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Department of Physiology, New York Medical College, Valhalla, New York 10595
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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It was shown
previously that the presence of endothelium modulates spontaneous
vasomotion of small lymphatic vessels. In the present study, we aimed
to elucidate the nature of endothelium-derived factors, produced in
basal conditions and in response to agonists, that affect the smooth
muscle tone of lymph microvessels in vitro. Afferent lymph microvessels
were isolated from rat iliac lymph nodes, cannulated with glass
micropipettes, and pressurized (6 cmH2O), and changes in their
diameter were investigated with video microscopy. In resting
conditions, isolated lymph vessels exhibited spontaneous constrictions
and dilations. The maximum and minimum diameters
(Dmax and
Dmin) were
149.8 ± 2.9 and 85.8 ± 3.6 µm, respectively. Acetylcholine
(ACh, 10
7 to
105 M) and sodium
nitroprusside (SNP, 108 to
106 M) temporarily
abolished diameter oscillations, increasing the diameter of lymphatics
dose dependently. For example,
105 M ACh and
106 M SNP increased the
diameter (Dmax)
by 15.2 ± 2.2 and 25.0 ± 2.7 µm, respectively. Treatment of
vessels with NG-nitro-L-arginine
(104 M) significantly
reduced the amplitude of diameter oscillations and nearly completely
eliminated ACh-induced dilation of lymph microvessels, whereas SNP
(106 M) elicited a
significantly greater dilation (55.6 ± 7.5 µm). Arachidonic acid
(AA, 108 to
106 M) constricted (up to
50 µm), whereas prostaglandin E2
(PGE2, 109 to
107 M) dilated (up to 40 µm), lymphatic vessels. Indomethacin
(105 M) increased both
Dmax and
Dmin and
completely inhibited AA-induced constrictions, but did not affect
PGE2-induced dilations of lymph microvessels. AA-induced constrictions of lymphatics were converted into dilations after treatment with SQ-29,548, a selective
PGH2-thromboxane A2
(PGH2-TxA2,
106 M) receptor antagonist,
whereas PGE2-induced dilations
were not affected. We conclude that endothelial nitric oxide and
prostaglandins are important modulators of lymphatic vasomotion, hence
pumping activity of lymph microvessels in vivo.
vasomotion; endothelium; prostaglandin E2; prostaglandin H2-thromboxane A2
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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THE LYMPHATIC SYSTEM is able to return great amounts of extravasated fluid and protein back to the circulation, thereby playing an essential role in the homeostasis of body fluids (3). In addition to passive forces, the transport of lymph depends on active driving forces, such as lymphatic vasomotion (3), provided by the spontaneous oscillation in smooth muscle tone of lymphatics. The characteristics of active spontaneous constriction and dilation present in lymphatics have been described previously (3, 9, 30). We have also shown that changes in intraluminal pressure in isolated lymphatic microvessels influence significantly the oscillation of the diameter and that these vessels are able to increase their spontaneous tone in response to increases in intraluminal pressure (18), a tone that is further modulated by endothelial factors. In arterioles and venules, it has been demonstrated that the endothelium produces nitric oxide and prostaglandins, both in basal and stimulated conditions, significantly affecting the diameter, hence the resistance in these vessels (6, 7, 11, 26, 27).
In vivo, changes in the interstitial and intraluminal environment can occur frequently and may affect the spontaneous oscillations in diameter of lymph microvessels via altering the synthesis/release of endothelium- derived vasoactive factors. In large collecting lymph vessels, a role for nitric oxide has already been demonstrated. Ohhashi and Takahashi (23) showed that acetylcholine (ACh) elicits an endothelium-derived nitric oxide-dependent relaxation of isolated canine thoracic ducts. Furthermore, Yokoyama and Ohhashi (30) showed that endothelium-derived nitric oxide regulates the frequency and amplitude of spontaneous contraction of isolated large mesenteric lymph vessels (2-3 mm OD). Metabolites of arachidonic acid have also been demonstrated to affect the tone of large lymphatic vessels (2, 13, 15, 22). On the other hand, ACh did not have discernible effects on the diameter of intestinal lymphatic microvessels in vivo (4). Thus our knowledge is limited regarding the nature of endothelial factors produced in response to vasoactive substances in lymph microvessels, whether they are released in basal conditions and what their vasomotor effects might be.
Based on previous studies, we hypothesized that the endothelium of microlymphatics is able to produce factors that modulate the tone of smooth muscle, thereby affecting lymphatic vasomotion. Thus the present investigation was undertaken to gain information regarding the nature of endothelial factors released from lymph microvessels stimulated by vasoactive agents and their possible role in modulation of the function of microlymphatics. To investigate the role of endothelial factors, we studied the responses of isolated afferent lymph microvessels of rat iliac lymph nodes at constant intraluminal pressure and in the presence or absence of the endothelium or specific inhibitors of the synthesis of endothelial factors, namely nitric oxide and prostaglandins.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Isolation and cannulation of lymphatics. Eleven-week-old male Wistar rats weighing ~360 g were anesthetized with pentobarbital sodium (50 mg/kg ip). The iliac lymph nodes and their afferent vessels were exposed by an incision of the abdomen, excised, and placed on a petri dish containing cold (4°C) Krebs solution (pH 7.4). The Krebs solution contained (in mM) 120.0 NaCl, 5.9 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 5.5 glucose, and 25.0 NaHCO3. With the use of microsurgical instruments and an operating microscope, lymph microvessels (n = 58, ~2 mm in length) were isolated and transferred to a vessel chamber (10 ml) containing Krebs solution and two glass micropipettes (18).
After the lymph microvessels were mounted on the primary pipette and secured with sutures, perfusion pressure was raised to 4 cmH2O to flush out and clear the vessels. Then the distal end of the vessels was mounted to the outflow micropipette. The proximal (inflow) micropipette was connected with Tygon tubing to a pressure transducer (Statham P23DC, Gould, MA) and a 50-ml syringe. The distal (outflow) micropipette was connected to Tygon tubing to which a stopcock was attached. A physiological salt solution (PSS, pH 7.4) bubbled with a gas mixture of 10% O2-5% CO2-85% N2 was superfused over the vessel. The total volume of the chamber and superfusion circuit was 80 ml, and the rate of flow of the superfusion solution was 20 ml/min. After cannulation of the lymph microvessels, the chamber was transferred to the stage of an intravital microscope (Olympus BH-2). The vessels were then warmed slowly to 37°C and allowed to equilibrate for 60 min at a perfusion pressure of 6 cmH2O.
Removal/disruption of endothelium. As described previously, perfusion of arterioles (11, 26, 27), venules (6, 7), and lymphatics (18) with air results in a loss or functional impairment of the endothelial cell layer. The lymphatic endothelium was removed carefully by infusion of 0.1 ml of air into the lumen of the lymph microvessels within a period of 2 min. The vessels were then flushed with 0.2 ml of PSS solution. Previous histological studies with light microscopy showed that the rat lymph microvessels studied have two or more layers of smooth muscle and that intraluminal perfusion of air injured or removed the endothelial cell layer without affecting the morphology of the smooth muscle layer (18).
After the equilibration period, the vasoactive function of lymphatic endothelium and smooth muscle was assessed by changes in diameter of lymph microvessels with or without endothelium in response to ACh and sodium nitroprusside (SNP). Then the vessel was washed for 20 min with Krebs solution until the maximum diameter and the vasomotion frequency returned to control. Endothelium-disrupted preparations that showed ACh-induced dilation were discarded from analysis. Two groups of vessels were studied: one with and another without the endothelium.
Measurements of diameter. Changes in maximum and minimum diameter of lymph microvessels (Dmax and Dmin, respectively) were recorded in basal conditions, and changes in Dmax were measured in response to vasoactive agents (in the presence of an intraluminal pressure of 6 cmH2O) with an image-shearing monitor (Instrumentation for Physiology and Medicine, IPM model 908), calibrated with a stage micrometer (Nikon) and recorded on a chart recorder (Grass, model 7WC8G). Pressure was increased to 6 cmH2O by elevation of a 50-ml syringe connected to the inflow tubing while the outflow tubing was closed with a stopcock throughout the experiment. Because oscillations in diameter of lymph microvessels may cause a small change in the volume of the vessels, we used a 50-ml syringe as a reservoir to minimize the changes in pressure. The height of the pressure column and the recorded intraluminal pressure were constant.
Responses to vasoactive agents.
Cumulative dose-dependent responses to ACh
(107 to
105 M) and SNP
(108 to
106 M) of lymph vessels
with or without endothelium or in the presence of
NG-nitro-L-arginine
(L-NNA;
104), an inhibitor of
nitric oxide synthase, were obtained.
Cumulative dose-dependent responses to arachidonic acid (AA,
108 to
106 M) and prostaglandin
E2
(PGE2,
109 to
107 M) were obtained in
control, without endothelium, or in the presence of indomethacin (Indo,
an inhibitor of cyclooxygenase;
105 M) or SQ-29,548 (a
selective PGH2-thromboxane
A2 receptor antagonist; PGH2-TxA2,
106 M). The effects of
SQ-29,548 on responses to U-46,619
(1010 to
108 M), a stable
PGH2-TxA2
agonist, were also determined. The vessels were incubated with the
various inhibitors for 30 min before responses to vasoactive agents
were obtained.
After each response subsided, 5-10 min were allowed for the
vessels to reach stable maximum diameter and spontaneous diameter oscillations. At the end of each experiment, the superfusion solution was changed to a Ca2+-free
solution that contained EDTA (1.0 mM). Lymph microvessels were
incubated with Ca2+-free PSS for
20 min, and then the passive diameters (PD) were measured at 6 cmH2O pressure. In the text and
Figs. 3 and 5-8, constrictions (
µm) are indicated by a
negative (
) sign.
Salts and drugs were obtained from J. T. Baker, Cayman Chemical, and Sigma. Stock solution of AA, PGE2, U-46,619, and SQ-29,548 were prepared with ethanol (10 mg/ml). Phosphate buffer was used for further dilution of AA. PGE2, U-46,619, and SQ-29,548; ACh and SNP were diluted with Krebs solution. Concentrations of drugs are expressed as the final concentration in the vessel chamber. All salts and drugs were prepared on the day of the experiment. The ethanol concentration did not exceed 0.003% in the vessel chamber. Vehicle solutions did not affect the diameter of lymph microvessels.
Statistics. Data are presented as means ± SE, and n indicates the number of vessels. Only one vessel was used from each rat. Significant differences (P < 0.05) were determined by analysis of variance, followed by a multiple-comparison test (Duncan's post hoc test) and paired and unpaired Student's t- test, as appropriate.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Effect of endothelium removal,
L-NNA, and Indo on lymphatic
vasomotion. Original records (Fig.
1) show that lymphatic microvessels exhibit
rhythmic spontaneous vasomotion at a perfusion pressure of 6 cmH2O, in a no flow condition. The
mean Dmax of the
vessels was 148.8 ± 4.0 µm, and the
Dmin was 85.8 ± 3.6 µm, whereas the frequency of vasomotion was 23.1 ± 0.8 min1.
In the absence of Ca2+ in the bath
solution, the spontaneous vasomotion was abolished, and the PD of lymph
microvessels increased to 198.4 ± 4.9 µm
(n = 58). In Table 1, the
Dmax and
Dmin and the
frequency of vasomotion of lymph microvessels in control, without
endothelium, and in the presence of
L-NNA
(104 M) or Indo
(105 M) are summarized.
Disruption of endothelium significantly reduced the amplitude and
increased the frequency of vasomotion. In the presence of
L-NNA, both
Dmax and
Dmin became
significantly reduced compared with control (Fig. 1 and Table 1). In
contrast, in the presence of Indo, both
Dmax and
Dmin of lymph
microvessels was greater than control, and the frequency of vasomotion
decreased (Fig. 1 and Table 1).
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Responses of microlymphatics to ACh and
SNP. Original records of changes in diameter indicate
that ACh and SNP temporarily abolished vasomotion of lymphatics (Fig.
2). ACh
(107 to
105 M) and SNP
(108 to
106 M) caused
dose-dependent increases in
Dmax of isolated
lymph vessels (Fig. 3). Higher doses of ACh
did not elicit further dilations. These dilations were eliminated after
removal and/or disruption of the endothelial cell layer (at
105 M ACh, from 15.4 ± 2.2 to 0.3 ± 0.3 µm, respectively) (Fig. 3A). Removal of endothelium
significantly enhanced SNP-induced dilations of lymph vessels (at
106 M SNP, from 24.0 ± 2.8 to 55.6 ± 7.5 µm) (Fig.
3B).
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Treatment of vessels with L-NNA
nearly completely inhibited ACh-induced dilation of lymphatics (Fig.
4A).
Dilations in response to
105 M ACh in the absence
and presence of L-NNA were 14.2 ± 2.3 and 1.8 ± 0.7 µm, respectively. SNP-induced dilations
of lymphatics were significantly increased after treatment with
L-NNA (Fig. 4B). SNP
(106 M)-induced dilations
of lymphatics in the absence and presence of
L-NNA were 25.3 ± 2.7 and
41.1 ± 4.7 µm, respectively. ACh (106 M)-induced dilations
of lymph vessels were not affected by Indo (8.0 ± 1.2 before and 10.7 ± 2.4 µm after Indo;
n = 6).
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Responses of microlymphatics to AA and
PGE2. Cumulative doses of AA
(108 to
106 M) caused constrictions
of isolated pressurized lymphatics (Fig. 5A). On
the other hand, lymph vessels showed dose-dependent dilation in
response to PGE2
(109 to
107 M) (Fig.
5B). After removal of endothelium,
AA (107 to
106 M)-induced
constrictions became significantly reduced compared with those obtained
in endothelium-intact vessels (Fig.
5A). On the other hand,
PGE2
(108 and
107 M)-induced dilations of
lymph microvessels without endothelium were significantly greater than
those with endothelium (at
107 M
PGE2 from 38.7 ± 2.6 to 59.8 ± 8.6 µm) (Fig. 5B).
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Effects of indomethacin and SQ-29,548 on AA- and
U-46,619-induced responses. AA-induced
constrictions of lymphatics were significantly inhibited by Indo (Fig.
6). In control, the highest dose of AA (106 M) elicited a
55.2 ± 15.3-µm reduction in diameter, whereas Indo blocked
this response completely (0.9 ± 0.9 µm). On the other
hand, there were no significant differences in dilations to
PGE2 before and after Indo
treatment (for example at
107 M
PGE2, responses were 38.6 ± 4.1 and 40.1 ± 5.7 µm, respectively).
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Cumulative doses of U-46,619
(1010 to
108 M), a stable
PGH2-TxA2
agonist, constricted lymphatic microvessels (Fig.
7). U-46,619-induced constriction of
lymphatics was completely eliminated after treatment with SQ-29,548
(106 M), a selective
PGH2-TxA2
receptor antagonist (at 108
M, 111.1 ± 7.8 µm before and 1.0 ± 0.5 µm after
SQ-29548, respectively) (Fig. 7). Interestingly, treatment of lymph
vessels with SQ-29,548 converted AA-induced constrictions into
dilations (at 106 M AA,
from 53.4 ± 12.6 to 16.0 ± 5.3 µm) (Fig.
8). At the same time,
PGE2-induced dilations of
lymphatics were not affected by treatment with SQ-29,548 (data not
shown).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The salient finding of the present study is that the endothelium of isolated rat lymph microvessels, in basal conditions and in response to agonists, can release nitric oxide and dilator and constrictor prostaglandins, affecting significantly the function of the vessels.
Basal release of nitric oxide and prostanoids. It has long been thought that spontaneous contraction and relaxation of smooth muscle of lymphatic vessels contribute to the active transport of lymph. Previous studies have already described the nature and characteristics of spontaneous oscillations in the diameter of lymphatic vessels of various sizes (3, 9). By now it is well known that the endothelium continuously releases vasoactive factors affecting the tone of arteriolar and venular smooth muscle and thereby local blood flow, both in physiological and pathological conditions. It has also been demonstrated that lymph microvessels exhibit a weak pressure-induced myogenic tone, similar to that observed in skeletal muscle venules (7) and that in the absence of endothelium pressure-induced myogenic tone is enhanced (18). Less is known, however, of the nature and capacity of endothelial factors to modulate the spontaneous diameter oscillation of lymph microvessels in basal or stimulated conditions.
To investigate the effect of endothelial factors, we isolated lymph microvessels and studied them under a constant perfusion pressure of 6 cmH2O. In this condition, the presence of parenchymal tissue and other confounding factors could be excluded. As in our previous study, removal of endothelium reduced the amplitude and enhanced the frequency of vasomotion (Table 1). In the absence of basal release of nitric oxide (after L-NNA administration), both the Dmax and Dmin of lymph vessels became significantly reduced (Table 1), suggesting that a constant release of nitric oxide increases the amplitude of vasomotion of lymph microvessels. A similar role for nitric oxide has been shown in bovine (8), sheep (17), and guinea pig lymphatics (29). In contrast, indomethacin increased the Dmax and Dmin of isolated lymphatic vessels, suggesting a basal release of constrictor prostanoids. This latter finding is in agreement with in vitro studies of large bovine mesenteric lymphatics, showing (2, 13, 15) that the cyclooxygenase inhibitor, aspirin, suppressed contractions, making it likely that constrictor prostaglandins are released in resting conditions.
The above findings suggest that the smooth muscle tone of lymphatic microvessels, developed in the presence of extracellular Ca2+ and intraluminal pressure, is continuously modulated by the release of nitric oxide and constrictor prostaglandins, but in an opposite manner, similar to what has been observed in skeletal muscle venules (6). Modulation of basal tone by nitric oxide and PGI2 has previously been shown in arterioles of normotensive animals, whereas a significant role for PGH2 seems to develop in arterioles of hypertensive animals (11). It remains an intriguing question as to why the endothelium, in the low-pressure segments of the circulation, such as the venous and lymphatic circulations, produces PGH2 to increase the smooth muscle tone of vessels and what the intracellular mechanisms are that are responsible for this regulation.
Stimulated release of endothelium-derived nitric oxide. In the present study we aimed to characterize the changes in diameter of isolated lymphatic microvessels to various vasoactive agents and the effect of inhibitors of the synthesis of endothelial mediators on the responses. ACh causes relaxation of isolated canine thoracic ducts (23) and porcine hepatic lymphatics (10), a response that is mediated by endothelium-derived nitric oxide. In addition, in vivo (4) and in vitro (29) studies have already demonstrated that nitric oxide is released by ACh in small lymphatics. In the present study, in response to ACh, the maximum diameter of lymphatic microvessels increased significantly and there was also a temporary cessation of oscillations in diameter (Fig. 2). After nitric oxide synthase inhibition by L-NNA, dilations to ACh were essentially eliminated (Fig. 3). We also found that injection of air, a method used to remove the endothelium in various microvessel preparations (6, 7, 11, 26, 27), eliminated ACh-induced dilation of lymph microvessels, whereas responses to SNP were enhanced (Fig. 3). This finding supports the idea that nitric oxide is released from lymphatic endothelium and that dilation to ACh is mediated primarily by this factor. In contrast, in arterioles (11), in addition to nitric oxide, a significant portion of the ACh-induced response is mediated by endothelium-derived relaxing factors, other than nitric oxide, whereas in venules (6) ACh elicits the release of PGH2, as well. The physiological roles of such differences are not yet clear, but they may well correlate with the differences in the structure and the functional role of lymphatic vessels and blood vessels.
Previously, Moncada et al. (20) showed that in the absence of nitric oxide (i.e., after endothelium removal) soluble guanylate cyclase in vascular smooth muscle becomes supersensitive to nitrovasodilators. Thus the basal release of nitric oxide from the endothelium of blood vessels may regulate in a negative feedback manner the guanosine 3',5'-cyclic monophosphate activity of smooth muscle. The gain of this mechanism seems to be rather high in lymphatic vessels, as indicated by the great enhancement of the SNP-induced response after removal of the endothelium or blockade of nitric oxide release, compared with similar findings in other vessel types (5, 20, 25). Also, norepinephrine-induced constrictions of lymph microvessels without endothelium are significantly enhanced compared with vessels with endothelium (18), suggesting further that nitric oxide may play an important role in the modulation of lymphatic function.
Histochemical studies have shown that there is cholinergic innervation in the wall of lymphatics (1, 22). Thus one can assume that ACh could diffuse to lymphatic endothelium from nerves and release nitric oxide to cause relaxation of lymphatic smooth muscle (10, 23). Yokoyama and Ohhoshi (30) demonstrated that nitric oxide causes negative inotropic and chronotropic effects on spontaneous contractions of isolated bovine mesenteric lymphatics, and thus, could modulate the transport of lymph in physiological conditions. As in other microvessels, several stimuli such as an increase in lymphatic flow, changes in PO2, pH, and tissue metabolites could cause the release of nitric oxide to affect the function of microlymphatics. On the other hand, in certain conditions lymphatic endothelial cells may express inducible, in addition to constitutive, nitric oxide synthase during activation of cytokines and lipopolysaccharide (17), similar to what has been observed in blood vessels (16). Moreover, the lymphatic system has an important role in the transport of macrophages, which produce and release large amounts of nitric oxide via inducible nitric oxide synthase, activated by various cytokines and toxins (19). Thus at the site of inflammation and infection the high concentrations of nitric oxide produced by the inducible isoform of nitric oxide synthase in lymphatic endothelium and macrophages (28) may also affect lymphatic tone and pumping activity (24).
Stimulated release of constrictor and dilator prostaglandins. In response to AA, the diameters of lymph microvessels decreased significantly, suggesting that constrictor prostaglandins are produced. Because indomethacin blocked the constriction (Fig. 5), we concluded that these prostaglandins are produced via cyclooxygenase. The finding that SQ-29,548 not only eliminated the constrictions induced by AA but reversed them to dilations suggests that in response to AA both PGH2-TxA2 and PGI2/PGE2 are released simultaneously, but with the preponderance of constrictor prostaglandins (Fig. 7). These findings are in accordance with those of previous studies of large lymphatics (2, 13, 15).
In the present study, PGE2 caused a dose-dependent dilation of rat lymphatic microvessels, in line with the report of PGE2 being a potent inhibitor of spontaneous contractions of bovine mesenteric lymphatics (15, 21). PGE2-induced dilations of isolated lymph microvessels were not affected by treatment with Indo and SQ-29,548. Removal of endothelium, however, enhanced responses to PGE2 (Fig. 5). The reason for this enhancement is not clear, but may be related to the basal release of nitric oxide and/or a change in the activity of smooth muscle adenylate cyclase after removal of the endothelium.
The data also show that removal of endothelium significantly inhibited, but did not eliminate, AA-induced constriction of isolated rat lymphatics (Fig. 5). These results suggest that nonendothelial cells in rat lymphatic vessels, perhaps smooth muscle cells or pericytes, may also release constrictor prostaglandins, indicating a marked heterogeneity of AA metabolism among different species and vessels (12). Thus, in addition to nitric oxide, prostaglandins, released from the endothelium of lymphatic microvessels, can greatly influence the diameter of the vessels. In this context, it should be noted that, at sites of inflammation, there are increases in prostaglandin concentration (14) as well, thus affecting the regulation of lymph transport. It is also likely that in vivo the flow of lymph generated by the vasomotion of lymphatics may continuously stimulate the lymphatic endothelium via changes in wall shear stress to modulate the release of both endothelial factors.
In conclusion, we have demonstrated that the tone of smooth muscle cells of lymphatic microvessels is modulated by endothelium-derived factors, nitric oxide, and PGH2, the latter perhaps masking the presence of PGI2/E2. These factors, released in basal conditions and on stimulation with vasoactive agents, affect significantly the diameter of microlymphatics. Hence, endothelial nitric oxide and prostaglandins may play important roles in modulating both the resistive and pumping activity of lymphatic microvessels in vivo.
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ACKNOWLEDGEMENTS |
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We thank Mary Browne and Miriam Nunez for excellent secretarial work.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants PO1 HL-43023, HL-46813, and an American Heart Association New York State Affiliate Grants 960104 and 970137.
Present address of R. Mizuno: The 1st Department of Physiology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390, Japan.
Address for reprint requests: G. Kaley, Dept. of Physiology, New York Medical College, Valhalla, NY 10595.
Received 14 August 1997; accepted in final form 19 November 1997.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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