(Circulation. 1995;92:2113-2118.)
© 1995 American Heart Association, Inc.
Articles |
Vasodilatation to Arachidonic Acid in Humans
An Insight Into Endogenous Prostanoids and Effects of Aspirin
From the Clinical Pharmacology Unit, Department of Pharmacology and Clinical Pharmacology, St George's Hospital Medical School, London, UK.
Correspondence to Dr Bhagat, Clinical Pharmacology Unit, Department of Pharmacology and Clinical Pharmacology, St George's Hospital Medical School, London SW17 ORE, UK.
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Abstract |
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Background Human endothelial and vascular smooth muscle cells synthesize prostanoids. Several of these have been implicated in the physiological and pathophysiological regulation of vascular tone; however, there is no direct evidence that human blood vessels synthesize sufficient prostanoid to alter vessel tone.
Methods and Results We explored the effects of local infusions of arachidonic acid on the tone of preconstricted superficial hand veins in healthy volunteers. Aspirin was used to assess the contribution of prostanoids to the responses seen. Local infusion of arachidonic acid produced a dose-dependent dilatation of preconstricted veins. This was abolished by local infusion of aspirin. Oral aspirin was also effective: a high (anti-inflammatory) dose of aspirin (1 g) taken 2 hours before the experiment blocked the arachidonic acid–induced venodilatation; however, a low (cardioprotective) dose of aspirin (75 mg) did not. Unlike the responses to arachidonic acid, responses to glyceryltrinitrate and bradykinin were unaltered by aspirin (1 g). Ex vivo platelet aggregation was inhibited by aspirin in both high and low doses. Aspirin (1 g) inhibited arachidonic acid–induced venodilatation for up to 5 days. The time course was similar for vascular and platelet effects.
Conclusions The present findings demonstrate that local generation of prostanoids in a human vessel in vivo alters vascular tone. The predominant prostanoid synthesized is a dilator and its synthesis can be blocked by an anti-inflammatory but not a cardioprotective dose of aspirin. The results suggest that selective inhibition of platelet aggregation by oral aspirin might be a function of dose rather than the interval between doses.
Key Words: vasodilation • aspirin
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Production of prostaglandins by vascular cells was first demonstrated over 20 years ago.1 It is now recognized that endothelial cells and smooth muscle cells have the capacity to synthesize constrictor and dilator prostanoids from the common precursor arachidonic acid. Indeed, continuous synthesis and release of prostacyclin is thought to contribute to the thromboresistant and vasodilator properties of the blood vessel wall and oppose the vasoconstrictor and prothrombotic effects of platelet-derived thromboxane.1 2 Studies in vitro and in vivo have demonstrated the capacity of human blood vessels to produce prostanoids; prostacyclin and thromboxane are synthesized by human endothelial cells in culture, and circulating metabolites of these prostanoids are found in plasma and urine.3 In healthy volunteers, prostacyclin synthesis can be stimulated further by the vasodilator bradykinin.4
Abnormalities of vascular prostanoid synthesis have been implicated in a number of pathophysiological states ranging from septic shock5 to hypertension6 and unstable angina.7 In experimental models of hypertension, a prostanoid endothelium–derived constrictor factor has been described,8 and in unstable angina and myocardial infarction, a shift in the balance of locally generated prostacyclin and thromboxane is thought to contribute to vasospasm and vessel occlusion. The potential importance of prostanoids in vascular physiology and pathophysiology is highlighted by the efficacy of aspirin; this drug irreversibly inhibits cyclooxygenase, the enzyme that converts arachidonic acid to endoperoxide9 and reduces mortality and morbidity in cardiovascular disease. When used as a prophylactic agent in patients with cardiovascular disease, aspirin is given in low doses10 and/or at long dose intervals in an attempt to inhibit thromboxane production in platelets while sparing the synthesis of prostacyclin in endothelial cells.3
Despite these observations, there is no direct evidence in vivo for the production from arachidonic acid of vasoactive amounts of prostanoids in human blood vessel under resting conditions. Indeed, aspirin or other inhibitors of cyclooxygenase appear to produce constriction in the renal vascular bed but not elsewhere, suggesting that basal release of prostanoids does not contribute significantly to resting vascular tone. However, the supply of endogenous arachidonic acid is rate limiting for prostanoid synthesis in many cell types,1 and addition of exogenous arachidonic acid has been shown to produce constriction or dilatation of isolated blood vessels from animals.8 11 12 13 14 In the present study we have explored the effects of local infusions of arachidonic acid on the tone of single superficial dorsal hand veins in vivo in an attempt to determine whether there is a prostanoid pathway in human vessels in vivo that is capable of altering vascular tone and that is rate limited by availability of substrate. We used cyclooxygenase inhibitors to determine the contribution of prostanoids to the responses seen and developed the experimental system to study directly the dose response and time course of the vascular effects of aspirin.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Studies were approved by the local ethics committee and were performed on male (n=15) and female (n=6) subjects aged 19 to 38 years. Subjects were included who stated that they were healthy and on no medication and who gave their written informed consent. Subjects lay supine in a temperature-controlled laboratory (28°C to 29°C) with one hand placed on an angled support above the level of the heart. A congesting cuff was placed around the upper arm and inflated to 40 mm Hg. Drugs or physiological saline (0.9%) were infused continuously (0.25 mL/min) through a 23-gauge "butterfly" needle placed in a dorsal hand vein. The diameter of the infused vein was measured 5 to 10 mm downstream from the tip of the infusion needle by recording the linear diplacement of a lightweight probe placed on the skin overlying the summit of the vessel when the pressure in the congesting cuff was lowered from 40 to 0 mm Hg.15 16 In all studies, saline was infused for at least 15 minutes until a stable baseline vein diameter was recorded. Provided subjects are comfortably warm and relaxed, dorsal hand veins have no intrinsic tone,16 and in order to observe dilator responses, it is necessary to preconstrict the vessel. In this study (unless stated othewise), after baseline recordings of stable vein size had been made, veins were preconstricted to between 30% and 50% of resting diameter by a continuous infusion of norepinephrine (20 to 160 pmol/min) for the remainder of the study. Study drugs were coinfused with norepinephrine. Measurements of vein size were made every 5 minutes.
Effects of Arachidonic Acid: Dose Response,
Reproducibility, and Effects of Local Aspirin
In 3 subjects, three
doses of arachidonic acid
(200 pmol/min, 2 nmol/min, and 20 nmol/min, each dose for 5 minutes)
were infused into a preconstricted vein. Dose increments were made at
10-minute intervals. To determine the reproducibility of the response
within a single experiment, 6 subjects were given two infusions of
arachidonic acid (20 nmol/min for 5 minutes) 30 to 45
minutes apart and when a stable norepinephrine constriction
was reestablished. In a separate study in the same 6 volunteers,
arachidonic acid (20 nmol/min for 5 minutes) was
infused into a preconstricted vein before and after local infusion of
aspirin (18 µmol/min for 30 minutes). The effects of
arachidonic acid (20 nmol/min for 5 minutes) on
unconstricted veins (n=3) and arachidonic acid vehicle
on preconstricted vessels (n=3) also were determined.
Effects, Dose Response, and Time Course of Oral Aspirin and
Paracetamol
Subjects were given soluble aspirin (75 mg, n=6, or
1 g, n=3) or
paracetamol (1 g, n=5), and the response to arachidonic
acid (20 nmol/min) was determined 2 hours later. In the subjects taking
1 g aspirin, glyceryltrinitrate (GTN; 20 pmol/min) was infused for 5
minutes at the end of the study to determine whether the preconstricted
vein would relax to an agent that does not utilize the prostanoid
pathway. In a further study, 10 subjects were given high-dose
aspirin (1 g). In 5, the response to arachidonic acid
was determined at 0 (predose), 2, 6, and 24 hours and in 5 at 0
(predose), 2, and 120 hours after aspirin. Response was determined as
the maximal change in vein diameter within 15 minutes of starting the
infusion of arachidonic acid. The effects of oral
aspirin (1 g) on the venodilator drugs bradykinin and GTN also were
studied. In 5 subjects, dose-response curves were constructed to
bradykinin (2, 4, and 8 pmol/min; each dose for 5 minutes) and GTN (1,
2, and 4 pmol/min; each dose for 5 minutes) before and 2 hours after
oral aspirin (1 g).
Platelet Studies
Blood was drawn for platelet aggregometry
from subjects
taking part in the studies of oral aspirin (75 mg, n=5; 1 g,
n=13) or
paracetamol therapy (1 g, n=5). Immediately before taking the drug and
2.5 hours later, 15 mL of venous blood was drawn into a syringe
containing 2.5 mL of 3.15% (wt/vol) trisodium citrate. Blood was
centrifuged at 200g for 20 minutes to obtain
platelet-rich plasma. One-milliliter aliquots of
platelet-rich plasma were placed in cuvettes, and the responses
to 10 µL of collagen and 300 µmol/L arachidonic
acid were determined using a dual-channel optical aggregometer
(Chronolog Corp). One milliliter of platelet-rich plasma was
placed in an Eppendorf microtube and centrifuged at
1300g for 5 minutes to produce a supernatant of
platelet-poor plasma, which was used as a control. The maximal
extent of aggregation was used for data analysis, and results
after drug administration were compared with control (predrug) values.
The predrug aggregatory response was taken as 100%.
Drugs
Sodium arachidonate (5 mg per vial) stored under
nitrogen was obtained from Sigma. Vials were stored at -20°C, and a
single vial was used for each study. Sodium arachidonate (5
mg) was dissolved in 154 µL absolute alcohol to produce a stock
solution of 1 mmol/L. Subsequent dilution was in saline, and the final
concentration of alcohol in the infusate was 0.0001%.
Arachidonic acid was always used within 6 hours of
preparation. Lysine acetylsalicylate (1 g per vial) was obtained from
Synthe Labo; paracetamol (500 mg) and norepinephrine (2 mg
per vial) from Sanofi Winthrop; dispersible aspirin from Aspar
Pharmaceuticals Ltd; GTN (5 mg per vial) from Dupont Pharma; bradykinin
(50 µg per vial) from Clinalfa AG; ascorbic acid (100 mg/mL) from
Evans Medical Ltd; and collagen reagent from Chrono-Log. Ascorbic acid
0.5 mL was added to norepinephrine stock solutions to
prevent auto-oxidation. All drugs were prepared fresh on the day of
the experiment and dissolved in sterile
physiological saline solution.
Calculations and Statistics
Changes in vein size were
measured in arbitrary units and
converted to millimeters after calibration of the transducer at the end
of each experiment. The response of the resting vein to drugs is
expressed as a reduction in diameter from that measured during infusion
of saline alone. The response of the
norepinephrine-preconstricted vein to drugs is
expressed as percentage reversal of the induced constriction. Results
are compared using the Student's t test for paired data or
ANOVA of the means as appropriate; P<.05 is considered
statistically significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Local infusion of arachidonic acid caused no adverse or systemic effects, and subjects did not report any discomfort. In 7 subjects, after the infusion of arachidonic acid, a flare appeared on the skin overlying the vein, and this persisted for up to 20 minutes. The internal diameters of veins and the degree of preconstriction for each part of the study are shown in the Table
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Effects of Arachidonic Acid: Dose Response
and Reproducibility
In the initial studies in 3 subjects, local
infusion of
arachidonic acid produced a dose-dependent
venodilatation such that 200 pmol/min, 2 nmol/min, and 20 nmol/min
(each dose for 5 minutes) resulted in dilatation of 27±3%,
42±3%,
and 87±10%, respectively. The lower two doses of
arachidonic acid produced transient dilatations
(lasting less than 10 minutes), whereas the duration of dilatation in
response to the highest dose was in the order of 15 to 25 minutes (Figs
1 and 2). For all subsequent studies, the
highest dose of arachidonic acid was used.
Arachidonic acid (20 nmol/min for 5 minutes) produced
identical responses when infused twice in a single experiment separated
by 30 minutes (Fig 2) with no evidence of tachyphylaxis
(n=6). The
maximum dilatation after the first infusion was 62±11% and after the
second was 56±7%.
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Five subjects participated in more than one part of the study, and the response in these individuals gives an indication of the reproducibility of the response to arachidonic acid in a single subject on different days; each subject responded to arachidonic acid on every occasion (mean dilatation, 77±4%; coefficient of variation ±20%; 5 subjects each studied on 3 occasions). However, the time of onset of dilatation to arachidonic acid and the time to reach maximal response varied between individuals and between days (maximal dilatation range, 68 to 84±11%; time to reach maximal response range, 5 to 15 minutes). Infusion of arachidonic acid vehicle (0.001% alcohol vol/vol) had no effect on a preconstricted vein. Infusion of arachidonic acid (20 nmol/min) for 5 minutes into a resting, unconstricted vein produced no change in venous diameter.
Effect of Local Aspirin
Aspirin (18 µmol/min) infused
directly into the study vein for
30 minutes before the arachidonic acid abolished the
dilator response (maximum dilatation before aspirin was 62±11% and
after aspirin 0.5±20%; n=6; P<.05). Assuming a flow
in
the vein of 0.5 to 1 mL/min, this dose of aspirin gives a local
concentration in the order of 18 to 36 mmol/L.
Effects, Dose Response, and Time Course of Oral Aspirin and
Paracetamol
Aspirin (75 mg) or paracetamol (1 g) had no effect on
arachidonic acid–induced venodilatation (82±11%,
n=6, and 83±11%, n=5, dilatation, respectively; Fig
3). In contrast, oral administration of aspirin (1 g)
taken 2 hours before the study inhibited arachidonic
acid–induced venodilatation (3.6±2% dilatation, n=3),
although
GTN still produced venodilatation (83±8% dilatation, n=3). This
result in 3 subjects was repeated in a further 10 subjects (Fig
4). The time course of the inhibitory
effects of oral aspirin on arachidonic
acid–induced venodilatation is shown in Fig 4. Oral
aspirin
(1 g) inhibited arachidonic acid–induced
venodilatation at 2, 6, and 24 hours (14±4%, 15±3%, and
30±7%
dilatation, respectively). However, 5 days after aspirin, the dilator
response to arachidonic acid had returned to 74±11%
of the control dilatation (NS).
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), all 13 subjects were studied at 2 hours. Five were also
studied at 6, 24, and 120 hours. At 6 and 24 hours, there was still a
significant (P<.05) degree of inhibition to
arachidonic acid–induced venodilatation, but by
120 hours the response had returned to 74±11% of the control value
(NS). Platelet aggregation studies (
) showed a similar time
course of recovery, reaching the control value at 120 hours.
Effects of Oral Aspirin on the Response to GTN and
Bradykinin
Oral aspirin (1 g) did not alter the constrictor response
to norepinephrine (Table
). The response to bradykinin and
GTN was unaltered by oral aspirin (Fig 5). The
dilatation to bradykinin 2, 4, and 8 pmol/min was 34±5%, 45±6%,
and
65±13% before aspirin and 38±2%, 60±7%, and 73±5%
2 hours after
oral aspirin. The dilatation to GTN 1, 2, and 4 pmol/min was 44±13%,
80±6%, and 92±6% before aspirin and 34±65%, 65±8%,
and 88±6%
2 hours after oral aspirin.
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Platelet Studies
Arachidonic acid–induced platelet
aggregation was inhibited by low- (n=6) and high-dose aspirin
(n=13) but not by paracetamol (n=5) (Fig 6). The
inhibitory effect of aspirin (1 g) was still evident at 24
hours but not at 120 hours (Fig 6). The time course of the
effect of
aspirin on arachidonic acid–induced platelet
aggregation was similar to the time course of the effect of aspirin on
arachidonic acid–induced venodilatation (Fig 6).
Collagen-induced platelet aggregation was not significantly
affected by aspirin or paracetamol.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The results of this study demonstrate that locally infused arachidonic acid causes dilatation of preconstricted human veins in vivo. The response was dose dependent, reproducible, and inhibited by the cyclooxygenase inhibitor aspirin. Together, these findings suggest that provision of substrate is rate limiting for prostanoid synthesis in vivo and that dilator prostanoids predominate, at least in these vessels. Using local infusions of arachidonic acid, it was also possible to explore the effects and time course of drugs on functional effects of endogenous prostanoids.
Arachidonic acid infused directly in a single blood-perfused preconstricted dorsal hand vein caused dose-dependent vasodilatation; there was no evidence of a constrictor response in preconstricted or unconstricted veins, and the vehicle alone had no effect. Assuming a blood flow in the vein of 0.5 to 1 mL/min,16 the dilatation occurred over the concentration range of 200 nmol/L to 20 µmol/L, with near-maximal dilatation occurring in response to 20 µmol/L arachidonic acid. This concentration range is an order of magnitude lower than that required to stimulate platelet aggregation (200 to 500 µmol/L).17 Dose-dependent dilatation to arachidonic acid over the concentration range 100 nmol/L to 600 µmol/L has been reported in animal blood vessels including cerebral arteries of the dog12 and cat,13 coronary artery of the pig,18 and rat aorta.19 20 However, constriction of certain vessels also has been reported; arachidonic acid contracts rabbit pulmonary artery21 and the aorta of hypertensive but not normotensive rats.22 23 The reasons for the differences in response between vessels, between species, and between health and disease22 are not known but might be due to differences in distribution of specific prostaglandin synthetases.14 23 It is also important to note that the effects of exogenously administered arachidonic acid are not necessarily the same as those produced by endogenous arachidonic acid liberated by the action of phopholipase A2.
In preconstricted hand veins, arachidonic
acid–induced vasodilatation was inhibited by local or systemically
administered (high-dose) aspirin, suggesting that prostanoids were
responsible. Similar results have been found in some studies in
animals,19 20 24 but it is also clear
that
arachidonic acid can produce prostanoid-independent
effects in certain vessels including pig coronary
artery.18 We cannot determine which prostanoid is
responsible for the dilatation of human hand veins, but it has been
shown previously that these vessels dilate in response to prostacyclin
and prostaglandin A2,
B1, and E226 ; furthermore,
with the use of radiolabeled arachidonic acid,
synthesis of prostaglandin D2,
E2, F2
,
6-keto-prostaglandin F1 (a stable
metabolite of prostacyclin), and
13,14-dihydro-15-keto-prostaglandin E2 (a
stable metabolite of prostaglandin E2) has been
demonstrated in the forearm vascular bed.27 Thus, it seems
probable that prostaglandin E2 and
D2 or prostacyclin account for the changes we observed. It
is unlikely that aspirin produced a nonspecific effect on dilatation,
since oral aspirin (1 g) did not affect the dilator response to GTN (a
nitric oxide donor) or bradykinin (an
endothelium-dependent dilator that acts largely
through the L-arginine:nitric oxide pathway in these
vessels).26
The demonstration of aspirin-inhibitable vasodilatation in humans
in vivo provides direct evidence for a possible role for prostanoids in
the regulation of vascular tone. Indeed, the degree of dilatation seen
was large and if reproduced systemically would cause profound changes
in hemodynamics. However, oral aspirin in doses
sufficient to inhibit arachidonic acid–induced
vasodilatation (1 g) did not alter resting vascular tone or the
constrictor response to norepinephrine (Table), and this
argues against basal release of vasoactive amounts of prostanoids, at
least in the hand veins. The reason for the decrease in constrictor
response to norepinephrine produced by local infusion of
aspirin (Table) is not clear, but the calculated concentrations
achieved in the vein in this part of the study were high, and in the
millimolar range, aspirin acetylates various plasma proteins,
enzymes, and DNA,28 and this might produce nonspecific
effects on the response to constrictors.
The dilatation to arachidonic acid was used to explore the time course and dose-dependent effects of aspirin. A systemic anti-inflammatory dose of aspirin (1 g) abolished the dilatation, whereas a cardioprotective dose (75 mg) was without effect. Paracetamol, a drug reported to inhibit cyclooxygenase in the central nervous system but not in the periphery,29 also was without effect. Despite the different effects of the two doses of aspirin on vascular responses, arachidonic acid–induced platelet aggregation was blocked by aspirin 75 mg and 1 g. This pattern of responses is consistent with a selective antiplatelet effect of low-dose aspirin (75 mg) even within 2 hours of administration.
High-dose aspirin (1 g) produced a long-lasting inhibition of venodilatation, and the time course of this effect was similar to the inhibitory action of the drug on platelet aggregation. This finding is in marked contrast to the results of certain studies of the time course of aspirin as assessed using biochemical measures of prostanoid production, which indicate that circulating metabolites of prostacyclin reappear in the circulation within 6 hours after oral dosing, whereas metabolites of thromboxane remain suppressed for 36 hours or longer.3 4 30 31 The reasons for this apparent discrepancy are not known but might indicate that the dilatation we have seen was due to prostanoids other than prostacyclin. Alternatively, it may be that the biochemical studies differ because they detect prostacyclin synthesis from many different vessels and nonvascular sources. Indeed, in biochemical studies, systemic infusions of bradykinin have been used to stimulate prostacyclin, yet the dilatation to bradykinin in the hand veins and certain other vascular beds in humans appears to be mediated largely through nitric oxide and other nonprostanoid pathways.4 26 Consistent with the results of our functional study is the observation that prostanoid production is inhibited in human saphenous vein examined ex vivo for up to 36 hours after oral aspirin therapy.33 Furthermore, smooth muscle cyclooxygenase remains inhibited for at least 24 hours after aspirin,34 and it is possible that the venodilator prostanoid produced in response to arachidonic acid arises from the smooth muscle cells rather than endothelium.
Whatever the mechanism, the results of acute administration of oral aspirin to healthy volunteers suggest that the selectivity of aspirin for platelets rather than blood vessels (at least in terms of dilatation) resides in the dose given rather than interval of dosing; low-dose aspirin preferentially inhibits platelet thromboxane while sparing the synthesis of dilator prostanoids in the vessel wall. It will now be important to determine whether chronic oral dosing with low-dose aspirin also spares vascular prostanoid synthesis. Our results do not preclude the possibility that antiaggregatory prostanoids derived from the vascular endothelium are influenced more by timing of dose than dose itself, but dilator prostanoids are also antiaggregatory,1 and the ability of the vessel to dilate to arachidonic acid after low-dose aspirin suggests that it would also retain certain antiaggregatory properties.
The demonstration that arachidonic acid produces aspirin-inhibitable vasodilatation in humans provides direct evidence for functional effects of locally generated prostanoids in the vessel wall. The relative simplicity and safety of the experimental system and the reproducibility of the response to arachidonic acid suggest that it may be possible to use this system to explore the role of locally generated prostanoids in disease states such as hypertension,6 35 diabetes,36 37 and liver disease,38 where endothelium-derived prostanoids have been implicated, or in conditions of chronic inflammation when the inducible isoform of cyclooxygenase is expressed.39
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Acknowledgments |
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Dr Bhagat is a recipient of a British Heart Foundation Junior Fellowship.
Received February 27, 1995; revision received April 3, 1995; accepted May 22, 1995.
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