Biotransformation and cardiovascular effects of arachidonic acid in the dog

doi:10.1016/0014-2999(79)90080-3

European Journal of Pharmacology

Volume 54, Issue 3, 1 March 1979, Pages 217-228

https://doi.org/10.1016/0014-2999(79)90080-3 Get rights and content

Abstract

The biotransformation and cardiovascular effects of arachidonic acid (AA) were studied in the circulation of anaesthetized dogs. Arterial blood was continuously bioassayed for arachidonate metabolites using the blood-bathed organ technique of Vane. AA (5–10 μg/ml) infused into an incubation coil of flowing blood was converted into a labile substance which contracted the vascular tissues (rabbit aorta, RbA, rabbit coeliac and mesenteric arteries, RbCA and RbMA; bovine coronary artery, BCA) and the gastrointestinal smooth muscle strips (rat stomach strip, RSS; rat colon, RC). These effects could be mimicked by exogenously generated thromboxane A₂ (TXA₂). Conversion of AA was inhibited by indomethacin and the selective thromboxane synthetase inhibitor, imidazole (100 μg/ml). The half-life of TXA₂ in blood was 30–47 sec, a similar value to that found in aqueous solutions at 37°C. PGH₂ was also converted in blood to other product(s) which contracted RSS and RC, relaxed RbCA and RbMA but had little effect on RbA. Intravenous infusion of AA (50–800 μg kg⁻¹ min⁻¹) caused effects on the bioassay tissues which could be mimicked by prostacyclin. The AA infusion also induced falls in pulmonary and systemic arterial pressures and bradycardia. All effects were abolished by indomethacin (5 mg/kg) or aspirin (200 mg/kg). Radioimmunoassay confirmed that the major product of intravenously infused AA was 6-oxo-PGF_1α, the chemical degradation product of prostacyclin. Thus, although AA is transformed to the vasoconstrictor TXA₂ when incubated for sufficient time with blood alone, on rapid pulmonary transit it is transformed into a prostacyclin-like substance.

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1. Prostaglandins A₁, B₁, E₁, and F_1α, (2–120 μg/kg), arachidonic acid and dihomo-γ-linolenic acid (0.1–2 mg/kg) were injected intravenously into Channa maculata and changes in arterial blood pressure were recorded.
2. Injection of PCF_1α 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-γ-linolenic acid and arachidonic acid were also depressor agents but dihomo-gg-linolenic acid was more potent.
4. A single bolus intravenous injection of indomethacin (5 mg/kg) or 4 daily intraperitoneal injections (4 × 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.
Pressor responses to arachidonic acid in pump-perfused sheep lungs
1986, Prostaglandins, Leukotrienes and Medicine
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.
Production of prostacyclin (PGI2) and thromboxane A2 (TXA2) by vessels draining and not-draining benign and malignant tumours of the breast
1985, Prostaglandins, Leukotrienes and Medicine
The production of PGI2 (determined by bioassay) and TXB2 (determined by radioimmunoassay) was studied in the supernatant solutions obtained after incubation of vessel rings prepared from veins draining and not draining benign and malignant tumours of the breast.
A significant increase (p < 0.01) was found in the production of PGI2 by vessels draining the malignant tumours as compared to those not draining such tumours or vessels draining benign tumours. The changes in PGI2, and the tendency for TXB2 to be higher in vessels draining malignant tumours, were in the same direction so that they balanced out when the ratio PGI2/TXB2 was calculated: in consequence no significant changes in this ratio were found in malignant tumours as compared to the benign.
A significant difference (p < 0.01) was observed in the ratios of vessels draining tumours:vessels not draining tumours between malignant and benign tumours in relation to the production of PGI2.
The present data demonstrate that the production of PGI2 by vessels draining malignant tumours of the breast is different to that obtained with vessels from patients with benign tumours, although the mechanism responsible for this difference is not known.
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1985, Kidney International
Intrarenal prostaglandin release: Effects of arachidonic acid and hyperchloremia. We measured the release of PGE₂, 6kPGF_1α, PGF_2α, 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 6kPGF_1α 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 + 6kPGF_1α) 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) hyperchloremia 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.
Relargage intrarénal de prostaglandines: Effets de l'acide arachidonique et de l'hyperchlorémie. Nous avons mesuré le relargage de PGE₂, 6kPGF_1α, et TXB₂ dans les urines (U) et la lymphe (L) hilaire rénale pour préciser les rôles possibles des prostaglandines intrarénales (PGs) sur la vasodilatation rénale induite par l'acide arachidonique (AA) et sur la vasoconstriction rénale induite par Cl (un modèle de feedback tubulo-glomérulaire, TG). AA a entrainé une chute ipsilatérale des résistances vasculaires rénales (RVR) et de la diurése et a augmenté le relargage de toutes les PGs dans U; le relargage de 6kPGF_1α dans L a augmenté de 9 fois. Une perfusion de NaCl hypertonique a entrainé une vasoconstriction ipsilatérale et a diminué GFR; le relargage de TXB₂ dans U et L a augmenté, mais les autres PGs n'étaient pas notablement modifiées. Au cours d'une perfusion continue d'AA, une perfusion de NaCl hypertonique a encore entrainé un relargage de TXB₂ dans U et L sans changements significatifs des autres PGs. AA a atténué la vasoconstriction rénale induite par le NaCl chez les chiens ayant les vitesses de relargage de PGE₂ dans L les plus grandes. Les modifications de RVR étaient corrélées au rapport d'excrétion de PG vasodilatatrices (PGE₂ + 6kPGF_1α) sur TXB₂ (r = -0,74). L'administration d'indométhacine a diminué, mais n'a pas aboli l'élévation de RVR induite par Cl. En conclusion, (1) AA entraine un relargage de PGs, surtout de prostacycline, dans le cortex rénal; (2) l'hyper-chlorémie augmente RVR et induit un relargage relativement sélectif de TX rénal; (3) la production de PGs vasodilatatrices par AA pourrait atténuer la vasoconstriction rénale induite par Cl; (4) les PGs vasodilatatrices et vasoconstrictrices rénales peuvent être relarguées de façon relativement indépendante. Leur équilibre pourrait moduler RVR au cours de l'activation de la résponse TG.
Arachidonic acid metabolism by neonatal lungs perfused with krebs bicarbonate buffer
1984, Prostaglandins, Leukotrienes and Medicine
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 PGI₂ (62.4 ± 5.8 (SEM)% of the total prostanoids (PGs) produced). An additional 23.1 ± 6.7% was metabolized PGI₂. PGE₂ (1.7 ± .3.0X) was produced also. Little thromboxane B₂ (TXB₂) (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 PGI₂, 2) arachidonic acid-induced pulmonary vasoconstriction is not caused by TXA₂, 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.
Prostanoids and cardiac reflexes of sympathetic and vagal origin
1983, The American Journal of Cardiology
Prostaglandins in concentrations too low to stimulate afferent nerve endings in the heart may sensitize them to chemical or mechanical stimuli that activate cardiac reflexes during myocardial ischemia. Bradykinin, which is released from the heart during ischemia, elicits sympathetically mediated reflex pressor effects and tachycardia when applied in low doses (0.1 to 1 μg) to the epicardium of the left ventricle in open-chest, anesthetized dogs. The reflex pressor effects evoked by bradykinin are reduced after inhibition of prostaglandins biosynthesis with indomethacin and potentiated by concomitant topical application of low doses (0.1 to 0.3 μg/min) of PGE₁ or PGE₂ and prostacyclin (PGI₂). The pressor and tachycardic responses to bradykinin are also enhanced after temporary (10-minute) coronary occlusion; this potentiation is abolished by indomethacin treatment and can be restored by superfusing the ventricle with prostaglandins. Nicotine is known to excite mechanosensitive vagal receptors with afferent C fibers, which supply the left ventricle, and to elicit reflex hypotension and bradycardia. This depressor vagal reflex evoked by epicardial or intracoronary administration of nicotine (10 to 50 μg) was not affected by either indomethacin or by topical application of PGE₁, PGE₂, or PGI₂. Also, intracoronary infusion of PGE₂ (0.1 to 0.3 μg/min), which enhanced the pressor reflex effects of bradykinin, was without effect on nicotine-induced depressor reflex. However, intracoronary infusion of PGI₂ (0.1 to 0.3 μg/min) significantly enhanced the hypotensive and bradycardic responses to nicotine and, at the same time, reduced sympathetically mediated reflex effects of bradykinin. The hypotensive effects induced by epicardial or intracoronary administration of nicotine were also significantly enhanced during intravenous infusion of subdepressor doses of PGI₂ (5 to 20 ng/kg/min). Treatment with captopril, which enhances the endogenous production of prostaglandins, greatly enhanced the reflex depressor effects of nicotine; this potentiating effect of captopril was completely abolished by indomethacin treatment. An increase in the magnitude of nicotine-induced reflex depressor effects was also observed after intravenous injection (1 μg/kg) or infusion (25 to 50 ng/kg/min) of prostaglandin D₂. A working hypothesis is proposed to account for the role of prostanoids in activation of cardiac reflexes during myocardial ischemia.

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^∗∗: Present address: University of Melbourne, Dept. of Medicine, Austin Hospital, Heidelberg, Victoria 3084, Australia.

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Regular paperBiotransformation and cardiovascular effects of arachidonic acid in the dog

Abstract

European J. Pharmacol.

Prostaglandins

Biochim. Biophys. Acta

Prostaglandins

European J. Pharmacol.

FEBS Letters

Biochim. Biophys. Acta

Prostaglandins

European J. Pharmacol.

Prostaglandins

Tetrahedron Letters

Cardiovascular actions of prostacyclin in chloralose anaesthetized dogs

Brit. J. Pharmacol.

Modifications of prostaglandin and thromboxane release by immunological sensitization and successive immunological challenges from guinea-pig lung

Intern. Arch. Allergy Appl. Immun.

The effects of prostaglandin endoperoxides and thromboxane A2 on strips of rabbit coeliac artery and other smooth muscle preparations

Brit. J. Pharmacol.

A vagal reflex contributes to the hypotensive effect of prostacyclin (PGI2) in anaesthetized dogs

J. Physiol.

Prostacyclin (PGI2) induces coronary vasodilation in anaesthetized dogs

Cardiovascular Res.

Recirculation of prostacyclin (PGI2) in the dog

Brit. J. Pharmacol.

Prostaglandins: their disappearance from and release into the circulation

Nature

Inhibition by non-steroid anti-inflammatory agents of rabbit aorta contracting activity generated in blood by slow reacting substance C

Brit. J. Pharmacol.

Prostaglandins released by the spleen

Nature

Generation of prostacyclin by lungs in vivo and its release into the arterial circulation

Nature

Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides

Regular paper
Biotransformation and cardiovascular effects of arachidonic acid in the dog

The effects of prostaglandin endoperoxides and thromboxane A₂ on strips of rabbit coeliac artery and other smooth muscle preparations

A vagal reflex contributes to the hypotensive effect of prostacyclin (PGI₂) in anaesthetized dogs

Prostacyclin (PGI₂) induces coronary vasodilation in anaesthetized dogs

Recirculation of prostacyclin (PGI₂) in the dog