© 1998 American Heart Association, Inc.
Original Contributions |
Endogenous Nitric Oxide Protects Against Thromboembolism in Venules But Not in Arterioles
From the Departments of Physiology (M.A.W.B., G.-J.T., R.S.R., M.G.A. oude E.) and Biophysics (D.W.S.), Cardiovascular Research Institute Maastricht, Maastricht University; and the Laboratory for Physiology, Institute for Cardiovascular Research, Free University, Amsterdam (G.-J.T.), the Netherlands.
Correspondence to M.G.A. oude Egbrink, PhD, Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, PO Box 616, 6200 MD Maastricht, the Netherlands. E-mail m.oudeegbrink{at}fys.unimaas.nl
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Abstract |
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Abstract—Because nitric oxide (NO) inhibits aggregation and adhesion of blood platelets, NO may play a role in platelet–vessel wall interactions. Therefore, the purpose of this study was to investigate the involvement of endogenous NO in thromboembolic processes, as induced by wall puncture, in rabbit mesenteric arterioles and venules (diameters 20 to 43 µm). In venules, inhibition of NO synthase by superfusion of the mesentery with N
-nitro-L-arginine (L-NA;
0.1 mmol/L) significantly increased the duration of embolization
(from 50 seconds to 511 seconds) and the number of emboli produced
(from 2 to 11 emboli per vessel), while the median period of time
needed to produce an embolus was not influenced. On the contrary, in
arterioles, L-NA had no significant effect on embolization (duration of
embolization: 426 seconds in the control and 382 seconds in the L-NA
group, with 20 and 12 emboli per vessel, respectively). Addition to the
L-NA superfusate of L-arginine (L-ARG; 1 mmol/L), the
active precursor for endogenous NO synthesis, resulted in a
complete reversal of the L-NA effects in venules, while addition of the
inactive D-arginine (D-ARG; 1 mmol/L) had no effect. Addition of
L-ARG and D-ARG had no significant effect in arterioles. Addition to
the L-NA superfusate of the exogenous NO donor sodium
nitroprusside (0.1 µmol/L) also resulted in reversal of the L-NA
effects in venules, while in arterioles, it slightly but significantly
decreased embolization duration. The differences in effect of L-NA on
embolization between arterioles and venules were not caused by
differences in fluid dynamic conditions. It is concluded that the role
of endogenous NO in inhibiting thromboembolic processes is
more important in venules than in arterioles.
Key Words: vessel wall injury • thromboembolism pathophysiology • nitric oxide • intravital microscopy • microcirculation
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Introduction |
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Among the various functions of NO, two are of major importance in the cardiovascular system: its vasodilatory capacity and its inhibitory effect on platelet aggregation and adhesion (for reviews on this issue, see References 1 through 51 2 3 4 5 ). NO is synthesized by the enzyme NOS.6 Up to now, three different isoforms of this enzyme have been identified. Endothelial NOS and neural NOS are both constitutively present in certain cell types. Endothelial NOS is found in endothelial cells7 and platelets,8 while neural NOS is present in nonadrenergic, noncholinergic peripheral neurons, in cerebellar and cerebral neurons, and in human skeletal muscle fibers.6 The third NOS isoform is not expressed under physiological conditions but can be induced within several hours after immunological activation with cytokines.6 This inducible NOS was first found in macrophages and more recently also in endothelial cells, smooth muscle cells, mast cells, and polymorphonuclear granulocytes.9
Because of its influence on blood platelets, NO may play a role in hemostatic plug formation and in thrombotic processes. Moreover, the constitutively present enzyme endothelial NOS can be activated in vivo by shear stress and chemical stimulators like thrombin and ADP, which are factors known also to influence platelet behavior.9 10 In vivo studies on the role of NO in thrombotic processes are scarce. Most of the studies performed have focused on the antithrombogenic properties of NO in arterioles11 12 13 or arteries,14 15 16 17 18 but not in venules. Since in vivo the thromboembolic reaction to vessel wall injury differs between arterioles and venules of the same tissue,19 20 it might be hypothesized that NO is differently involved in this process in these microvessels.
Therefore, the aim of the present study was to investigate in vivo the antithrombotic role of NO in platelet–vessel wall interactions in arterioles and venules of the same tissue by using an experimental model developed in our laboratory.19 In the mesentery of anesthetized rabbits, the wall of arterioles and venules was punctured with a micropipet, and the ensuing thromboembolic reaction was studied with the use of intravital videomicroscopy. In the first series of experiments, the mesentery of one group of rabbits was locally superfused with L-NA or its vehicle; L-NA is an irreversible inhibitor of NOS5 in the wall of rabbit blood vessels21 22 23 and in rabbit platelets.24 25 To provide evidence that NO production was indeed inhibited under L-NA superfusion, a second series of control experiments was performed. The aim of these experiments was to investigate whether the effects of L-NA superfusion could be reversed by adding either the exogenous NO donor SNP or the active precursor for endogenous NO synthesis, L-ARG; as a control for the latter, the inactive D-ARG was added in a separate group of animals.
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Methods |
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Animals and Intravital Video Microscopy
All experiments were approved by the local ethical committee on the use of laboratory animals. Experiments were performed on 44 New Zealand White rabbits (weight range, 2.4 to 3.1 kg) of either sex. Anesthesia was induced with intramuscular injections of 40 mg/kg body weight ketamine hydrochloride (Nimatek, AUV) and 5 mg/kg body weight xylazine hydrochloride (Sedamun, AUV). Anesthesia was maintained with ketamine (40 mg · kg-1 · h-1) and xylazine (5 mg · kg-1 · h-1) dissolved in a lactetrol solution (15 mL/h; Aesculaap) and continuously infused through a catheter (PE-50) in the femoral vein. Throughout the experiments, arterial blood pressure was measured through a catheter (PE-60) in the femoral artery (Uniflow external pressure transducer, Baxter). Heart rate was assessed from the instantaneous pressure signal. To keep the arterial catheter patent, it was continuously perfused with physiological saline (3 mL/h) via the Uniflow system; no heparin was used. Both arterial pressure and heart rate were continuously recorded on hard disk with the use of a hemodynamic data acquisition program.
During surgery and throughout the experiment, body temperature was kept at 37°C to 38°C, using an infrared heating lamp controlled by a thermoanalyzer system (Hugo Sachs Elektronik) connected to a rectal probe. After surgery, blood was collected from a central ear artery in EDTA (0.9 mL blood/0.1 mL EDTA; 0.027 mol/L) for electronic platelet counts (Coulter counter; model ZF) and assessment of hemoglobin concentration (OSM 2 Hemoxymeter) and hematocrit (Autocrit II centrifuge; Clay Adams); these values were corrected for the EDTA dilution.
The rabbits were ventilated throughout the experiments with a mixture of nitrogen (75%), oxygen (24.5%), and carbon dioxide (0.5%) to maintain systemic arterial pH, PCO2, and PO2 at normal values. To this purpose, the trachea was cannulated and the cannula (3.5 or 4.5 mm ID; Mallinckrodt) connected to an animal ventilator (Technical & Scientific Equipment; model 4601). Ventilation was performed with a positive end-expiratory pressure of 2 cm H2O. The respiratory rate was 60 per minute, and the tidal volume varied between 16 and 21 mL, depending on the weight of the rabbit. Blood gas and pH values were measured with an acid-base analyzer (ABL 3 Radiometer) in blood collected from a central ear artery. Average values throughout the experiments were pH 7.43±0.03, Pco2 34±6 mm Hg, and Po2 93±13 mm Hg (mean±SD). These values are within the normal ranges for rabbits.19 26 No statistical differences existed between the experimental groups (see "Results").
Through a small midline incision, a segment of the distal ileum was brought outside the abdomen. The mesentery was carefully spread over a siliconized glass plate mounted in an electrically heated microscope table (37°C). It was continuously superfused with a buffered Tyrode's solution (37°C, pH 7.35 to 7.40) that was saturated with 95% N2 and 5% CO2. The exteriorized ileum was kept moist with overlying wet gauze. The mesenteric tissue was visualized with a Leitz intravital microscope adapted for telescopic imaging,27 using a long-working-distance objective (Leitz LL 25x, numerical aperture 0.35). Transillumination was performed with a tungsten lamp. Images were recorded on videotape (Sony Betamax or Panasonic SVHS) through a CCD camera (Hamamatsu; model C2400, 2/3 inch) or a Grundig TV camera (model FA 32, 1 inch) for off-line analysis. Final magnification at the front plane of the camera was x40.
In all selected vessels, vascular diameter was measured off-line with an image shearing device.28 Mean red blood cell velocity was measured on-line using a dual-slit system connected to a tracking correlator (IPM)29 and was recorded on hard disk with the use of the hemodynamic data acquisition program. Reduced velocity (U), which is a measure of wall shear rate, was calculated by dividing mean red blood cell velocity by vessel diameter.
Vessel Wall Puncture and the Thromboembolic Reaction
Arterioles and venules with an estimated diameter ranging from
20 to 40 µm were selected. Vessel wall injury was induced
mechanically by puncture with a glass micropipet (tip diameter
6 µm), as previously described.19
To be certain that all layers of the wall were damaged, puncture was
considered to be successful only if red blood cells could be seen
leaving the vessel.
Immediately after puncture, the thromboembolic reaction started. In all vessels, a white thrombus formed, height and shape of which remained constant, except for one venule in which the whole thrombus embolized after 137 seconds. In most vessels, circulating platelets adhered to this stationary thrombus mainly on its downstream side. From time to time, these newly formed parts embolized. After a certain period of time, embolization stopped, while the thrombus remained at the site of injury for the rest of the observation period of at least 600 seconds. To quantify this thromboembolic reaction, the following variables were determined off-line from videotape: the duration of bleeding (bleeding time), the maximal thrombus height relative to the local vessel diameter, the total duration of embolization, the number of emboli produced within 600 seconds after puncture, and the median embolus production time per vessel, ie, the median of all periods of time needed to produce an embolus per vessel. The latter parameter is a measure of the rate of embolus formation. Emboli were taken into account only when their short axis perpendicular to the vessel wall was greater than 25% of the local vessel diameter. Aggregates of smaller dimensions could not always be distinguished from the background with enough accuracy. In case of rebleedings through the thrombus, their frequency was determined.
Superfusion of the Mesentery With L-NA, Vehicle, or Combinations of
L-NA and D-ARG, L-ARG, or SNP
To determine the role of endogenous NO in the
thromboembolic reaction, in a first series of experiments, the effect
of the NOS inhibitor L-NA (molecular weight 219.2; Sigma)
was studied. The mesentery of a group of 12 rabbits (L-NA group; see
Table 1
) was superfused with L-NA in a
concentration of 0.1 mmol/L; this concentration has been shown to
be high enough to effectively inhibit NOS in rabbit tissues and blood
cells.21 22 23 24 25 Moreover, superfusion of
higher L-NA concentrations results in an undesirable rise of systemic
blood pressure (M.A.W.B., unpublished observations, 1995). In the
control group (CON; 14 rabbits; see Table 1), the mesentery was
superfused with the vehicle, a buffered Tyrode's solution. Rabbits
were assigned at random to one of these two groups.
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A second series of experiments was performed to determine whether the
L-NA effects as found in the first series of experiments could be
reversed, using a modified protocol as described by Yao and
colleagues.15 For these experiments, 18
rabbits were equally assigned at random to one of three groups (see
Table 1
). The mesentery of these rabbits was superfused with a
combination of either L-NA (0.1 mmol/L) and excess D-ARG (1
mmol/L, molecular weight 210.7, Sigma; L-NA+D-ARG group), L-NA
(0.1 mmol/L) and excess L-ARG (1 mmol/L, molecular weight
210.7, Sigma; L-NA+L-ARG group), or L-NA (0.1 mmol/L) and SNP
(0.1 µmol/L, molecular weight 298.0, Sigma; L-NA+SNP group).
All drugs were dissolved in buffered Tyrode's solution on the day of the experiment. L-NA was dissolved by sonication and subsequent stirring. Because of its light sensitivity, SNP was dissolved and used with minimal exposure to light.
In all groups, the mesentery was allowed to stabilize during a period of 30 to 35 minutes after exteriorization under continuous superfusion with buffered Tyrode's solution. After this stabilization period, the superfusion was switched to the L-NA solution alone or to a combination of L-NA and D-ARG, L-ARG, or SNP. Superfusion with buffered Tyrode's solution was continued in the CON group. To study the direct effect of L-NA or the combination of drugs on fluid dynamics, in each experiment, a video recording was made and flow velocity was measured in arterioles and venules from 5 minutes before until 5 minutes after the switch of superfusion. The same measurements were performed in the CON group. Per mesentery, a median number of three vessels (range 1 to 6 vessels) were punctured from about 15 minutes up to 3 hours after the start of the superfusion with L-NA (with or without D-ARG, L-ARG, or SNP) or the vehicle. Each puncture was preceded by a 4-minute period during which mean red blood cell velocity was measured. This 4-minute period, the puncture itself, and the subsequent observation period of at least 600 seconds were recorded on videotape.
Statistics
Because of their nonsymmetrical distribution, the data are
presented and displayed as medians with their interquartile
ranges unless otherwise indicated. First, differences between all five
groups were tested with the nonparametric Kruskal-Wallis
one-way analysis of variance. If a significant difference was
found, the same test was used to compare the groups within each series.
To test for a possible difference between the two series, the L-NA and
L-NA+D-ARG groups were compared. Paired data groups were compared with
the Wilcoxon signed rank test. Correlations were performed with
the nonparametric Spearman's rank correlation test
(coefficient=rs). In all tests, the
level of significance was set at 5%.
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Results |
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Effect of L-NA Alone or Combined With D-ARG, L-ARG, or SNP on the Thromboembolic Reaction in Venules and Arterioles
In all vessels, bleeding, as well as thrombus formation, started immediately after wall puncture. A thrombus started to grow within 0.1 second after puncture and reached its maximal size within 1 to 2 seconds.
Venules
The effect of L-NA on the venular embolization process is
illustrated in Fig 1. The total duration
of embolization per vessel was 50 seconds (median value) in the CON
venules and was significantly prolonged by L-NA superfusion (511
seconds; P=.0002). In accordance with this longer duration
of embolization, the number of emboli produced per venule increased
significantly (P=.002) from a median value of 2 emboli in
the CON venules to 11 emboli in the L-NA venules. As shown in Fig 1, the addition of L-ARG or SNP to L-NA completely reversed the effects of
L-NA on the duration of embolization duration and the number of emboli
produced in the venules.
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The median embolus production time per venule, as a measure of
the rate of embolus production, was not influenced by L-NA (CON
venules, 16 seconds; L-NA venules, 12 seconds). Concomitantly, the
median embolus production time was not influenced by any of the
drugs added to the L-NA superfusate (Fig 1).
No significant differences in production time of the first
embolus, thrombus height, and number of rebleedings could be detected
between groups (Table 2). The venular
bleeding period was slightly shortened by L-NA (P=.06; see
Table 2). This shortening could not be reversed by addition of L-ARG or
SNP to L-NA.
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Arterioles
Fig 2 illustrates the effect of L-NA
on arteriolar embolization. In contrast to venules, in arterioles, the
total duration of embolization per vessel was not significantly
different between the CON and L-NA groups (medians 426 and 382 seconds,
respectively). This also holds for the total number of emboli produced
per arteriole (medians 20 and 12 emboli, respectively;
P=.61). Addition of the active precursor for
endogenous NO synthesis, L-ARG, to the L-NA
superfusate also did not significantly affect embolization
duration and the number of emboli produced per vessel (all
P>.10). In contrast, addition of the exogenous NO donor SNP
slightly but significantly shortened the embolization duration (147
seconds; P=.04), but not the number of emboli produced per
arteriole. The median embolus production time was not
influenced by L-NA or any of the drug combinations (Fig 2).
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After wall puncture, the production of emboli started
significantly later in the L-NA arterioles than in the CON arterioles
(P=.02; see Table 2). This effect, however, could not be
reversed by the addition of L-ARG or SNP to L-NA. No significant
differences could be detected between the groups in any of the other
arteriolar thromboembolic parameters determined (Table 2).
Arterioles Versus Venules
Embolization was significantly different between arterioles and
venules in the CON group, the L-NA+L-ARG group, and the L-NA+SNP group:
the total duration of embolization was significantly longer (all
P<.0010) in arterioles, in which significantly more emboli
were produced (all P<.0010). In contrast, in the L-NA group
and in the L-NA+D-ARG group, the embolization parameters
were similar in venules and arterioles (all P>.33).
Fluid Dynamic Conditions
Five minutes' superfusion with L-NA or any of the drug
combinations had no significant effect on the local fluid dynamic
parameters compared with their values during superfusion
with Tyrode's solution. The fluid dynamic parameters as
measured in the vessels immediately before puncture are
presented in Table 3. Diameter,
red blood cell velocity, and reduced velocity were similar in the
venules of all groups. The same holds for diameter and red blood cell
velocity in the arterioles of all groups. Reduced velocity was similar
in the arterioles of most of the groups, but it was slightly lower in
the L-NA arterioles compared with the CON arterioles
(P=.02). In the L-NA arterioles, however, no correlation was
found between reduced velocity on the one hand and any of the
embolization parameters on the other (all
rs<.28; all P>.22).
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Whole-Animal Parameters
Data concerning the rabbits used in the five groups are shown in
Table 1. All values are within the ranges normally found in
anesthetized rabbits.19 26 30 No
significant difference in weight, hemoglobin, hematocrit,
platelets, or heart rate was found between rabbits of the different
groups. In the course of the experiment, the combination of SNP with
L-NA, however, reduced mean arterial blood pressure,
resulting in a significantly lower blood pressure in this group than in
the other groups (P<.001). In all groups, no significant
correlations were found between the whole-animal parameters
shown in Table 2 on the one hand and the embolization
parameters (see "Discussion") in arterioles and venules
on the other. These findings indicate that these whole-animal
parameters do not significantly influence the
thromboembolic reaction after wall puncture in rabbit mesenteric
microvessels.
Five minutes of superfusion with L-NA or combinations of L-NA and D-ARG, L-ARG, or SNP had no direct effect on mean arterial blood pressure and heart rate.
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Discussion |
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The findings in the present study show that inhibition of endogenous NO production with the NOS inhibitor L-NA affects the thromboembolic reaction after wall puncture differently in arterioles and venules of the rabbit mesentery. L-NA superfusion of the mesentery results in a prolongation of the period of embolization and in a concomitant increase in the number of emboli produced in venules, while it has no such effect in arterioles. These effects of L-NA on embolization in venules could be reversed by addition of either the active precursor for endogenous NO synthesis, L-ARG, or the exogenous NO donor SNP, but not by the inactive D-ARG. This finding indicates that the venular L-NA effects are the consequence of inhibition of endogenous NO production and therefore suggests that the role of endogenous NO in inhibiting thromboembolism is more important in venules than in arterioles.
The observation that NO plays a more important role in inhibiting thromboembolism in venules than in arterioles could be explained by a difference in production of NO in these microvessels. Most of the cells likely to be involved in the thromboembolic process studied are able to produce NO. Although smooth muscle cells and mast cells can produce NO through inducible NOS, these cells are less likely candidates because the upregulation of inducible NOS requires immunological stimulation with cytokines, and transcription of the enzyme takes several hours.6 Peripheral neurons may be another source of NOS, but by means of the NADPH-diaphorase technique,31 we were unable to demonstrate the presence of NOS-positive neurons in the rabbit mesentery (M.A.W.B., unpublished observations, 1997). Cells containing endothelial NOS are platelets and endothelial cells. It is unlikely that the NO released by platelets is different in arterioles and venules, because electron and light microscopy showed that the composition of the stationary thrombus, mainly tightly packed platelets, is not different in both types of microvessels (M.A.W.B., unpublished observations, 1997). Moreover, the size of the stationary thrombus was similar in arterioles and venules. Therefore, we conclude that the more important role of NO in inhibiting thromboembolism in venules than in arterioles might be explained by a difference in NO production by these microvessels. Unfortunately, at the present state of the art, it is technically impossible to assess in vivo quantitatively the amount of NO produced by endothelial cells of arterioles and venules with a diameter between 20 and 40 µm.
An alternative explanation for the observed difference in the role of NO in inhibiting thromboembolism in arterioles and venules may be the interplay of NO with other mediators involved in the thromboembolic reaction. For example, superoxide anions can inactivate NO32 and have been reported to be involved in mediating platelet aggregation in thrombosis models in arteries in vivo.33 34 Because Suzuki and colleagues (1995)35 recently showed that in rat mesentery more superoxide is generated in arterioles than in venules, it is conceivable that the less pronounced role of NO in arterioles as antithrombotic mediator is caused by its inactivation by reactive oxygen species. Prostaglandins may also interfere with NO production or its action. In some preliminary experiments (n=10), cyclooxygenase and hence prostaglandin formation was blocked completely with a high dose of aspirin, as previously described.20 In these experiments, in venules, inhibition of endogenous NO production by L-NA had an effect similar to that of L-NA without cyclooxygenase inhibition, ie, a significant increase in the duration of embolization (M.A.W.B., unpublished data, 1997). This observation further illustrates the importance of NO as an antithrombotic agent in venules, in contrast to arterioles in which prostaglandins were shown to play a significant role.20 Finally, it is conceivable that the effect of NO on the effector cells, ie, the blood platelets, differs in arterioles and venules because the intravascular milieu is not the same in both vessel types. It is unlikely, however, that differences in blood gas and pH levels are responsible for such a difference in NO sensitivity, because large changes in these parameters have practically no effect on the thromboembolic reaction in these microvessels.26
Wall shear rate is considered to be a platelet-stimulating factor in vitro36 and in damaged blood vessels in vivo.37 In vivo, however, shear forces also stimulate the production of platelet-inhibiting factors by the endothelium.38 Because no differences in any of the fluid dynamic parameters were found between the venules of the control and L-NA groups, we may conclude that the effect of L-NA on embolization in venules cannot be explained by differences in wall shear rate. In the arterioles, fluid dynamic parameters were also similar in most groups. The reduced velocity, however, was somewhat lower in the L-NA than in control arterioles, although the ranges were similar. This small difference is likely to be of minor biological importance, because in the L-NA arterioles, no correlation was found between reduced velocity on the one hand and any of the embolization parameters on the other. The finding that inhibition or stimulation of NO production has no apparent fluid dynamic consequences in rabbit mesenteric microvessels is in correspondence with our observation that local fluid dynamic conditions do not change after superfusion of the same tissue with vasodilators, such as prostacyclin or adenosine, or with vasoconstrictors, such as noradrenaline or potassium chloride (M.A.W.B., unpublished data, 1995). Apparently, the mesenteric microcirculation of the rabbit is not vasoactive.
One could argue that the superfused agents entered the lumen of the mesenteric venules better than that of the arterioles. In experiments with fluorescence microscopy, however, we were able to show that superfusion of the mesentery with the fluorescent dye acridine red results in the simultaneous appearance of fluorescence in both arterioles and venules within a few seconds (M.A.W.B., unpublished data, 1996). Because L-NA, L-ARG, D-ARG, SNP, and acridine red have similar neutral charges and molecular weights (acridine red: 274.7), the superfused drugs likely enter the lumen of arterioles and venules with little difference.
This is the first in vivo study in which the role of NO in
thromboembolism, as evoked by a mechanical trauma, is investigated in
the microcirculation of the rabbit mesentery. Differences between
arterioles and venules, as far as the importance of NO as a
platelet-inhibiting agent is concerned, have been demonstrated
earlier in only one other in vivo study. In this particular study of
Lindberg and coworkers,39 topical application of
the NOS inhibitor
N-nitro-L-arginine methyl
ester (0.2 mmol/L) enhanced photoactivation-induced thrombus
formation more in arterioles (diameter 38 to 68 µm) than in
venules (diameter 76 to 98 µm) of the rat cremaster
muscle.39 Based on these findings, the authors
postulated that after photoactivation, the arteriolar
endothelium may have a greater capacity for the
production of NO than the venular endothelium.
The discrepancy between their results and the findings in our study in
rabbit mesenteric microvessels (diameter 20 to 43 µm) may be due
to differences in the functional properties of microvessels in
different organs and/or species and/or in vessels of different
diameters. In addition, it cannot be excluded that the NOS
inhibitor used40 and/or differences
in the technique used for induction of platelet–vessel wall
interactions may explain this discrepancy. To the best of our
knowledge, there are no other studies that have investigated the
antithrombogenic role of NO in vivo, comparing either arterioles with
venules or arteries with veins. Our observation that NOS plays a more
important role in thromboembolic processes in venules than in
arterioles is supported by the observations that inhibition of NOS
induced spontaneous aggregation of platelets and leukocytes in
venules,41 42 43 but not in
arterioles.43
An interesting additional finding in the present study, which is
illustrated in Fig 3, is that NOS
inhibition with L-NA abolishes the difference in duration of
embolization between arterioles and venules, which under control
conditions is longer in arterioles (present
study).19 20 26 Hence, the more important
functional role of NO in venules compared with arterioles may explain
the difference in thromboembolic reaction normally found between the
two vessel types.
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In conclusion, the involvement of endogenous NO in inhibiting the thromboembolic reaction induced by vessel wall injury is different in rabbit mesenteric arterioles and venules, playing a more important role in this reaction in venules.
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Acknowledgments |
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This study was supported by the Netherlands Heart Foundation, grant 92.339. The authors are indebted to Sabrina van Velzen and Rinus Alewijnse for their skillful technical assistance.
Received March 3, 1997; accepted September 15, 1997.
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