Infusion Of Arachidonic Acid Research Articles

Possible involvement of prostaglandins in vasoconstriction induced by zymosan and arachidonic acid in the perfused rat liver

Exposure of perfused livers to zymosan, arachidonic acid or phenylephrine but not to latex particles, stimulates hepatic constriction. The effects of arachidonic acid are rapid, reach a maximum after 2–3 min and then decline. They are blocked by the cyclooxygenase inhibitor indomethacin but not by the lipoxygenase inhibitor nordihydroguaiaretic acid. This suggests a role for prostaglandins in this action. Zymosan progressively increases hepatic pressure after a lag time of about 1 min. Perfusion of bromophenacyl bromide, indomethacin and nordihydroguaiaretic acid only partially inhibits the zymosan-induced vasoconstriction. None of these inhibitors affect the phenylephrine-induced response. Repeated infusion of arachidonic acid leads to homologous desensitization of the response whereas the response of the liver to phenylephrine is unaffected. The present data indicate that prostaglandins, produced and released within the liver, affect vasoconstriction in this organ.

Regulation of microvascular prostacyclin and thromboxane with inhibitors or arachidonic acid metabolism

The levels of the stable degradation products of prostacyclin (PGI 2) and thromboxane A 2 (TXA 2): 6-oxo-prostaglandin F 1α(6-oxo-PGE 1α) and thromboxane B 2 (TXB 2) respectively were determined in the effluent of the rabbit epigastric skin flap after infusion of exogenous arachidonic acid. The blood to the flap passes through the microcirculation and thus the changes in eicosanoid biosynthesis in this part of the vasculature were recorded. The aim was to use inhibitors of arachidonic acid metabolism to increase the PGI 2/TXA 2 ratio. This may be potentially beneficial to ischaemic skin flaps by reducing platelet aggregation associated with damaged microvascular endothelium, overcoming vasospasm and increasing microvascular blood flow. Increased PGI 2/TXA 2 ratios (up to 5-fold) were best achieved using TXA 2 synthetase inhibitors such as dazoxiben hydrochloride. These were significantly more potent than the phosphodiesterase inhibitor dipyridamole, and the lipoxygenase inhibitor Bay g6575. No increase in blood flow was achieved. The cyclooxygenase inhibitor indomethacin did slow the blood flow at high concentrations (above 10 −5 M), and inhibited both PGI 2 and TXA 2 synthesis. Approximately 2-fold higher concentrations of dazoxiben hydrochloride and dipyridamole were required to produce the same TXA 2 synthetase inhibition in the flap microvasculature in vivo compared with platelets in vitro .

Pressor responses to arachidonic acid in pump-perfused sheep lungs

The reported actions of arachidonic acid in the adult pulmonary circulation are controversial. Some authors reported that arachidonic acid causes only pulmonary vasoconstriction; others have found decreases in pulmonary vascular resistance with low-dose infusions. We have previously reported that arachidonic acid causes only pulmonary vasoconstriction in perinatal lambs during both normoxia and hypoxia. The effects of arachidonic acid on pulmonary vascular resistance were determined in adult sheep using an in situ pump-perfused left lower lung preparation. Arachidonic acid infusions (10.5–31.9 μg/kg·min) resulted in pulmonary vasoconstriction. The pulmonary vascular response to arachidonic acid was not altered by hypoxia or by infusion of PGF 2α. However, the pulmonary pressor response to hypoxia was increased by concomitant arachidonate infusions. Infusions of arachidonic acid during hypoxia resulted in systemic hypotension. Thus, pulmonary arachidonate metabolism appears to be unaffected by hypoxia or PGF 2α; however, hypoxia may enhance the formation of dilator PG's from the lung.

Attenuated cardiovascular effects of prostaglandin I2 and prostaglandin F2 alpha in cold acclimated American bullfrogs, Rana catesbeiana.

American bullfrogs, Rana catesbeiana respond to prostaglandins with changes in heart rate and blood pressure. These studies compare responses of warm (22 degrees C) and cold acclimated (5 degrees C) bullfrogs to prostaglandins. Gas chromatographic analysis determined equivalent fatty acid profiles in total lipids of heart and artery tissue from warm and cold acclimated animals. Arachidonic acid was the fatty acid precursor found in greatest abundance in both groups. For cardiovascular experiments, bullfrogs were cannulated by using a T-cannula implanted in the right sciatic artery. In warm acclimated bullfrogs, preinfusion systemic arterial pressure (SAP) was 14.7 +/- 0.5 mm Hg, and heart rate was 33.0 +/- 1.7 beats/min. Cold acclimated bullfrogs had SAP values of 8.0 +/- 0.8 mm Hg, and heart rate was 6.9 +/- 0.3 beats/min. Arachidonic and eicosapentaenoic acid infusions (2,000 micrograms/kg body weight [bw]) were hypertensive in cold acclimated and hypotensive in warm acclimated animals. These effects were blocked by indomethacin (4 mg/kg bw). In both warm and cold acclimated bullfrogs, prostaglandin F2 alpha (3-100 micrograms/kg bw) was hypertensive, while prostaglandin I2 (0.03-3 micrograms/kg bw) was hypotensive, with both prostaglandins stimulating a greater absolute response in warm acclimated animals. In addition, both prostaglandins increased heart rate in warm but not in cold acclimated bullfrogs. The results suggest diminished cardiovascular sensitivity to prostaglandins at low environmental temperatures.

Production of eicosanoids by deendothelialized rabbit aorta: interaction between platelets and vascular wall in the synthesis of prostacyclin

Production of eicosanoids by deendothelialized aorta in response to continuous infusions of arachidonic acid and platelet suspensions was determined in a rabbit aorta perfusion model. 6-keto-PGF 1α production was stimulated by AA infusion in a dose-related manner. Infusion of AA at 4 μ/ml/min led to an initial production rate of 0.64±0.29 ng/min which gradually increased to 0.93±0. ll ng/min at the 20th min of infusion. When the concentration of AA infusion was increased to 10 μg/ml/min, 6-keto-PGF 1α production increased to 1.14±0.86 ng/min initially but declined with time. PGE 2 production in response to AA 10 μg/min/ml was steady at around 5 ng/min while PGF 2α and TXB 2 production were only slightly above the control Perifusion of rabbit washed platelet suspensions at a rate of 3X10 8 plt/ml/min raised 6KPGF 1α production. The production was further increased when platelets were pretreated with 1-benzylimidazole (5 mM), along with a concurrent reduction in TXB 2 release. Pre-treatment of platelets with aspirin, on the other hand, abolished the increase in 6KPGF 1α production. Our data indicated that the vascular smooth muscle cells can efficiently utilize PGH 2 produced by platelets to synthesize PGI 2.

PGI2 synthesis and excretion in dog kidney: evidence for renal PG compartmentalization.

To assess the concept of compartmentalization of renal prostaglandins (PG), we compared entry of PGE2 and the PGI2 metabolite 6-keto-PGF1 alpha into the renal vascular and tubular compartments, in sodium pentobarbital-anesthetized dogs. Renal arterial 6-keto-PGF1 alpha infusion increased both renal venous and urinary 6-keto-PGF1 alpha outflow. In contrast, renal arterial infusion of arachidonic acid (AA) or bradykinin (BK) increased renal venous 6-keto-PGF1 alpha outflow but had no effect on its urinary outflow. Both urinary and renal venous PGE2 outflows increased during AA or BK infusion. Ureteral stopped-flow studies revealed no postglomerular 6-keto-PGF1 alpha entry into tubular fluid. During renal arterial infusion of [3H]PGI2 and inulin, first-pass 3H clearance was 40% of inulin clearance; 35% of urinary 3H was 6-keto-PGF1 alpha, and two other urinary metabolites were found. During renal arterial infusion of [3H]6-keto-PGF1 alpha and inulin, first-pass 3H clearance was 150% of inulin clearance; 75% of urinary 3H was 6-keto-PGF1 alpha, and only one other metabolite was found. We conclude that in the dog PGE2 synthesized in the kidney enters directly into both the renal vascular and tubular compartments, but 6-keto-PGF1 alpha of renal origin enters directly into only the renal vascular compartment.

Stimulation of ovine placental lactogen secretion by arachidonic acid

To determine whether arachidonic acid stimulates the secretion of ovine placental lactogen (oPL), arachidonic acid was infused as an intravenous bolus into pregnant ewes and fetuses. Plasma oPL concentrations were determined in mothers and fetuses before and for 5 h after infusion. The administration of 12.5 mg arachidonic acid (0.15-0.2 mg/kg, n = 11 experiments) to the pregnant ewes caused an increase in maternal plasma oPL concentrations of 73.9 +/- 15.6% (S.E.M.) and 60.8 +/- 18.1% above the pretreatment concentrations at 4 and 5 h respectively (P less than 0.01 in each instance). The infusion of 25 mg arachidonic acid (n = 8) caused increases of 96.0 +/- 19.1% and 100.3 +/- 26.4% (P less than 0.005), and the stimulation was not inhibited by the cyclo-oxygenase inhibitors indomethacin and ibuprofen. In contrast to arachidonic acid, vehicle alone or palmitic acid had no effects on plasma oPL concentrations. Despite the increase in maternal plasma oPL concentrations, plasma oPL concentrations in the fetus remained unchanged after the maternal infusions. The infusion of arachidonic acid (0.5-1.5 mg/kg) directly into six fetuses had no effects on either fetal or maternal oPL concentrations. These studies indicate that arachidonic acid stimulates maternal plasma oPL concentrations but has no effect on fetal oPL concentrations and the stimulation of oPL secretion is not due to the conversion of arachidonic acid to prostaglandins or other cyclo-oxygenase products.

Intrarenal prostaglandin release: Effects of arachidonic acid and hyperchloremia

We measured the release of PGE2, 6kPGF1 alpha, PGF2 alpha, and TXB2 into urine (U) and renal hilar lymph (L) to assess the possible roles of intrarenal prostaglandins (PGs) in arachidonic acid (AA)-induced renal vasodilation and Cl-induced renal vasoconstriction, (a model of tubuloglomerular feedback, TG). AA caused an ipsilateral fall in renal vascular resistance (RVR) and diuresis and increased release of all PGs into U; release of 6kPGF1 alpha into L increased ninefold. Hypertonic NaCl infusion caused ipsilateral vasoconstriction and decreased GFR; the release of TXB2 into U and L increased, but other PGs were not altered consistently. During a background infusion of AA, hypertonic NaCl infusion again evoked TXB2 release into U and L without significant changes in other PGs. AA attenuated the NaCl-induced renal vasoconstriction in dogs with the highest rates of PGE2 release into L. Changes in RVR correlated with the ratio of excretion of vasodilator PG (PGE2 + 6kPGF1 alpha) to TXB2 (r = -0.74). Indomethacin administration blunted, but did not abolish, the Cl-induced increase in RVR. In conclusion, (1) AA evokes the release of PGs, especially prostacyclin, into renal cortex; (2) hypercholoremia increases RVR and evokes a rather selective release of renal TX; (3) the production of vasodilator PGs by AA may attenuate Cl-induced renal vasoconstriction; (4) renal vasodilator and vasoconstrictor PGs can be released relatively independently--their balance could modulate RVR during activation of the TG response.

Nafazatrom (Bay G 6575) blunts canine hypoxic pulmonary vasoconstriction: Evidence for a prostaglandin-mediated mechanism

The eicosanoids are circulating vasoactive substances which may serve as modulators of pulmonary vasomotor tone. Nafazatrom (Bay g 6575) has been reported to raise circulating levels of prostaglandin I 2 (PGI 2) either by stimulating its synthesis or inhibiting its metabolism, and may also decrease leukotriene synthesis by inhibiting lipoxygenase. We evaluated the hemodynamic effects of nafazatrom administered intravenously in doses of 2,5, and 10 mg/kg in intact, anesthetized dogs ventilated with 21% and 10% oxygen. The hypoxia-induced increase in pulmonary vascular resistance was blunted by nafazatrom in an inverse dose-dependent fashion. Pretreatment with the cyclooxygenase inhibitor indomethacin (5 mg/kg subcutaneously twice daily for two days) abolished the response to low-dose nafazatrom. The pulmonary vasodilator response to the infusion of arachidonic acid (100 μg/kg/min) during hypoxic ventilation was blocked by the 10 mg/kg dose of nafazatrom. We conclude that nafazatrom blunts hypoxic pulmonary vasoconstriction in a manner consistent with a drug-induced increase in PGI2 activity, and that the inverse dose-dependent effects of the drug which we observed are due to an inhibition of cyclooxygenase at higher doses.

Reversal of reflex pulmonary vasoconstriction induced by main pulmonary arterial distension

Distension of the main pulmonary artery (MPA) induces pulmonary hypertension, most probably by neurogenic reflex pulmonary vasoconstriction, although constriction of the pulmonary vessels has not actually been demonstrated. In previous studies in dogs with increased pulmonary vascular resistance produced by airway hypoxia, exogenous arachidonic acid has led to the production of pulmonary vasodilator prostaglandins. Hence, in the present study, we investigated the effect of arachidonic acid in seven intact anesthetized dogs after pulmonary vascular resistance was increased by MPA distention. After steady-state pulmonary hypertension was established, arachidonic acid (1.0 mg/min) was infused into the right ventricle for 16 min; 15-20 min later a 16-mg bolus of arachidonic acid was injected. MPA distension was maintained throughout the study. Although the infusion of arachidonic acid significantly lowered the elevated pulmonary vascular resistance induced by MPA distension, the pulmonary vascular resistance returned to control levels only after the bolus injection of arachidonic acid. Notably, the bolus injection caused a biphasic response which first increased the pulmonary vascular resistance transiently before lowering it to control levels. In dogs with resting levels of pulmonary vascular resistance, administration of arachidonic acid in the same manner did not alter the pulmonary vascular resistance. It is concluded that MPA distension does indeed cause reflex pulmonary vasoconstriction which can be reversed by vasodilator metabolites of arachidonic acid. Even though this reflex may help maintain high pulmonary vascular resistance in the fetus, its function in the adult is obscure.

Thromboxane synthase inhibition and perinatal pulmonary response to arachidonic acid.

Arachidonic acid causes dose-dependent increases in pulmonary vascular resistance in perinatal lambs. The specific metabolites that produce this effect are not known; however, a role for thromboxanes (TX's), potent constrictors of vascular smooth muscle, has been proposed. The effects of a specific inhibitor of TX synthase, OKY-1581, were tested in newborn and ventilated fetal lambs using an in situ pump-perfused lower left lobe preparation. Pulmonary and systemic responses of newborns and ventilated fetuses to infusions of arachidonic acid were evaluated in the presence and absence of OKY-1581. Increases in pulmonary vascular resistance caused by arachidonic acid were diminished by TX synthase inhibition. The degree of systemic hypotension observed with arachidonic acid infusions was significantly greater in animals receiving OKY-1581 than in animals without the inhibitor. The effect of OKY-1581 on periods of hypoxia was also evaluated in newborn lambs. There were no significant differences in the hypoxic pressor response in lambs with and without TX synthase inhibition. These results suggest that OKY-1581 can reduce most of the pulmonary vasoconstriction produced by arachidonic acid in perinatal lambs.

Effects of arachidonate on permeability and resistance distribution in canine lungs

In this study, 14 canine lung lobes were isolated and perfused with autologous blood at constant pressure (CP) or constant flow (CF). Pulmonary capillary pressure (Pc) was measured via venous occlusion or simultaneous arterial and venous occlusions. Arterial and venous pressures and blood flow were measured concurrently so that total pulmonary vascular resistance (RT) as well as pre- (Ra) and post- (Rv) capillary resistances could be calculated. In both CP and CF perfused lobes, 5-min arachidonic acid (AA) infusions (0.085 +/- 0.005 to 2.80 +/- 0.16 mg X min-1 X 100 g lung-1) increased RT, Rv, and Pc (P less than 0.05 at the highest dose), while Ra was not significantly altered and Ra/Rv fell (P less than 0.05 at the highest AA dose). In five CP-perfused lobes, the effect of AA infusion on the pulmonary capillary filtration coefficient (Kf,C) was also determined. Neither low-dose AA (0.167 +/- 0.033 mg X min-1 X 100 g-1) nor high-dose AA (1.35 +/- 0.39 mg X min-1 X 100 g-1) altered Kf,C from control values (0.19 +/- 0.02 ml X min-1 X cmH2O-1 X 100 g-1). The hemodynamic response to AA was attenuated by prior administration of indomethacin (n = 2). We conclude that AA infusion in blood-perfused canine lung lobes increased RT and Pc by increasing Rv and that microvascular permeability is unaltered by AA infusion.

Thromboxane-induced pulmonary vasoconstriction: involvement of calcium.

Infusion of tert-butyl hydroperoxide (t-bu-OOH) or arachidonic acid into rabbit pulmonary arteries stimulated thromboxane B2 (TxB2) production and caused pulmonary vasoconstriction. Both phenomena were blocked by cyclooxygenase inhibitors or a thromboxane synthase inhibitor. The increase in pulmonary arterial pressure caused by either t-bu-OOH or arachidonic acid infusion correlated with the concentration of TxB2 in the effluent perfusate. The concentration of TxB2 in the effluent perfusate, however, was always 10-fold greater after arachidonic acid infusion. In the rabbit pulmonary vascular bed lipoxygenase products did not appear involved in the vasoactive response to t-bu-OOH or exogenous arachidonic acid infusion. Calcium entry blockers or a calcium-free perfusate prevented the thromboxane-induced pulmonary vasoconstriction. Calmodulin inhibitors also blocked the pulmonary vasoconstriction induced by t-bu-OOH without affecting the production of TxB2 or prostacyclin. These results suggest that thromboxane causes pulmonary vasoconstriction by increasing cytosol calcium concentration.

Renal venous and urinary PGE2 output during intrarenal arachidonic acid infusion in dogs.

Inferences about total renal (venous and urinary) PGE2 output from determinations of urinary excretion rates (U PGE2 V) cannot be made unless the distribution of PGE2 between renal venous plasma and urine is known. Therefore, in the present study on intact kidneys of anesthetized dogs both urinary excretion of PGE2 and the renal venous output (the product of plasma flow and venous concentration of PGE2) was determined during low and high rates of renal PGE2 synthesis. PGE2 was measured in urine and arterial and renal venous plasma by radioimmunoassay during the following conditions: (1) Hydropenia. In the control condition U PGE2 V averaged 0.041 +/- 0.012 pmol/g . min and varied between 4 and 70% of the total PGE2 output. With infusion of arachidonic acid (AA, 160 micrograms/kg . min) into the renal artery total PGE2 output increased from 0.18 +/- 0.03 to 3.23 +/- 0.51 pmol/g . min, whereas arterial concentrations of PGE2 were unchanged. The urinary fraction still varied between 6 and 46% of total renal PGE2 output. (2) High urine flows caused by mannitol, saline or saline and ethacrynic acid (ECA) infusion. These procedures did not stimulate total renal PGE2 output and the urinary fraction varied between 4 and 49%. ECA combined with saline infusion increased the urinary fraction significantly to 34.7 +/- 4.0%. AA increased the total PGE2 output as during hydropenia, but the urinary fraction fell to 13% in 13 dogs and was unchanged at about 8% in six dogs. On average the urinary fraction of total PGE2 output was significantly lower than in hydropenia. Thus, the urinary fraction of total renal PGE2 output is not constant, and urinary excretion of PGE2 does not give reliable information about renal synthetic rates of prostaglandins.

Arachidonic acid metabolism by neonatal lungs perfused with krebs bicarbonate buffer

We characterized and quantified products of exogenous arachidonic acid metabolism by neonatal lamb lungs perfused with Krebs solution and determined effects of alveolar hypoxia upon this metabolism. The predominant metabolite was PGI 2 (62.4 ± 5.8 (SEM)% of the total prostanoids (PGs) produced). An additional 23.1 ± 6.7% was metabolized PGI 2. PGE 2 (1.7 ± .3.0X) was produced also. Little thromboxane B 2 (TXB 2) (3.3 ± 1.7%) was synthesized by these platelet-free lungs. Although the pulmonary vasoconstrictor response to arachidonic acid infusion reached a plateau in 71 ± 19 seconds, the PG efflux was greater 8–15 minutes after beginning arachidonic acid infusion (3066 ± 1353 ng/min) than 1–8 minutes into the infusion (899 ± 343 ng/min). Reduction of F I O2 from 20% to 3% 02 which produces vasoconstriction in the absence of exogenous arachidonic acid, did not alter the PG profile nor quantity produced. With respect to the neonatal lamb pulmonary vasculature perfused with Krebs solution, we conclude; 1) exogenous arachidonic acid ultimately is metabolized predominantly to PGI 2, 2) arachidonic acid-induced pulmonary vasoconstriction is not caused by TXA 2, 3) short term hypoxia does not alter the conversion of excess arachidonic acid to PGs, and 4) a lag between intrapulmonary PG synthesis and pulmonary venous efflux may occur.

Arachidonic acid and postprandial intestinal hyperemia

The effects of prostaglandin synthesis on food-induced increases in intestinal blood flow and O2 uptake were examined in the jejunum of anesthetized dogs. Intravenous (40 micrograms X kg-1 X min-1) or intra-arterial (0.8-1.6 microgram X min-1) infusions and luminal placement (6.5 X 10(-4) M or 200 micrograms/ml) of arachidonic acid (AA) significantly attenuated the food-induced jejunal hyperemia. Furthermore, luminal placement of AA significantly attenuated the food-induced increase in jejunal O2 uptake. Changes in blood flow and O2 uptake were significantly correlated both before and after arachidonic acid administration. Although intravenous infusion of AA decreased blood flow, intra-arterial infusion and luminal placement of AA did not significantly alter resting blood flow under free-flow conditions. In another series of experiments, intravenous infusions of AA under constant-flow conditions produced a biphasic response: vascular resistance rose when local blood AA concentration was raised to the range between 1 and 6 micrograms/ml blood and fell when the concentration was raised between 8 and 12 micrograms/ml blood. This study indicates that prostaglandin synthesis has a marked effect on both resting intestinal blood flow and postprandial intestinal hyperemia. The attenuation of the hyperemia may be due to its attenuation of the food-induced increase in intestinal oxidative metabolism.

Glomerulotubular balance and prostaglandin synthesis.

We have tested a hypothesis proposed to explain glomerulotubular balance (GTB) as a consequence of variations in prostaglandin synthesis. Arachidonic acid (40 micrograms x kg-1 x min-1) infused into the renal artery of anesthetized dogs raised renal blood flow (RBF) by 41 +/- 5% in hydropenic and by 24 +/- 11% in volume-expanded dogs, but the absolute changes were similar. The infusion of arachidonic acid after the administration of indomethacin (10 mg x kg-1) had no effect on RBF. Arachidonic acid infusion increased the excretion of sodium and chloride in hydropenic dogs but not after the administration of ethacrynic acid in volume-expanded dogs. During continued infusion of ethacrynic acid, the glomerular filtration rate (GFR) was lowered by suprarenal aortic constriction and raised by carotid constriction. A linear relationship between electrolyte reabsorption and GFR (GTB) was observed when GFR was varied between 20 and 110% of control. GTB and tubular reabsorption at comparable GFR were not significantly altered during arachidonic acid infusion or after indomethacin administration. In all experimental settings, bicarbonate, chloride, and sodium reabsorption were altered in molar ratios of 1:2:3 during variations in GFR. We conclude that GTB is independent of variations in prostaglandin synthesis.

Cyclooxygenase products and cyclic nucleotide levels with infusion of arachidonic acid, PGI2, PGE2, PGF2, and 6-keto-PGF1 in an isolated dog lung.

Arachidonic acid (AA) was infused into the pulmonary artery of an isolated dog lung perfused with a physiologic salt solution. This led to elevations in pulmonary cyclic AMP and prostaglandins (PGs) including PGE2, PGF2 alpha, TXB2 (a metabolite of TXA2), and 6-keto-PGF1 alpha (a metabolite of PGI2). The elevations were prevented by PG synthesis inhibitors. A dose of PGI2 comparable to that produced from AA led to elevations in cyclic AMP. These elevations were not reduced by PG synthesis inhibitors; this indicated that the inhibitors did not reduce cyclic AMP except by inhibiting metabolism of AA. The PGE2 led to lesser elevations in cyclic AMP than did PGI2; PGF2 alpha and 6-keto-PGF1 alpha did not increase cyclic AMP. Levels of cyclic AMP were not elevated. We conclude that some of the elevation in cyclic AMP from AA was most likely from production of PGs since elevations in both were prevented by the inhibitors. However, the possibility remains that AA metabolites other than PGs also contributed to elevations in cyclic AMP. We also conclude that PGI2 most likely accounted for some of the cyclic AMP elevation from AA since PGI2 could be readily produced in amounts that elevate cyclic AMP. However, the possibility remains that PGE2, the less consistent cyclic AMP stimulators (l.e., PGF2 alpha and 6-keto-PGF1 alpha), TXA2 or TXB2, or PGs not measured in this study also contributed to the elevations in cyclic AMP from AA.

Sensitivity of rabbit platelet and aortic cyclooxygenase to inhibition by aspirin

It has been suggested that aspirin (ASA) would be more effective as an antithrombotic agent if employed in a dose which inhibits platelet thromboxane synthesis selectively, sparing vascular synthesis of prostaglandin I 2 (PGI 2). We have studied the effect of ASA concentration on rabbit platelet and aortic cyclooxygenase activity in vitro and the effect of administration of varying doses of ASA to rabbits on the cyclooxygenase activity of these tissues ex vivo . We also measured plasma levels of thromboxane B 2 (TXB 2) and 6-keto-prostaglandin F 1α 6-keto-PGF 1α) after infusion of arachidonic acid into rabbits pretreated with varying doses of ASA. Concentrations or doses of ASA required for 50% inhibition were about 10 times greater for the arterial enzyme than for the platelet enzyme in the in vitro and ex vivo studies. However, the dose required for complete inhibition of the platelet enzyme was 1 mg/kg and this dose inhibited the vascular enzyme by 62%. We conclude that meaningful selective inhibition of cyclooxygenase activity of the two tissues is difficult to achieve in the rabbit. Since doses of ASA which are antithrombotic appear to be high enough to almost totally inhibit vascular PGI 2 synthesis, PGI 2 synthesis may be a relatively unimportant mechanism for prevention of thrombosis.

Influence of arachidonic acid on vasoconstrictor responses in the rabbit hindquarters vascular bed

The effects of infusion of arachidonic acid (AA) on responses to pressor hormones and sympathetic nerve stimulation were investigated in the hindquarters vascular bed of the rabbit. During infusion of AA, vasoconstrictor responses to norepinephrine, nerve stimulation and angiotensin II were reduced to a similar extent. In addition, AA decreased hindquarters perfusion pressure and systemic arterial pressure. Following the administration of indomethacin, vasoconstrictor responses as well as perfusion pressure and aortic pressure remained unchanged during infusion of AA. The present data show that AA possesses the ability to modulate responses to nerve stimulation and pressor hormones. In addition, AA dilates the hindquarters vascular bed and produces a systemic depressor response. The present data suggest that cyclooxygenase products possessing vasodilator activity may mediate the effects of AA on the sympathetic nervous system and responses to pressor hormones in the rabbit hindquarters vascular bed.