Streptozocin-induced diabetes decreases formation of prostacyclin from arachidonic acid in intact rat lungs

Lubawy, William C.; Valentovic, Monica

doi:10.1016/0006-2944(82)90082-5

Cited by 20 publications

(7 citation statements)

References 16 publications

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“…Tissues from patients and animals with different forms of diabetes mellitus have been reported to produce less prostacyclin in vitro than tissues from their non-diabetic controls (Watts et al 1982;Lubawy & Valentovic, 1982;Roth et al, 1983). We were therefore surprised by the lack of marked effect of diabetics on prostacyclin release from perfused lung in the present study.…”

Section: Discussioncontrasting

confidence: 47%

“…Others have also noted a large withingroup variability in protacyclin release from isolated lung (Watts et al, 1982) and, against such a background, it is difficult to resolve differences between experimental groups. Previous studies have demonstrated reduced arachidonic acid (AA)-stimulated release of prostacyclin from perfused lungs of diabetic rats (Lubawy & Valentovic, 1982), albeit with a recirculating perfusion system which amplified differences. In another study using the lung, basal prostacyclin release was reduced, but AA-stimulated release, although numerically reduced, was not significantly different from control (Watts et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

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Vasoreactivity and prostacyclin release in streptozotocin‐diabetic rats: effects of insulin or aldose reductase inhibition

Stevens

Willars

Lidbury

et al. 1993

British J Pharmacology

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Alterations in vasoreactivity and endothelial cell function could underlie some of the vascular abnormalities in diabetes. To examine aspects of these phenomena we studied the effects of 4‐ 6 weeks streptozotocin‐induced diabetes in the rat on basal and angiotensin II (AII)‐stimulated prostacyclin release from isolated lung, perfused at constant flow. In addition, pressure was monitored throughout the lung perfusion as an index of vasomotor tone. The experiment also included lungs from groups of diabetic rats treated with either insulin or an aldose reductase inhibitor (imirestat), to determine whether these treatments influenced the development of any defects seen in untreated diabetes. Despite some indication of a trend towards reduced prostacyclin release in lungs from diabetic rats, neither the basal nor AII‐stimulated release was significantly different from that seen in tissues from control animals. There were no significant differences between groups in the average basal perfusion pressure and in either the absolute pressure response to AII or the time of this peak. The area under the perfusion pressure curve during AII infusion was greater in lungs from diabetic animals than in controls indicating a prolonged vasoconstrictor response. This increased pressor response may indicate increased sensitivity of diabetic tissue to AII or a reduced production of vasodilators in response to the vasoconstriction. Whichever mechanism was responsible, this alteration was prevented by insulin treatment but not by aldose reductase inhibition, implicating mechanisms probably unrelated to exaggerated polyol pathway flux.

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Section: Discussioncontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Vasoreactivity and prostacyclin release in streptozotocin‐diabetic rats: effects of insulin or aldose reductase inhibition

Stevens

Willars

Lidbury

et al. 1993

British J Pharmacology

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“…In the pancreas a possible role for abnormalities of PG metabolism in the pathophysiology of impaired insulin secretion in diabetics has been inferred from the observation that PGE infusion inhibits glucose-induced acute insulin responses in normal human subjects and infusion of sodium salicylate partially restores the acute insulin response to glucose infusion in type II diabetics (48). Similarly, changes in PG metabolism in lung (49)(50)(51), heart (52), and seminal vesicles eluting at 26 min, co-migrated with both 8-HETE and HHT standards in this system. When this peak was collected and injected into a reverse-phase system, it was determined to be entirely HHT.…”

Section: Discussionmentioning

confidence: 99%

Increased prostaglandin production by glomeruli isolated from rats with streptozotocin-induced diabetes mellitus.

Schambelan¹,

Blake²,

Sraer³

et al. 1985

J. Clin. Invest.

175

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Abnormalities in glomerular function have been observed frequently in the early stages of both clinical and experimental diabetes mellitus. Because prostaglandins (PGs) are present in the glomerulus and have profound effects on glomerular hemodynamics, and because abnormalities of PG metabolism have been noted in other tissues from diabetics, we studied PG biosynthesis in glomeruli obtained from rats in the early stages of experimental diabetes mellitus. Streptozotocin, 60 mg/kg, was administered intravenously to male Sprague-Dawley rats. Control rats received an equal volume of the vehicle. Glomeruli were isolated 9-23 d later. Production of eicosanoids was determined by two methods: by direct radioimmunoassay after incubation of glomeruli under basal conditions and in the presence of arachidonic acid (C20:4), 30 pM, and by radiometric high-performance liquid chromatography (HPLC) after incubation of glomeruli with ['4C]C20:4. When assessed by radioimmunoassay, mean basal production of both prostaglandin E2 (PGE2) and prostaglandin F2. (PGF2.) was twofold greater in the diabetic animals whereas production of thromboxane B2 (TXB2) was not significantly greater than control. In response to C20:4, both PGE2 and PGF7, were also greater in the diabetic animals, but these differences were not statistically significant. The increased rate of basal PG production did not appear to be related directly to the severity of the diabetic state as reflected by the degree of hyperglycemia at the time of sacrifice. In fact, the rates of glomerular PG production in the individual diabetic animals correlated inversely with the plasma glucose concentration. The increased rate of PG synthesis did not appear to be due to a nonspecific effect of streptozotocin inasmuch as glomerular PG production was not increased significantly in streptozotocin-treated rats which were made euglycemic by insulin therapy. Furthermore, addition of streptozotocin, 1-10 mM, to the incubation media had no effect on PGE2 production by normal glomeruli. PGE2 production by normal glomeruli was also not influenced by varying the glucose concentration in the incubation media over a range of 1-40 mM. When metabolism of I'4C1C20:4 was evaluated by high-performance liquid chromatography conversion to labeled PGE2, PGFu,, TXB2, and hydroxyheptadecatrienoic acid by diabetic glomeruli was two-to threefold greater compared with that in control glomeruli, whereas no significant difference in conversion to 12-and 15-hydroxyeicosatetraenoic acid occurred. These findings indicate that glomerular cyclooxygenase but not lipoxygenase activity was increased in the diabetic animals. A concomitant increase in glomerular phospholipase activity may also have been present to account for the more pronounced differences in PG production noted in the absence of exogenous unlabeled C20:4. These abnormalities in PG biosynthesis by diabetic glomeruli may contribute to the altered glomerular hemodynamics in this pathophysiologic setting.

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“…With regard to the kidney, previous studies demonstrate increased production of PGE2, 6-keto-PGFia, and TXB2 by glomeruli isolated from rats with early streptozotocin-induced diabetes mellitus (8,9,(11)(12)(13).…”

Section: Introductionmentioning

confidence: 98%

“…Diabetes mellitus in experimental animals and humans is associated with qualitative and quantitative changes in PG and TX production by many tissues (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). With regard to the kidney, previous studies demonstrate increased production of PGE2, 6-keto-PGFia, and TXB2 by glomeruli isolated from rats with early streptozotocin-induced diabetes mellitus (8,9,(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Glucose-induced protein kinase C activity regulates arachidonic acid release and eicosanoid production by cultured glomerular mesangial cells.

Williams¹,

Schrier²

1993

J. Clin. Invest.

137

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Changes in glomerular eicosanoid production have been implicated in the development of diabetes-induced glomerular hyperfiltration and glomerular mesangial cells (GMC) are major eicosanoid-producing cells within the glomerulus. However, the mechanism for the effect of diabetes mellitus on glomerular mesangial eicosanoid production is unknown. The present study therefore examined whether elevated glucose concentrations activate protein kinase C (PKC) in GMC and whether this PKC activation mediates an effect of elevated glucose concentrations to increase the release of arachidonic acid and eicosanoid production by GMC. The percentage of [3HIarachidonic acid release per 30 min by preloaded GMC monolayers was significantly increased after 3-h exposure to high glucose (20 mM) medium (177% vs control medium) and this increase was sustained after 24-h exposure to high glucose concentrations. 3-h and 24-h exposure to high glucose medium also increased PGE2, 6-keto-PGFia, and thromboxane (TXB2) production by GMC. High glucose medium (20 mM) increased PKC activity in GMC at 3 and 24 h (168% vs control). In contrast, osmotic control media containing either L-glucose or mannitol did not increase arachidonic acid release, eicosanoid production, or PKC activity in GMC. Inhibiting glucose-induced PKC activation with either H-7 (50 gM) or staurosporine (1 MM) prevented glucose-induced increases in arachidonic acid release and eicosanoid production by GMC. These data demonstrate that elevated extracellular glucose concentrations directly increase the release of endogenous arachidonic acid and eicosanoids by GMC via mechanisms dependent on glucose-induced PKC activation. (J. Clin. Invest. 1993. 92:2889-2896

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Streptozocin-induced diabetes decreases formation of prostacyclin from arachidonic acid in intact rat lungs

Cited by 20 publications

References 16 publications

Vasoreactivity and prostacyclin release in streptozotocin‐diabetic rats: effects of insulin or aldose reductase inhibition

Vasoreactivity and prostacyclin release in streptozotocin‐diabetic rats: effects of insulin or aldose reductase inhibition

Increased prostaglandin production by glomeruli isolated from rats with streptozotocin-induced diabetes mellitus.

Glucose-induced protein kinase C activity regulates arachidonic acid release and eicosanoid production by cultured glomerular mesangial cells.

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