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Circulation. 1995;92:2113-2118

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(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

Kiran Bhagat, BSc, MRCP; Joe Collier, MA, MD, FRCP; Patrick Vallance, BSc, MD, FRCP

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.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
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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


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
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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.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
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.


*    Results
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 up arrowIntroduction
 up arrowMethods
*Results
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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 TableDown.


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  		Table 1. Initial Vein Size, Dose of Norepinephrine Used, and Degree of Preconstriction for Each Part of the Study

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 1Down and 2Down). 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 2Down) 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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  		Figure 1. Top, Bar graph shows dose response to arachidonic acid (n=3). Each subject received three doses of arachidonic acid. Each dose was given into a preconstricted vein for 5 minutes and the maximum dilatation recorded. Incremental doses were given at 10-minute intervals. Bottom, Original trace shows arachidonic acid–induced dilatation. Vein size is recorded when the pressure in a congesting cuff placed around the upper arm (lower trace) is decreased from 40 to 0 mm Hg.



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  		Figure 2. Plot shows response to arachidonic acid (AA) infused twice in a single study (n=6). Each 5-minute infusion of arachidonic acid was separated by an interval of at least 30 minutes. Maximal dilatation occurred at about 15 minutes, and this dilatation persisted for 20 minutes.

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 3Down). 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 4Down). The time course of the inhibitory effects of oral aspirin on arachidonic acid–induced venodilatation is shown in Fig 4Down. 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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  		Figure 3. Plot shows effects of oral cyclooxygenase inhibitors on the response to arachidonic acid (AA). Three subjects received 1 g of oral aspirin (A), 6 received 75 mg (B), and 5 received 1 g of paracetamol (C). The response to arachidonic acid was determined 2 hours later. In subjects receiving high-dose aspirin, a 5-minute infusion of glyceryltrinitrate (GTN) was given at the end of the experiment. Low-dose aspirin and paracetamol did not affect the dilatation to arachidonic acid, whereas the response was abolished with 1 g of oral aspirin.



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  		Figure 4. Plot shows time course of the effects of 1 g aspirin on the response to arachidonic acid. All subjects (n=13) received 1 g of oral aspirin. For studies of dilatation ({bullet}), 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 ({blacktriangleup}) 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 (TableUp). The response to bradykinin and GTN was unaltered by oral aspirin (Fig 5Down). 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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  		Figure 5. In 5 subjects dose-response curves constructed to bradykinin (A) (2, 4, and 8 pmol/min, each dose for 5 minutes) and glyceryltrinitrate (GTN; B) (1, 2, and 4 pmol/min, each dose for 5 minutes) before (filled symbols) and 2 hours after (open symbols) oral aspirin (1 g). Oral aspirin did not affect the response to bradykinin or glyceryltrinitrate.

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 6Down). The inhibitory effect of aspirin (1 g) was still evident at 24 hours but not at 120 hours (Fig 6Down). 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 6Down). Collagen-induced platelet aggregation was not significantly affected by aspirin or paracetamol.



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  		Figure 6. Tracings of platelet aggregation before and after 75 mg aspirin: platelet response to 300 µmol/L arachidonic acid or 10 µL collagen before and 2 hours after 75 g oral aspirin. Low-dose aspirin completely abolished aggregation to arachidonic acid. Collagen-induced aggregation was not significantly affected.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
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{alpha}, 6-keto-prostaglandin F1{alpha} (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 (TableUp), 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 (TableUp) 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


*    Acknowledgments
 
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.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

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