Diabetes alters the reactivity of myocardium to a thromboxane analogue

Atrial contractile response to U-46619 was studied in auricles from normal and acutely diabetic rats. U-46619 induced an increment of dF/dt in diabetic atria, whereas nondiabetic auricles elicited a negative contractile effect. Blockers of arachidonic acid metabolism via cyclooxygenase inhibited the stimulatory action of U-46619 in diabetic preparations. Moreover, inhibitors of thromboxane synthesis completely blocked the stimulatory effects of U-46619. The stimulant action of the thromboxane A2 mimetic was attenuated when diabetic auricles were incubated with lipoxygenase(s) blocking agents. Results suggest that in diabetic atria, the abnormal inotropic effect induced by U-46619 may be associated with thromboxane formation and with lipoxygenase(s) metabolites.

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Potential role for arachidonic acid and eicosanoids in modulating progesterone secretion by ovine chorionic cells

Acta Endocrinologica ◽

10.1530/acta.0.1280478 ◽

1993 ◽

Vol 128 (5) ◽

pp. 478-484

Author(s):

MP de la Llosa-Hermier ◽

C Fernandez ◽

J Martal ◽

C Hermier

Keyword(s):

Arachidonic Acid ◽

Fatty Acid ◽

Potential Role ◽

Acid Metabolism ◽

Nordihydroguaiaretic Acid ◽

Eicosatrienoic Acid ◽

Arachidonic Acid Metabolism ◽

Dual Effect ◽

Stimulatory Action ◽

Progesterone Secretion

The present study was conducted to investigate whether arachidonic acid and its metabolites can modulate progesterone (P4) secretion in ovine chorionic cells. At concentrations of 7.5 μmol/l and 12.5 μmol/l, arachidonic acid caused an increase of basal P4 secretion (about 1.8-fold (p< 0.01) and 2.5-fold (p<0.001), respectively, over control). Such a stimulatory effect was suppressed when the concentration of arachidonic acid attained 25 μmol/l, and at 50 μmol/l the fatty acid led to a decline of basal P4 synthesis (about 35%, p <0.01). Phospholipase A2 (PLA2) and melittin had a similar dual effect to that observed when arachidonic acid was added exogenously. In contrast, eicosatrienoic acid (a closely related fatty acid) did not stimulate P4 secretion but inhibited it at a concentration of 50 μmol/l (about 40% inhibition, p <0.01). The possible involvement of calcium on the effects of arachidonic acid was explored. Interestingly, 3 mmol/l ethylene glycol bis(β-aminoethyl ether)-N,N,N,N′-tetraacetic acid (EGTA) and 10 μmol/l 8-N, N-diethylamino-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8) further enhanced the steroidogenic effect of 12.5 μmol/l arachidonic acid (p<0.05 and p<0.01 vs the corresponding value in the absence of EGTA or TMB-8, respectively). In contrast, these agents failed to modify P4 secretion observed in the presence of 50 μmol/l arachidonic acid. We also tested the effect of inhibition of arachidonic acid metabolism via cyclooxygenase and lipoxygenase pathways. Indomethacin (10 μmol/l) failed to block the effects of arachidonic acid, but nordihydroguaiaretic acid (10 μmol/l) prevented the stimulatory action of this fatty acid. Taken together, these data suggest that arachidonic acid and its metabolites (perhaps its lipoxygenated metabolites) may be important intracellular regulators of P4 secretion in ovine chorionic cells.

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Impaired arachidonic acid metabolism of platelets and vessel wall in experimental diabetic rats and its restoration by insulin administration.

Blood & Vessel ◽

10.2491/jjsth1970.16.524 ◽

1985 ◽

Vol 16 (5) ◽

pp. 524-527

Author(s):

Kenhiro RIN ◽

Shohei SAWADA ◽

Norihiko MAEBO ◽

Isamu NIWA ◽

Takeo TOYODA ◽

...

Keyword(s):

Arachidonic Acid ◽

Vessel Wall ◽

Acid Metabolism ◽

Diabetic Rats ◽

Arachidonic Acid Metabolism ◽

Insulin Administration

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Abnormal Arachidonic Acid Metabolism In Diabetes: Effect Of Normalisation With Drugs

10.1055/s-0038-1652565 ◽

1981 ◽

Author(s):

M Johnson ◽

A H Reece ◽

H E Harrison

Keyword(s):

Arachidonic Acid ◽

Platelet Aggregation ◽

Acid Metabolism ◽

Microvascular Complications ◽

Vascular Complications ◽

Diabetic Rats ◽

Arachidonic Acid Metabolism ◽

Thromboxane Synthetase ◽

Low Dose Aspirin ◽

Patients With Diabetes

Patients with diabetes mellitus develop microvascular complications and have an increased susceptibility to both atherosclerosis and arterial thrombosis. We have demonstrated an imbalance in arachidonic acid metabolism in diabetes, vascular prostacyclin (PGI2) being reduced and platelet thromboxane (TxA2) being elevated. Platelet aggregation in response to ADP and arachidonic acid is also increased, and platelet survival is decreased. Treatment of diabetic rats with a specific thromboxane synthetase inhibitor, 1-nonyl-imidazole (50mg/Kg), for 7 days significantly (p<0.05) inhibited platelet aggregation and TxA2 synthesis. Aortic PGI2 production was increased and there was now no difference between treated animals (0.39 ± 0.05ng/mg) and non-diabetic controls (0.4l ± 0.04ng/mg). “Low dose” aspirin (2.5mg/Kg) further decreased PGI2 levels. Chronic treatment of diabetic animals for 3 months with 1-nonyl-imidazole restored both TxA2 and PGI2 production to normal, and significantly reduced the incidence and severity of microvascular lesions. If an imbalance in arachidonic acid metabolism plays a role in the vascular complications of diabetes, then the apparent beneficial effect of some drugs has important implications for therapy.

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Mechanism of action of platelet-activating factor on guinea-pig lung parenchyma strips

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y88-195 ◽

1988 ◽

Vol 66 (9) ◽

pp. 1187-1191 ◽

Cited By ~ 7

Author(s):

Sonia Jancar ◽

Patrick Thériault ◽

Brigitte Provençal ◽

Solange Cloutier ◽

Pierre Sirois

Keyword(s):

Arachidonic Acid ◽

Guinea Pig ◽

Acid Metabolism ◽

Contractile Response ◽

Platelet Activating Factor ◽

Lung Parenchyma ◽

Arachidonic Acid Metabolism ◽

Lipoxygenase Inhibitor ◽

Lipoxygenase Pathway ◽

Thromboxane Synthetase

The contribution of thromboxane A2 to platelet-activating factor (PAF)induced contraction of guinea-pig lung parenchyma strips (GPLPS) was investigated using an experimental design that allowed us to record the contractions of the tissues in parallel with the determination of thromboxane B2 (TXB2) levels in the organ baths by enzyme immunoassay. It was found that the first injection of PAF induced the contraction of GPLPS and the release of TXB2. Following subsequent additions of PAF to the same tissue, the contractile response was abolished but TXB2 levels were not significantly reduced. Pretreatment of the tissue with the thromboxane synthetase inhibitor OKY-046 (3.5, 170, and 350 μM) strongly inhibited the release of TXB2 but had no effect on the contraction of the tissues induced by PAF. The mechanism of PAF-induced contraction of GPLPS was further investigated using several drugs that interfere with arachidonic acid metabolism. It was found that pretreatment of the tissues with the cyclooxygenase and thromboxane synthetase inhibitors indomethacin (2.8, 28, and 56 μM) and OKY-046 (170 μM) or with the thromboxane antagonist SKF-88046 (1.25 and 12.5 μM) had no significant effect on the contractile response to PAF. The compound L-655,240 (2.5, 25, and 50 μM), which acts simultaneously as an antagonist of thromboxane and inhibitor of lipoxygenase, significantly reduced GPLPS contractions induced by PAF. Another lipoxygenase inhibitor, nordihydroguaiaretic acid (33 μM), and the inhibitor of both pathways of arachidonic acid metabolism, BW775c (110 μM), both reduced PAF-induced contractions of GPLPS. We conclude that although PAF induces release of thromboxane from GPLPS, this mediator does not contribute significantly to the myotropic activity of PAF, which seems to be mediated by products of the lipoxygenase pathway.

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