Muscle pump does not enhance blood flow in exercising skeletal muscle.

The muscle pump theory holds that contraction aids muscle perfusion by emptying the venous circulation, which lowers venous pressure during relaxation and increases the pressure gradient across the muscle. We reasoned that the influence of a reduction in venous pressure could be determined after maximal pharmacological vasodilation, in which the changes in vascular tone would be minimized. Mongrel dogs (n = 7), instrumented for measurement of hindlimb blood flow, ran on a treadmill during continuous intra-arterial infusion of saline or adenosine (15-35 mg/min). Adenosine infusion was initiated at rest to achieve the highest blood flow possible. Peak hindlimb blood flow during exercise increased from baseline by 438 +/- 34 ml/min under saline conditions but decreased by 27 +/- 18 ml/min during adenosine infusion. The absence of an increase in blood flow in the vasodilated limb indicates that any change in venous pressure elicited by the muscle pump was not adequate to elevate hindlimb blood flow. The implication of this finding is that the hyperemic response to exercise is primarily attributable to vasodilation in the skeletal muscle vasculature.     

NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo?

Nitric oxide is a major endothelium-derived vascular smooth muscle relaxing factor; its synthesis from L-arginine is selectively inhibited by L-NG-methylarginine. To assess whether basal nitric oxide release contributes to blood pressure regulation in vivo, we have investigated the cardiovascular effects of L-NG-methylarginine in the anesthetized guinea pig. L-NG-methylarginine (0.1-10 mg/kg, i.v. bolus) elicited a sustained, dose-dependent, increase in arterial pressure and a moderate bradycardia. L-arginine (30 mg/kg i.v.) prevented or reversed the pressor effect of L-NG-methylarginine, while atropine (2 mg/kg) abolished the associated bradycardia. In contrast, L-arginine did not attenuate the pressor effect of norepinephrine or angiotensin. Our findings suggest that basal nitric oxide production is sufficient to modulate peripheral vascular resistance; hence nitric oxide may play a role in arterial pressure homeostasis.     

Role of endogenous nitric oxide on PAF-induced vascular and respiratory effects

The role of endogenous nitric oxide (NO) on vascular and respiratory smooth muscle basal tone was evaluated in six anaesthetized, paralysed, mechanically ventilated pigs. The involvement of endogenous NO in PAF-induced shock and airway hyperresponsiveness was also studied. PAF (50 ng/kg, i.v.) was administered before and after pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.v.), an NO synthesis inhibitor. PAF was also administered to three of these pigs after indomethacin infusion (3 mg/kg, i.v.). In normal pigs, L-NAME increased systemic and pulmonary vascular resistances, caused pulmonary hypertension and reduced cardiac output and stroke volume. The pulmonary vascular responses were correlated with the increase in static and dynamic lung elastances, without changing lung resistance. Inhibition of NO synthesis enhanced the PAF-dependent increase in total, intrinsic and viscoelastic lung resistances, without affecting lung elastances or cardiac activity. The systemic hypotensive effect of PAF was not abolished by pretreatment with L-NAME or indomethacin. This indicates that systemic hypotension is not correlated with the release of endogenous NO or prostacyclines. Indomethacin completely abolished the PAF-dependent respiratory effects.     

Effect of indomethacin and propranolol on the blood pressure and renin response to atriopeptin III in conscious rats

The effect of prostaglandin synthesis inhibition and of beta-adrenoceptor blockade on the blood pressure and renin response to the synthetic atrial natriuretic peptide atriopeptin III was assessed in unanesthetized normotensive rats. This peptide was infused i.v. for 30 min at a rate of 1 microgram/min in rats pretreated either with indomethacin (5 mg i.v.) or propranolol (1 mg i.v.). The blood pressure reducing effect of atriopeptin III was attenuated neither by indomethacin nor by propranolol. Atriopeptin III per se did not modify plasma renin activity. Both the administration of indomethacin and of propranolol had a suppressing effect on renin release during atriopeptin III infusion. These data suggest that the vasodilating properties of atrial natriuretic peptides do not depend in the conscious normotensive rats on the production of prostaglandins. They also provide evidence that during infusion of such peptides, both prostaglandins and beta-adrenergic mechanisms are still involved in the regulation of renin secretion.     

Effects of indomethacin on local blood flow regulation in canine heart and kidney.

In two series of experiments we studied the effects of indomethacin on (a) coronary reactive hyperemia and, (b) renal blood flow, autoregulation, and reactive dilation. Coronary blood flow was measured in closed-chest dogs. Reactive hyperemia was induced by coronary occlusion for 5 and 15 sec. Indomethacin, an inhibitor of prostaglandin synthesis, was infused intra-arterially in doses of 90-200 mg over periods ranging from 30-120 min. Coronary reactive hyperemia was not affected by indomethacin. The canine renal vascular bed was studied under conditions of natural flow, controlled flow, and controlled pressure. Intra-arterial infusion of 90 mg of indomethacin over a 30- to 60- min period caused increased renal vascular resistance and an attenuation of reactive dilation (induced by stopping renal blood flow for 90 sec). Indomethacin slightly attenuated the autoregulatory response to decreasing perfusion pressures, but did not affect the respone to increasing pressures. Thus the study fails to provide evidence for participation of the prostaglandins in regulation of coronary blood flow and suggests only minimal participation of prostaglandings in renal blood flow regulation.     

The role of alpha-adrenergic receptors in carbon monoxide hypoxia

The importance of alpha-adrenergic receptors in the cardiac output and peripheral circulatory responses to carbon monoxide (CO) hypoxia was studied in anesthetized dogs. Phenoxybenzamine (3 mg/kg i.v.) was injected to block alpha-receptor activity and the data obtained were then compared with those from a previous study of CO hypoxia in unblocked animals. Values for cardiac output, hindlimb blood flow, vascular resistance, and oxygen uptake were obtained prior to and at 30 and 60 min of CO hypoxia which reduced arterial oxygen content by approximately 50%. alpha-Adrenergic blockade resulted in a lower (p less than 0.05) control value for cardiac output than observed in unblocked animals, but no differences were present between the two groups at 30 or 60 min of CO hypoxia. Similarly, limb blood flow was lower (p less than 0.05) during the control period in the alpha-blocked group but rose to the same level as that in the unblocked animals at 60 min of COH. No change in limb blood flow occurred during CO hypoxia in the unblocked group. These findings demonstrated that during CO hypoxia alpha-receptor mediated venoconstriction does not contribute to the cardiac output response and alpha-receptor mediated vasoconstriction probably does prevent a rise in hindlimb skeletal muscle blood flow.     

Cardiovascular responses to V1-vasopressinergic antagonism in conscious versus anesthetized rats

Experiments were performed to compare the possible effect of endogenous arginine vasopressin on renal hemodynamics between anesthetized, surgically stressed rats and conscious rats. Animals were instrumented with arterial and venous catheters as well as with a pulsed Doppler flow probe on the left renal artery. The rats were studied under the following conditions: (1) conscious and unrestrained; (2) anesthetized only; (3) anesthetized with minor surgical stress; and (4) anesthetized with major surgical stress. Two anesthetic agents were also compared, a mixture of ketamine (110 mg/kg i.m.) and acepromazine (1 mg/kg i.m.), and sodium pentobarbital (50 mg/kg i.p.). Baseline mean arterial blood pressure was significantly higher in pentobarbital-anesthetized rats following surgical stress compared with conscious animals, but blood pressure was not affected by ketamine-acepromazine anesthesia. After baseline measurements of blood pressure, heart rate, and renal blood flow, a specific V1-vasopressinergic antagonist (d(CH2)5Tyr(Me) arginine vasopressin, 10 mg/kg i.v.) was administered to each group. Mean arterial blood pressure, heart rate, and renal blood flow were monitored for an additional 15 min. Mean arterial blood pressure and renal blood flow decreased after V1 antagonism in ketamine-acepromazine-anesthetized rats with major surgical stress, but were not affected in pentobarbital-anesthetized animals. Heart rate and renal vascular resistance were not affected following V1 blockade with either anesthetic agent. These data suggest that arginine vasopressin plays a role in maintaining blood pressure and renal perfusion in ketamine-acepromazine-anesthetized rats following surgical stress, but does not have a significant effect on renal hemodynamics under pentobarbital anesthesia.     

Influence of adrenergic nervous and prostaglandin systems on hydralazine-induced renin release

The role of the beta-adrenergic nervous and prostaglandin systems in vasodilator-induced activation of the renin-angiotensin system was studied in conscious rats. The plasma renin activity (PRA) response to intravenous hydralazine (0.25, 0.5 and 1 mg/kg body wt.) was compared to the PRA response following administration of similar doses of hydralazine to rats pretreated with either indomethacin (3 mg/kg body wt. i.v.) or indomethacin and propranolol (1 mg/kg body wt. i.v.). PRA increased significantly above control levels after each of the hydralazine doses. In rats pretreated with indomethacin, PRA did not increase with the 0.25 mg/kg dose of hydralazine; increased significantly with the 0.5 mg/kg dose but remained significantly lower than the PRA response in the absence of indomethacin; and increased with the 1 mg/kg dose to a level not significantly different from PRA in rats receiving only hydralazine. When rats were pretreated with indomethacin and propranolol, PRA did not increase significantly in response to either the 0.25 or 0.5 mg/kg doses of hydralazine. Although a statistically significant increase in PRA was noted with the 1 mg/kg dose of hydralazine, the level of PRA achieved was very low and only 15% of that observed with the other two treatment regimens (i.e., hydralazine alone or indomethacin and hydralazine). These results demonstrate that vasodilator-induced renin release is only partially mediated via the prostaglandin system, that the degree of this control is related to the intensity of vasodilator stimulus and that renin release following administration of hydralazine can be attributed almost entirely to activation of the beta-adrenergic nervous and prostaglandin systems.     

Endothelin-induced sudden death and the possible involvement of platelet activating factor (PAF)

Endothelin (5 nmol/kg, i.v.) caused a transient hypotension followed by a lasting hypertension in rats. However, an abrupt fall in the blood pressure was observed in most rats 6 to 30 min after the injection of endothelin and sudden death followed with lethality noted over 60 min. An abnormal electrocardiogram (ECG) (ventricular arrhythmias) was observed in rats injected with endothelin. Endothelin (i.v.) also caused sudden death in mice. Pretreatment (5 or 60 min) with specific PAF antagonists, CV-6209 (0.1-3 mg/kg, i.v.) and WEB 2086 (30 mg/kg, p.o.), and a calcium channel blocker, diltiazem (60 mg/kg, p.o.) prevented death and attenuated the ECG changes induced by endothelin, but CV-6209 did not prevent the blood pressure changes induced by endothelin. CV-6209 (0.5-3 mg/kg, i.v.), WEB 2086, diltiazem and dexamethasone (5 mg/kg, i.v.) protected mice against the death induced by endothelin. On the other hand, aspirin (cyclooxygenase inhibitor, 100 mg/kg, p.o.) did not protect mice from the death. Thus, endothelin is a highly toxic peptide with cardiotoxic effects, and PAF may be involved in the pathogenesis of the sudden death.     

Regulation of canine skeletal muscle and hindlimb blood flow in acute anemia

Redistribution of blood flow away from resting skeletal muscles does not occur during anemic hypoxia even when whole body oxygen uptake is not maintained. In the present study, the effects of sympathetic nerve stimulation on both skeletal muscle and hindlimb blood flow were studied prior to and during anemia in anesthetized, paralyzed, and ventilated dogs. In one series (skeletal muscle group, n = 8) paw blood flow was excluded by placing a tourniquet around the ankle; in a second series (hindlimb group, n = 8) no tourniquet was placed at the ankle. The distal end of the transected left sciatic nerve was stimulated to produce a maximal vasoconstrictor response for 4-min intervals at normal hematocrit (Hct.) and at 30 min of anemia (Hct. = 14%). Arterial blood pressure and hindlimb or muscle blood flow were measured; resistance and vascular hindrance were calculated. Nerve stimulation decreased blood flow (p less than 0.05) in the hindlimb and muscle groups at normal Hct. Blood flow rose (p less than 0.05) during anemia and was decreased (p less than 0.05) in both groups during nerve stimulation. However, the blood flow values in both groups during nerve stimulation in anemic animals were greater (p less than 0.05) than those at normal Hct. Hindlimb and muscle vascular resistance fell significantly during anemia and nerve stimulation produced a greater increase in vascular resistance at normal Hct. Vascular hindrance in muscle, but not hindlimb, was less during nerve stimulation in anemia than at normal Hct.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological modulation of the bronchopulmonary action of the vasoactive peptide, endothelin, administered by aerosol in the guinea-pig

Administration by aerosol for 1 min of solutions of endothelin (ENDO; 1, 5 or 10 micrograms/ml) to anaesthetized and ventilated guinea-pigs induced a dose-dependent bronchopulmonary response (BR) which was maximal within 4 to 5 min. In contrast, no significant change of the mean arterial blood pressure was observed. Pretreatment of guinea-pigs with propranolol (1 mg/kg, i.v.), mepyramine (1 mg/kg, i.v.), nifedipine (50 mg/kg, i.p.) or verapamil (0.3 mg/kg, i.v.) did not significantly affect the BR induced by an aerosol of a solution of 10 micrograms/ml ENDO. In contrast, BR was significantly reduced when the animals were pretreated with the cyclooxygenase inhibitor, indomethacin (10 mg/kg, i.v.) or the platelet-activating factor (PAF) receptor antagonist, BN 52021 (10 mg/kg, i.v.). These results indicate that aerosolized ENDO induces a BR via the generation of secondary mediators such as cyclooxygenase products and PAF in a process which is unaffected by the blockers of the voltage-dependent calcium channels.     

Beneficial haemodynamic effect of indomethacin during endotoxin shock in anaesthetized pigsputative involvement of nitric oxide?

Endotoxin shock was induced in 31 anaesthetized pigs by infusion of 5 mug/kg of Escbeicbia coli endotoxin (LPS) over 60 min into the superior mesenteric artery. Fifteen of these pigs died within 30 min of the start of LPS infusion whereas the remaining 16 survived the experimental period of 2 h. In a group of nine pigs indomethacin (2 mg/kg, i.v.)was inected 20-25 rain after the start of LPS infusion at which time mean arterial blood pressure (MABP) had decreased below 40 mmHg indicating imminent death. Indomethacin immediately reversed the hypotension. In another group of five pigs, N(G)-nitro L-arginine-methyl ester (L-NAME, 1 and 3 mg/kg)was iniected 10 and 5 min, respectively, before the expected death without any beneficial effect on the hypotension. Three rain after the last dose of L-NAME, indomethacin (2 mg/kg, i.v.) was iniected. In three animals the hypotension was reserved by indomethacin, although this beneficial effect was delayed in comparison with the LP-Streated group not receiving L-NAME. Four pigs were pretreated with L-NAME, 3 mg/kg, i.v., 10 min prior to LPS infusion. All pretreated animals tended to die within 30 min of the start of the LPS infusion. Five rain before the expected death (20-25 rain after the start of LPS infusion) indomethacin (2 mg/kg) was inected. In three of these animals indomethacin reversed hypotenston and prevented death. Interestingly, this rise in the MABP developed very slowly. These results suggest that the beneficial effect of indomethacin in endotoxin shock might be related partially to interference with nitric oxide, which is not the only factor determining blood pressure levels during endotoxic shock.     

Dissociation of beta-adrenergic stimulation of renin secretion and prostacyclin synthesis in the rabbit kidney

The effect of inhibition of prostaglandin (PG) synthesis with indomethacin on basal and isoproterenol-stimulated renin secretion was examined in the isolated perfused rabbit kidney. 6-keto PGF1 alpha' the stable metabolite of prostacyclin, was measured in urine by radioimmunoassay using 125I labelled histamine coupled to 6-keto PGF1 alpha as ligand. The level in urine, prior to isolation and perfusion of the kidney, was 10.7 +/- 5.6 ng/min, and this was reduced to 0.32 +/- 0.25 ng/min (P less than 0.05) in rabbits treated with 2.0 mg/kg of indomethacin. Renin release was markedly stimulated by intrarenal infusion of isoproterenol (0.1 microgram/min) but urinary 6-keto PGF1 alpha did not change. These responses were not affected by indomethacin treatment. Renal perfusion pressure, perfusate flow rate and consequently renal vascular resistance, remained relatively constant during the course of perfusion and were unaltered by indomethacin treatment. These results therefore do not support a role for PGs, and in particular prostacyclin, in the renin response to beta-adrenergic stimulation with isoproterenol.     

Effects of prostanoids on phenylephrine-induced contractions in the mesenteric vascular bed of rats with streptozotocin-induced diabetes mellitus

The main aim of this study was to compare the vascular reactivity of the perfused (Krebs, 4 ml/min) mesenteric vascular bed (MVB) isolated from rats with streptozotocin (STZ)-induced diabetes of 8 weeks duration to that of the MVB from non-diabetic (ND) Wistar rats. There were no differences in basal perfusion pressure between the MVB isolated from STZ and ND rats. The addition of indomethacin to the perfusate increased the basal perfusion pressure in both ND (18.8 +/- 0.7 vs 29.4 +/- 3.7 mmHg, p < 0.05) and STZ rats (18.3 +/- 0.9 vs 27.2 +/- 2.6 mmHg, p < 0.05), suggesting the release of a vasodilator prostaglandin. Remotion of the endothelium did not affect this response, indicating that prostaglandin was released from vascular smooth muscle. The response to phenylephrine was reduced in STZ rats compared to ND rats (2.3 [1.6-3.8] vs 8.3 [3.5-19.4], ED50. [IC 95%]) and was not modified by removal of the endothelium or by perfusion of L-nitro-arginine (50 microM). In contrast, indomethacin was able to reduce the response to phenylephrine in ND but not in STZ rats (2.3 [1.6-3.8] vs 4.7 [3.2-6.0], ED50. [IC 95%], p=0.02), suggesting that the blunted response to phenylephrine observed in STZ was due to the abolition of the release of prostaglandin by vascular smooth muscle. In conclusion, experimental diabetes induction in the rat is followed by a reduction of the contractile effect of phenylephrine due to the lack of release of a vasoconstrictor prostaglandin from vascular smooth muscle.     

Central cardiovascular and thermal effects of prostaglandin F2α in rats

Administration of PGF_2α (0.2–6.4 μg) into the lateral cerebral ventricle (i.c.v.) induced dosedependent increases in blood pressure, heart rate and body temperature in urethane-anaesthetised rats, but had no effect on these parameters when the same dose range was administered intravenously. Peripheral pretreatment with sodium meclofenamate (50 mg/kg s.c.) shifted all the dose-response curves for PGF_2α (i.c.v.) to the left, but indomethacin (50 mg/kg s.c.) did not significantly affect those changes. Central pretreatment with sodium meclofenamate or indomethacin (1.25 mg per rat i.c.v.) failed to modify significantly the effects of centrally administered PGF_2α.The results support previous suggestions that PGF_2α may participate in the central control of the cardiovascular and thermoregulatory systems, and also suggest that there may be differences in the sites and/or modes of action between sodium meclofenamate and indomethacin.     

The renal haemodynamic and excretory actions of prostacyclin and 6-oxo-PGF1 alpha in anaesthetized dogs.

Intrarenal arterial (i.a.) infusions of prostacyclin (PGI2) at 30-300 ng/min to anaesthetized dogs reduced renal vascular resistance (RVR) and filtration fraction (FF), increased mean renal blood flow (MRBF) but did not alter mean arterial pressure (MAP)or glomerular filtration rate (GFR). The urinary excretion of sodium (UNaV), potassium (UKV) and chloride ions (UC1V) were increased through inhibition of net tubular ion reabsorption. PGI2 (3000 ng/min, i.a.) reduced MAP and increased heart rate. Intravenous (i.v.) infusions of PGI2 (3000 gn/min) reduced MAP, GFR, FF, urine volume and ion excretion, with elevation of heart rate. The measured variables were unaltered by 6-oxo-PGF1 alpha (10,000 ng/min i.a.). Treatment of the dogs with the PG synthetase inhibitor meclofenamic acid (2.5 mg/kg i.v.) did not antagonise the elevation of MRBF to PGI2 (300 ng/min i.a.). Thus the renal effects of PGI2 were due to a direct action rather than through conversion to 6-oxo-PGF1 alpha or through stimulation of endogenous renal PG biosynthesis and release.     

Role of thromboxane receptor activation in the bronchospastic response to endothelin

The selective TxA2/PGH2 (TP) receptor antagonist, SQ 30,741, was used to test the hypothesis that TP-receptor activation contributes to the reactivity of airways and isolated trachea to endothelin-1 (ET-1). Dose-dependent contractions of guinea pig tracheal strips to ET-1 in vitro were unaffected by either SQ 30,741 (1 microM) or indomethacin (2.8 microM). In contrast, maximal bronchospastic responses (increases in airways resistance and decreases in dynamic lung compliance) of anesthetized guinea pigs to ET-1 (0.5 and 1.5 nmole/kg i.v.) in vivo were blocked greater than 90% by SQ 30,741 (1 mg/kg i.v.). Concurrent increases in arterial blood pressure and decreases in leukocyte counts induced by ET-1 were unaffected by SQ 30,741. In rats, ET-1 (1.5 nmole/kg i.v.) did not affect lung mechanics, but did cause biphasic blood pressure and leukopenia responses which were unaltered by SQ 30,741. These data demonstrate that there is considerable species variability in the bronchospastic response to ET-1, and that in guinea pigs, this response is caused predominantly by the activation of TP-receptors.     

Vasoactive properties of dihomo-gamma-linolenic acid and series one prostaglandins in a freshwater teleost, Channa maculata

1. Prostaglandins A1, B1, E1 and F1 alpha (2-120 micrograms/kg), arachidonic acid and dihomo-gamma-linolenic acid (0.1-2 mg/kg) were injected intravenously into Channa maculata and changes in arterial blood pressure were recorded. 2. Injection of PGF1 alpha had no significant effect on arterial blood pressure. Injection of PGA1 and PGE1 was followed by dose-dependent hypotension whereas injection of PGB1 elicited significant dose-dependent increase in arterial blood pressure. 3. Both dihomo-gamma-linolenic acid and arachidonic acid were also depressor agents but dihomo-gamma-linolenic acid was more potent. 4. A single bolus intravenous injection of indomethacin (5 mg/kg) or 4 daily intraperitoneal injections (4 x 10 mg/kg) significantly lowered arterial blood pressure. One hour after pre-treatment of indomethacin, the vascular effects of both prostaglandin precursors were abolished. 5. It appears that the vascular effects of prostaglandins in Channa maculata are qualitatively different from those reported for mammals.     

Effect of indomethacin on prostaglandin content of several rabbit tissues

The prostaglandin (PG) content of several tissues and fluids from 6 day pregnant rabbits was evaluated following treatment with indomethacin or vehicle . PGE and PGF were measured by radioimmunoassay. More complete depletion of PGE and PGF was accomplished by 3 injections of indomethacin (s.c.) given during the 18 h before sacrifice at a dose of 10 mg indomethacin per kg body weight than was accomplished by 1 injection of the same amount of indomethacin (i.v.) 1.5 h before sacrifice. Levels of PGF were more easily depressed by indomethacin than were those of PGE. PG levels in the kidney and blastocysts were depressed to a greater extent by indomethacin than were those in the uterus, uterine fluid or peritoneal fluid. Evaluation of the effect of indomethacin on a particular physiological function should be interpreted with caution unless the extent of PG depletion in that tissue is also measured.     

Potentiation of bradykinin-induced vascular permeability increase by prostaglandin E2 and arachidonic acid in rabbit skin.

The activity of prostaglandins (PG) in producing vascular permeability was quantitated by dye extraction method in skin of anaesthetized rabbits. PGE1 and PGE2 (0.01-10 mug) produced increase in vascular permeability. Activity was approximately equal to that of histamine (Hist) and 1/20 of that of bradykinin (BK) on a weight basis. The activity of PGF1alpha and PGF2alpha was only 1/20 of that of PGE1 or PGE2. In spite of the relatively low potency of PGE1 and PGE2 in the rabbit, near threshold doses (0.1 or 1 mug) of PGE2 could potentiate permeability responses to bradykinin (0.1 mug) by 10 or 100-fold, respectively. Equivalent doses (0.1 or 1 mug) of histamine could not potentiate the bradykinin responses. Arachidonic acid (AA) at 1 mug, produced a 10-fold potentiation in the permeability response to bradykinin (0.1 mug). Pretreatment of the rabbits with indomethacin (20 mg/kg, i.p.) reduced the responses of BK (0.1 mug) + AA (1 mug) down to a similar magnitude of those seen with bradykinin alone. However, indomethacin did not block responses to either, BK alone, BK + PGE2, or BK + Hist. Various doses (1, 10, 100 and 300 mug) of arachidonic acid alone also produced increase in cutaneous vascular permeability, although its potency was only 1/3-1/8 of that of PGE2. This activity of arachidonic acid was attributed in part to its bioconversion to PGE2, since its activity was significantly reduced by the prostaglandin antagonist, diphloretin phosphate (DPP) (60 mg/kg, i.v.) and by indomethacin (20 mg/kg, i.p.), which blocks conversion of arachidonic acid to prostaglandins. Arachidonic acid may owe some of its permeability increasing effects to histamine release, since its effects were also reduced by the anti-histamine, pyrilamine (2.5 mg/kg, i.v.).