding is in contrast to results from a host of other major tissues which clearly show an increase in blood flow during pregnancy and which have been postulated to be mediated by sex hormones such as relaxin (4, 5) and estrogen (23, 34). In light of estrogen receptors having been identified in human (24, 31) and rabbit (36) ligaments, the expected result of this study would have been a rise in ligament perfusion. However, estrogen is thought to play only a minor role in tissue vasoregulation, and therefore any effects of the hormone on ligament blood flow may only be secondary to the more potent effects of altered neuropeptidergic/adrenergic mechanisms outlined here. One possible purpose for the reduction in blood flow to the medial collateral ligament may be local enhancement of a shunting system whereby blood is redirected away from certain peripheral organs toward reproductive tissues such as the placenta. Because most articular tissues require a constant blood supply to maintain their integrity (29), this beneficial physiological response to pregnancy may occur at the expense of ligament homeostasis.
In summary, the results of the present study demonstrate that, during pregnancy, perfusion of the medial collateral ligament is reduced and this may be implemented by altered vasoregulatory mechanisms occurring at the tissue level. In addition to a hormonal component of ligament instability, pregnancy-induced hypoemia of the medial collateral ligament may also lead to a loss of tissue function and these effects may begin to explain the higher incidence of ligament injuries and joint degeneration in women.
Perspectives
It appears that intrapartuant ligament laxity is not a direct result of vascular changes occurring in gravid tissues but is likely due to a complex combination of factors, including relaxin, which are upregulated in the pregnant animal. This principle is in contrast to what has previously been described in a ligament injury model in which tissue laxity occurred in conjunction with an increase in ligament perfusion (8). This apparent blood flow/biomechanical paradox may be allayed somewhat by recognizing that pregnancy and joint injury are two very disparate models, each with their own unique set of physiological parameters. In gravid animals, for example, connective tissues are subjected to heightened levels of pregnancy-associated hormones which may act directly on the tissue to induce laxity, whereas adaptive responses to ligament injury involve overt inflammatory mediators and proangiogenic events which may conspire to bring about changes in ligament function (26). Furthermore, joint injury tends to involve irreversible chronic disturbances to ligament homeostasis, whereas pregnancy is a temporary process, although it has yet to be ascertained whether these tissues return to prepregnancy conditions. Therefore, a variety of physiological mechanisms may bring about alterations in ligament function in a model and time-specific manner.| |
ACKNOWLEDGEMENTS |
|---|
We thank Dr. W. Giles for helpful comments and Carol Reno for technical assistance.
| |
FOOTNOTES |
|---|
Financial support for this work was provided by the Medical Research Council of Canada (MRC) and the Alberta Heritage Foundation for Medical Research (AHFMR). J. J. McDougall is an MRC and AHFMR Postdoctoral Fellow, D. A. Hart is the Calgary Foundation-Grace Glaum Professor, and R. C. Bray is an AHFMR Scholar.
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.
Address for reprint requests: J. J. McDougall, Dept. of Surgery, Joint Injury and Arthritis Research Group, The Univ. of Calgary, Calgary, Alberta, Canada T2N 4N1.
Received 10 February 1998; accepted in final form 10 July 1998.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
1.
Abramson, D.,
S. M. Roberts,
and
P. D. Wilson.
Relaxation of the pelvic joints in pregnancy.
Surg. Gynecol. Obstet.
58:
595-613,
1934.
2.
Annibale, D. J.,
C. R. Rosenfeld,
and
K. E. Kamm.
Alterations in vascular smooth muscle contractility during ovine pregnancy.
Am. J. Physiol.
256 (Heart Circ. Physiol. 25):
H1282-H1288,
1989
3.
Anouar, A.,
A. Schirar,
and
G. Germain.
Relaxant effect of the calcitonin gene-related peptide (CGRP) on the nonpregnant and pregnant rat uterus. Comparison with vascular tissue.
Naunyn Schmiedebergs Arch. Pharmacol.
357:
446-453,
1998[Medline].
4.
Bani, G.,
T. Bani Sacchi,
M. Bigazzi,
and
S. Bianchi.
Effects of relaxin on the microvasculature of mouse mammary gland.
Histol. Histopathol.
3:
337-343,
1988[Medline].
5.
Bigazzi, M.,
A. Del Messe,
F. Petrucci,
R. Casali,
and
G. P. Novelli.
The local administration of relaxin induces changes in the microcirculation of the rat mesocaecum.
Acta Endocrinol.
112:
296-299,
1986.
6.
Block, R. A.,
L. A. Hess,
E. V. Timpano,
and
C. Serlo.
Physiologic changes in the foot during pregnancy.
J. Am. Podiatr. Med. Assoc.
75:
297-299,
1985[Medline].
7.
Bouet-Alard, R.,
S. Mhaouty-Kodja,
I. Limon-Boulez,
N. Coudouel,
J. P. Maltier,
and
C. Legrand.
Heterogeneity of 2-adrenoceptors in human and rat myometrium and differential expression during pregnancy.
Br. J. Pharmacol.
122:
1732-1738,
1997[Medline].
8.
Bray, R. C.,
M. R. Doschak,
T. S. Gross,
and
R. F. Zernicke.
Physiological and mechanical adaptations of rabbit medial collateral ligament after anterior cruciate ligament transection.
J. Orthop. Res.
15:
830-836,
1997[Medline].
9.
Bray, R. C.,
A. W. F. Fisher,
and
C. B. Frank.
Fine vascular anatomy of rabbit knee ligaments.
J. Anat.
172:
69-79,
1990[Medline].
10.
Bray, R.,
K. Forrester,
J. J. McDougall,
A. Damji,
and
W. R. Ferrell.
Evaluation of laser Doppler imaging to measure blood flow in knee ligaments of adult rabbits.
Med. Biol. Eng. Comput.
34:
227-231,
1996[Medline].
11.
Calguneri, M.,
H. A. Bird,
and
V. Wright.
Changes in joint laxity occurring during pregnancy.
Ann. Rheum. Dis.
41:
126-128,
1982
12.
Chowdhury, P.,
J. R. Matyas,
and
C. B. Frank.
The "epiligament" of the rabbit medial collateral ligament: a quantitative morphological study.
Connect. Tissue Res.
27:
33-50,
1991[Medline].
13.
D'Angelo, G.,
and
G. Osol.
Regional variation in resistance artery diameter response to -adrenergic stimulation during pregnancy.
Am. J. Physiol.
264 (Heart Circ. Physiol. 33):
H78-H85,
1993
14.
Dumas, G. A.,
and
J. G. Reid.
Laxity of knee cruciate ligaments during pregnancy.
J. Orthop. Sports Phys. Ther.
26:
2-6,
1997[Medline].
15.
Ferrell, W. R.,
J. J. McDougall,
and
R. C. Bray.
Spatial heterogeneity in the effects of calcitonin gene-related peptide (CGRP) on the microvasculature of ligaments in the rabbit knee joint.
Br. J. Pharmacol.
121:
1397-1405,
1997[Medline].
16.
Frank, C. B., D. A. Hart, and N. G. Shrive. Molecular biology and biomechanics of normal and healing
ligaments. Osteoarth. Cart. In press.
17.
Gin, T.
Pharmacokinetic optimisation of general anaesthesia in pregnancy.
Clin. Pharmacokinet.
25:
59-70,
1993[Medline].
18.
Hama, H.,
T. Yamamuro,
and
T. Takeda.
Experimental studies on connective tissue of the capsular ligament: influence of ageing and sex hormones.
Acta Orthop. Scand.
47:
473-479,
1976[Medline].
19.
Hart, D. A.,
L. Roux,
C. B. Frank,
and
N. Shrive.
Sex hormone influences on rabbit ligaments in vivo and in vitro (Abstract).
Trans. Orthop. Res. Soc.
21:
792,
1996.
20.
Hart, D. A.,
P. Sciore,
R. Boykiw,
and
C. Reno.
Pregnancy induces complex changes in the pattern of gene expression in knee ligaments of the adolescent rabbit.
Matrix Biol.
17:
21-34,
1998[Medline].
21.
Humphreys, P. W.,
and
N. Joels.
The response of the hind-limb vascular bed of the rabbit to sympathetic stimulation and its modification by pregnancy.
J. Physiol. (Lond.)
330:
475-488,
1982
22.
Karimian, S. M.,
J. J. McDougall,
and
W. R. Ferrell.
Neuropeptidergic and autonomic control of the vasculature of the rat knee joint revealed by laser Doppler perfusion imaging.
Exp. Physiol.
80:
341-348,
1995[Abstract].
23.
Lang, U.,
R. Baker,
and
K. E. Clark.
Estrogen-induced increases in coronary blood flow are antagonized by inhibitors of nitric oxide synthesis.
Eur. J. Obstet. Gynecol. Reprod. Biol.
74:
229-235,
1997[Medline].
24.
Liu, S. H.,
R. Al-Shaikh,
V. Panossian,
R.-S. Yang,
S. D. Nelson,
N. Soleiman,
G. A. M. Finerman,
and
J. M. Lane.
Primary immunolocalization of estrogen and progesterone target cells in the human anterior cruciate ligament.
J. Orthop. Res.
14:
526-533,
1996[Medline].
25.
MacLennan, A. H.,
R. Nicholson,
R. C. Green,
and
M. Bath.
Serum relaxin and pelvis pain of pregnancy.
Lancet
2:
243-245,
1986[Medline].
26.
McDougall, J. J., and R. C. Bray.
Animal Models in Orthopaedic Research. Boca Raton, FL: CRC. In
press.
27.
McDougall, J. J.,
R. C. Bray,
and
K. A. Sharkey.
A morphological and immunohistochemical examination of nerves in normal and injured collateral ligaments of rat, rabbit and human knee joints.
Anat. Rec.
248:
29-39,
1997[Medline].
28.
McDougall, J. J.,
W. R. Ferrell,
and
R. C. Bray.
Spatial variation in sympathetic influences on the vasculature of the synovium and medial collateral ligament of the rabbit knee joint.
J. Physiol. (Lond.)
503:
435-443,
1997
29.
McKibbin, B.,
and
A. Maroudas.
Adult Articular Cartilage. Tunbridge Wells, UK: Pitman Medical, 1979, p. 461-486.
30.
McLaughlin, M. K.,
M. S. Quinn,
and
J. G. Farnham.
Vascular reactivity in the hind limb of the pregnant ewe.
Am. J. Obstet. Gynecol.
152:
593-598,
1985[Medline].
31.
Mokrzycki, M. L.,
K. Mittal,
S. W. Smilen,
A. N. Blechman,
R. F. Porges,
and
R. I. Demopolous.
Estrogen and progesterone receptors in the uterosacral ligament.
Obstet. Gynecol.
90:
402-404,
1997[Medline].
32.
Ostgaard, H. C.,
G. B. J. Anderson,
A. B. Schultz,
and
J. A. A. Miller.
Influence of some biomechanical factors on low-back pain in pregnancy.
Spine
18:
61-65,
1993[Medline].
33.
Roberts, J. M.,
P. A. Insel,
R. D. Goldfien,
and
A. Goldfien.
-Adrenoceptors but not -adrenoceptors increase in rabbit uterus with oestrogen.
Nature
270:
624-625,
1977[Medline].
34.
Rosenfeld, C. R.,
F. H. Morris,
F. C. Battaglia,
E. L. Makowski,
and
G. Meschia.
Effect of estradiol-17 on blood flow to reproductive and nonreproductive tissues in pregnant ewes.
Am. J. Obstet. Gynecol.
124:
618-629,
1976[Medline].
35.
Schauberger, C. W.,
B. L. Rooney,
L. Goldsmith,
D. Shenton,
P. D. Silva,
and
A. Scharper.
Peripheral joint laxity increases in pregnancy but does not correlate with serum relaxin levels.
Am. J. Obstet. Gynecol.
174:
667-671,
1996[Medline].
36.
Sciore, P.,
S. Smith,
C. B. Frank,
and
D. A. Hart.
Detection of receptors for estrogen and progesterone in human ligaments and rabbit ligaments and tendons by RT-PCR (Abstract).
Trans. Orthop. Res. Soc.
22:
51,
1997.
37.
Shikata, J.,
H. Sanada,
T. Tamamuro,
and
T. Takeda.
Experimental studies of the elastic fiber of the capsular ligament: influence of ageing and sex hormones on the hip joint capsule of rats.
Connect. Tissue Res.
7:
21-27,
1979[Medline].
38.
Sladek, S. M.,
R. R. Magness,
and
K. P. Conrad.
Nitric oxide and pregnancy.
Am. J. Physiol.
272 (Regulatory Integrative Comp. Physiol. 41):
R441-R463,
1997
39.
Stevenson, J. C.,
D. W. R. MacDonald,
R. C. Warren,
M. W. Booker,
and
M. I. Whitehead.
Increased concentration of circulating calcitonin gene related peptide during normal human pregnancy.
Br. Med. J.
293:
1329-1330,
1986.
40.
Wårdell, K.,
A. Jakobsson,
and
G. E. Nilsson.
Laser Doppler perfusion imaging by dynamic light scattering.
IEEE Trans. Biomed. Eng.
40:
309-316,
1993[Medline].
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
