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PubMed1989

Prostaglandin I2 and glucocorticoid-induced rise in arterial pressure in the rat.

The mechanism of glucocorticoid-induced hypertension is not known. Although glucocorticoids can exert an inhibitory effect on prostaglandin synthesis in vitro, their in vivo influence on this system is controversial. The goal of the present study was to determine whether dexamethasone-induced hypertension in Wistar rats is due to inhibition of the synthesis of the vasodilator prostaglandin I2 (PGI2) in vivo. Dexamethasone caused a profound reduction (7 +/- 1 versus 21 +/- 5 ng per 24 h) in the urinary excretion of PGI-M (PGI-M), a major metabolite of PGI2, and a sustained rise in systolic arterial pressure which was maximal after 5 days (144 +/- 9 versus 103 +/- 3 mmHg). A study of the metabolism of [3H]-labeled 6-oxo-PGF1 alpha and PGI2 revealed that dexamethasone exerted a dual action on the prostaglandin system in vivo: an inhibition of PGI2 biosynthesis and an alteration of its metabolism, both effects contributing to the observed reduction in urinary levels of PGI-M. Exogenous arachidonic acid induced a fourfold increase in urinary PGI-M in normal rats (from 14 +/- 3 to 61 +/- 6 ng per 24 h). Despite a large decrease upon addition of dexamethasone, urinary PGI-M remained in the high-normal range in arachidonic acid-treated rats (21 +/- 8 ng per 24 h). Arachidonic acid exerted antihypertensive effects which were marginal initially but significant in the later phase of dexamethasone-induced hypertension (124 +/- 8 versus 139 +/- 8 mmHg in arachidonic acid-treated versus control rats after 7 days of dexamethasone).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Influence of eicosanoids on renal function of DOCA-salt hypertensive rats.

The present study examined the contribution of changes in the synthesis or degradation (or both) of renal eicosanoids to the alterations in renal hemodynamics observed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Renal blood flow and glomerular filtration rate were markedly reduced in DOCA-salt hypertensive rats compared with values observed in control rats given water or saline to drink. The abnormalities in renal hemodynamics in the hypertensive rats were associated with an increase in the excretion of thromboxane B2, an increase in the release of thromboxane B2 from renal cortical tissue slices, and a diminished release of prostaglandin E2 (PGE2) from renal medullary tissue. Additionally, the urinary excretion of PGE2 and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and the release of 6-keto-PGF1 alpha from renal cortical and medullary tissue were elevated in rats with DOCA-salt hypertension. Since the excretion of PGE2 and 6-keto-PGF1 alpha and the release of 6-keto-PGF1 alpha by medullary tissue were also elevated in normotensive rats given 1% NaCl solution to drink, these latter changes probably were related to an elevation of sodium intake rather than to the development of hypertension. The functional significance of the alterations in the renal production of thromboxane in DOCA-salt hypertensive rats was evaluated by comparing the effects of a thromboxane synthesis inhibitor and a receptor antagonist on renal function in normotensive and DOCA-salt hypertensive rats. The administration of the thromboxane synthetase inhibitor furegrelate and the thromboxane receptor blocker SQ 29548 had no effect on renal hemodynamics in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Modulation by prostaglandins of adrenergic transmission in the isolated perfused rabbit and rat kidney.

In the isolated perfused rabbit kidney prostaglandins (PGS) E1 (0.02-0-1 ng/ml), E2 (0.02-0.1 ng/ml), and A2 (1-5 ng/ml) inhibited the vasoconstrictor responses to sympathetic nerve stimulation by 21-44%, 31-39%, and 20-23%, respectively, without alerting those to injected norepinephrine. In contrast, in the rat kidney PGE1 (0.5 ng/ml), PGE2 (0.5 ng/ml), and PGA2 (5 ng/ml) enhanced the vasoconstrictor responses to sympathetic nerve stimulation by 41%, 27%, and 11%, respectively; the equiconstrictor responses to injected norepinephrine remained unaltered. Higher concentrations of these agents produced vasodilation in the rabbit kidney and vasoconstriction in the rat kidney. In both species PGF2alpha produced vasoconstriction and enhanced the response to both adrenergic stumuli. In the rabbit kidney inhibitors of PG synthesis augmented the responses to sympathetic nerve stimulation without altering those to injected norepinephrine, whereas in the rat kidney inhibition of the responses to both adrenergic stimuli occurred. Arachidonic acid inhibited the vasoconstrictor responses to sympathetic nerve stimulation in the rabbit kidney, but in the rat kidney it caused augmentation of these responses. Since these effects of arachidonic acid were reduced by indomethacin, they appear to be mediated through the acid's conversion to PGS. We conclude that PGS of the E series modulate adrenergic transmission in the kidney and that their modulatory actions are species dependent.

Animals↗
PubMed1988

Angiotensin feedback inhibition on renin is expressed via the lipoxygenase pathway.

Angiotensin II (AII) action on adrenal and smooth muscle cells is mediated via mechanisms that include changes in calcium flux and phosphoinositide hydrolysis. Phosphoinositide metabolism results in the release of arachidonic acid, a precursor of both the cyclooxygenase (CO) and lipoxygenase (LO) pathway. The effects of both LO and CO inhibitors on AII action were studied using both static incubations and perifusions of rat renal cortical slices. 12-Hydroperoxyeicosatetraenoic acid and its stable metabolite 12-hydroxyacid mimicked the inhibitory actions of AII on renin. A specific CO blocker did not alter AII inhibition of renin and a 5-LO blocker U60,257 was also ineffective, whereas the LO blockers BW755c, phenidone, and baicalein all eliminated or interfered with the action of AII on renin. All inhibition in the presence of a LO blocker was restored by adding nanomolar concentrations of 12-hydroperoxyeicosatetraenoic acid. LO inhibitors were specific for blocking AII, as they did not interfere with potassium (K+)-induced renin inhibition. These results imply that 12 and/or 15 products of the LO pathway are involved in AII action.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1977

Changes in systolic arterial blood pressure in normal and spontaneously hypertensive rats produced by acute administration of inhibitors of prostaglandin biosynthesis.

Six non-steroidal agents having the property of being able to inhibit prostaglandin (PG) biosynthesis or action were tested for their ability to affect systolic blood pressure in unanesthetized normotensive (WKY) and Spontaneously Hypertensive Rats (SHR). In WKY and pre-hypertensive young SHR, s.c. injection of indomethacin (1.0 mg/kg) had no significant effect on blood pressure measured 30 minutes after injection. In older SHR, indomethacin (15 mg/kg) caused a significant pressor response, while in age-matched WKY, this dose had no significant effect. Indomethacin also showed a pro-hypertensive action in 10-14, 23-38 and 23-27 week old SHR with doses of 1.0 and 3.0 mg/kg, respectively. Tiaramide (5 mg/kg), ETYA (5 mg/kg), tolmetin (25 mg/kg), and meclofanamate (15 mg/kg) caused a significant elevation of blood pressure in mature (7-8 month old) SHR. Age matched WKY showed no significant response to the same doses of these four agents. Fenoprofen (75 mg/kg) caused a significant elevation in pressure in 12-13 weeks old SHR which persisted for at least 2 hours. Tiaramide had no significant effect on pre-hypertensive SHR. The results are consistent with the concept that inhibition of prostaglandin in synthesis may result in a diminished turnover of anti-hypertensive prostaglandins in SHR which are being elaborated in response to the hypertensive state. In normal rats and pre-hypertensive SHR, inhibition of prostaglandin synthesis or function may not result in a hypertensive response since pro-hypertensive factors either are absent, or other antihypertensive substances may still predominate to help maintain normal blood pressure.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1977

Studies on alkaline phosphatase activity cultured cells from a patient with fibrodysplasia ossificans progressiva.

The cytoplasm of tumor cells from a subdermal nodule in a patient with fibrodysplasia ossificans progressiva (FOP) exhibited intense enzymatic activity in cryostat sections processed for demonstration of alkaline phosphatase. Nuclear heterochromatin and nucleoli, particularly in the area of the dense component, also showed strong reactivity. Finely minced blocks from the lesion of the patient with FOP revealed lighter reactivity which, in the tumor cells, avoided membrane limited spaces and appeared to be confined to hyaloplasm. Extracellular spaces disclosed very little or no reactivity and specimens from the patient's uninvolved skin lacked staining. The tumor cells from the subdermal nodule did not exhibit increased acid phosphatase activity. Cells (L-FOP) derived from a subdermal nodule and grown by tissue culture techniques also synthesized large amounts of prostaglandin E-like material and alkaline phosphatase. The amounts of prostaglandin E-like material synthesized by these L-FOP cells was reduced by more than 31 per cent by the antiinflammatory drugs indomethacin and sodium meclofenmate. Also, the production of alkaline phosphatase by these L-FOP cells was reduced by more than 40 per cent by ethane-1-hydroxyl-1,1-diphosphonate. Addition of prostaglandin E to nonlesion cells did not result in increased alkaline phosphatase activity.

Alkaline Phosphatase↗
PubMed1980

Augmentation of allergic histamine release from human leukocytes by nonsteroidal anti-inflammatory-analgesic agents.

Augmentation of allergic histamine release in vitro with human leukocytes was produced by numerous nonsteroidal anti-inflammatory--analgesic agents, primarily the arylalkanoic and anthranilic acids. Augmentation occurred without release of histamine by the agents in the absence of the allergen (ragweed) and only under conditions of an accompanying release by the allergen. As a consequence of augmentation, less allergen was necessary to produce a given response in the presence of these agents. It is suggested that some of these agents might enhance mediator release in immediate-type hypersensitivity reactions. The same agents reported to exacerbate chronic urticaria, i.e., indomethacin, mefenamic acid, sodium salicylate, aspirin, sodium benzoate, and tartrazine, also augmented allergic histamine release. Pharmacologically mediated augmentation of mediator release from stimulated cells is suggested to be involved in the exacerbation of existing chronic urticaria by the acidic nonsteroidal anti-inflammatory-analgesic agents.

Adult↗
PubMed1985

Metabolites of arachidonic acid in experimental lung vascular injury.

Several metabolites of arachidonic acid have potent effects on lung vascular and airway function. Some of these substances are released from the lungs when the lungs are diffusely injured. For example, after infusion of Escherichia coli endotoxin into unanesthetized sheep, high concentrations of both cyclooxygenase and lipoxygenase products appear in lung lymph. These products appear in sequential waves: thromboxane B2 peaks early, coincident with peak pulmonary artery pressure and maximum changes in lung mechanics; a prostacyclin metabolite peaks slightly later as pulmonary artery pressure begins to fall; both 5- and 12-lipoxygenation products peak even later, as lung vascular permeability begins to increase. Cyclooxygenase inhibitors attenuate the early changes in lung mechanics and pulmonary artery pressure caused by endotoxemia in sheep but do not prevent the later increase in lung vascular permeability. High doses of corticosteroids attenuate both the late phase increase in lung lymph lipoxygenation products and the increase in vascular permeability. These unequivocal associations between lung injury and endogenous generation of biologically active arachidonate metabolites suggest but do not prove that these substances mediate the pathophysiology.

Animals↗
PubMed2005

Nonsynaptic GABA signaling in postnatal subventricular zone controls proliferation of GFAP-expressing progenitors.

In the postnatal subventricular zone (SVZ), local cues or signaling molecules released from neuroblasts limit the proliferation of glial fibrillary acidic protein (GFAP)-expressing progenitors thought to be stem cells. However, signals between SVZ cells have not been identified. We show that depolarization of neuroblasts induces nonsynaptic SNARE-independent GABA(A) receptor currents in GFAP-expressing cells, the time course of which depends on GABA uptake in acute mouse slices. We found that GABA(A) receptors are tonically activated in GFAP-expressing cells, consistent with the presence of spontaneous depolarizations in neuroblasts that are sufficient to induce GABA release. These data demonstrate the existence of nonsynaptic GABAergic signaling between neuroblasts and GFAP-expressing cells. Furthermore, we show that GABA(A) receptor activation in GFAP-expressing cells limits their progression through the cell cycle. Thus, as GFAP-expressing cells generate neuroblasts, GABA released from neuroblasts provides a feedback mechanism to control the proliferation of GFAP-expressing progenitors by activating GABA(A) receptors.

Animals↗
PubMed1992

TNF-alpha augments pulmonary vasoconstriction via the inhibition of nitrovasodilator activity.

We tested the hypothesis that tumor necrosis factor-alpha (TNF-alpha) increases pulmonary vasoconstriction by decreases in nitric oxide- (NO) dependent vasodilation. Lungs were isolated from guinea pigs 18 h after intraperitoneal injection of either TNF-alpha (1.60 x 10(5) U/kg) or control. U-46619 (365 mM/min) caused increases in pulmonary arterial and capillary pressures, pulmonary arterial and venous resistances, and lung weight. TNF-alpha augmented the U-46619-induced increases in pulmonary arterial and capillary pressures, pulmonary arterial and venous resistances, and lung weight. Methylene blue (1 microM), which inhibits the activation of soluble guanylate cyclase by NO, had an effect similar to TNF-alpha on the pulmonary response to U-46619 alone but was not additive to the effect of TNF-alpha. NG-monomethyl-L-arginine (270 microM), an inhibitor of NO generation, also enhanced the response to U-46619. Lung effluent levels of nitrite, the oxidation product of NO, were reduced after treatment with either TNF-alpha or NG-monomethyl-L-arginine compared with U-46619 alone. In addition, lungs isolated after TNF-alpha treatment showed decreased vasodilation in response to acetylcholine (10(-8)-10(-5) M) compared with control; however, vasodilation in response to L-arginine (10 mM) and nitroprusside (10(-6.3) and 10(-6) M), agents that promote NO release, was not decreased in TNF-alpha-treated lungs. The data indicate that TNF-alpha induces an increase in vascular constriction in response to U-46619 and a decrease in vasodilation in response to acetylcholine. The mechanism for the TNF-alpha-induced alteration in pulmonary vascular reactivity may be decreased generation of NO.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

The effects of cyclooxygenase inhibition on chemiluminescence and aggregation in sheep neutrophils.

Antiinflammatory actions of cyclooxygenase inhibitors may be related to inhibition of the synthesis and release of prostaglandins and thromboxane or to nonspecific actions of particular drugs. The role of cyclooxygenase products of arachidonic acid was studied in two leukocyte functions, free radical release and aggregation, after complement activation. Dose response curves were constructed after treatment with meclofenamate or ibuprofen. To differentiate between effects on free radical release from complement activated neutrophils and scavenging free radicals, additional experiments were made with a cell free system to generate free radicals. Both drugs inhibited complement initiated neutrophil chemiluminescence in a dose dependent manner. Meclofenamate acted primarily as a scavenger while ibuprofen inhibited free radical release. Neither drug had any inhibitory effects on complement induced leukocyte aggregation.

Animals↗
PubMed1990

Bradykinin-2 receptor-mediated release of 3H-arachidonic acid and formation of prostaglandin E2 in human gingival fibroblasts.

Bradykinin stimulated production of prostaglandin E2 (PGE2) and the release of 3H-arachidonic acid by gingival fibroblasts in a time- and dose-dependent manner. The effect on PGE2 biosynthesis was seen already after 15 seconds and was maximal after 5 minutes. Several structurally unrelated inhibitors of arachidonic acid metabolism via the cyclooxygenase pathway totally abolished the PGE2 response to bradykinin. The stimulation of PGE2 formation was seen at and above 10 nmol/l of bradykinin. Des-Arg9-bradykinin was 100-fold less potent compared to bradykinin. Des-Arg9-Leu8-bradykinin did not antagonize bradykinin-induced PGE2 formation. Met-Lys-bradykinin and Lys-bradykinin also enhanced PGE2 formation in gingival fibroblasts. The stimulatory action of bradykinin on 3H-arachidonic acid release was observed after 30 s and progressively increased for at least 15 min. The stimulatory effect on 3H-arachidonic acid release by bradykinin was seen at and above 10 nmol/l, whereas des-Arg9-bradykinin was without effect up to a concentration of 1 mumol/l. Indomethacin did not affect bradykinin-induced 3H-arachidonic acid release. These data show that bradykinin, via a B2-receptor-mediated pathway, can stimulate arachidonic acid release and subsequent prostanoid formation in gingival fibroblasts. Consequently, gingival fibroblasts may contribute, by a bradykinin-regulated reaction, to the enhanced amounts of prostanoids found in gingival tissues and crevicular fluids in patients with periodontal diseases.

Analysis of Variance↗