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J G Filep

Publications and source records attributed to J G Filep.

64 records · Page 4Linked to original sources
PubMed1991

Antiaggregatory and hypotensive effects of endothelin-1 in beagle dogs: role for prostacyclin.

The effects of endothelin-1 (ET-1) on blood pressure and platelet aggregation were studied in anesthetized beagle dogs. Platelet aggregation was monitored in vivo by a filter-loop technique and in vitro by using platelet-rich plasma and whole blood. ET-1 (0.03-0.3 nmol/kg) induced a transient dose-dependent hypotension and inhibited platelet aggregation in vivo. These changes were accompanied by dose-dependent elevation of plasma 6-keto-PGF1 alpha levels. Pretreatment of animals with indomethacin (2 mg/kg plus 3 mg/kg/h) completely abolished the antiaggregatory action of ET-1 and significantly attenuated the hypotensive response to ET-1. Intra-arterial infusion of prostacyclin at concentrations similar to those observed following ET-1 injections mimicked the antiaggregatory and hypotensive actions of ET-1. ET-1 (0.1-100 nM) did not modify platelet aggregation induced by ADP, collagen, and platelet-activating factor in vitro, suggesting that dog platelets do not possess ET-1 receptors. These findings indicate that the antiaggregatory and hypotensive actions of ET-1 in beagle dogs are mediated through release of prostacyclin.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Pharmacological modulation of endothelin-induced contraction of guinea-pig isolated airways and thromboxane release.

1. The aim of the present experiments was to study the possible involvement of known bronchoconstrictor substances in mediating the myotropic action of endothelin-1 (ET-1, human-porcine endothelin) in guinea-pig isolated airways. 2. ET-1 (1-100 nM) caused a dose-dependent contraction of guinea-pig trachea, upper bronchus and parenchyma. The contractions developed slowly, reaching maximal values 4-6 min after addition of the peptide. 3. The contractile action of ET-1 was significantly attenuated by indomethacin (10 microM), a cyclo-oxygenase blocker. BM 13505 (5 microM), a thromboxane receptor antagonist, FPL 55712 (19 microM) and YM 16638 (1 microM), antagonists of the sulphidopeptide leukotrienes, BN 52021 (10 microM) and WEB 2086 (1 microM), platelet-activating factor receptor antagonists in all three tissue preparations studied. 4. Pretreatment of the airway tissues with compound U 75302 (3 microM), a selective leukotriene B4 receptor antagonist, or with a mixture of antagonists containing methysergide (0.75 microM), phentolamine (0.4 microM), propranolol (13 microM), atropine (0.4 microM) and diphenhydramine (0.45 microM) did not modify the myotropic action of ET-1. 5. ET-1, 10 and 100 nM induced three, and nine fold increases in thromboxane A2 release from lung parenchymal strips. 6. ET-1-induced thromboxane A2 release was completely abolished by indomethacin, and was significantly attenuated by BN 52021, WEB 2086 and FPL 55712. Neither BM 13505 nor YM 16638 exerted a significant effect on thromboxane release. 7. The present findings show that contraction of guinea-pig airway smooth muscle by ET-1 is mediated, in part, by the release of thromboxane A2, sulphidopeptide leukotrienes and platelet-activating factor, and suggest that the increased thromboxane A2 release following ET-1 is partly a consequence of enhanced synthesis of sulphidopeptide leukotrienes and platelet-activating factor.

Animals↗
PubMed1991

Effects of endothelin-1 on vascular permeability in the conscious rat: interactions with platelet-activating factor.

1. The objectives of the present experiments were to assess the effects of endothelin-1 on the macrovascular permeability in selected vascular beds, to study the involvement of platelet-activating factor (PAF) in vascular responses to endothelin-1 and to examine the vascular effects of combined administration of endothelin-1 and PAF in conscious rats. 2. Intravenous bolus injection of endothelin-1 (0.1-2 nmol kg-1) resulted in a dose-dependent biphasic change in mean arterial blood pressure (MABP) with initial transient hypotension followed by a prolonged pressor action. These changes were accompanied by a dose-dependent increase in haematocrit values. 3. Endothelin-1 (0.1 and 1 nmol kg-1) increased dose-dependently the vascular permeability of the trachea, upper and lower bronchi, stomach, duodenum, spleen and kidney (up to 240%) as measured by the extravasation of Evans blue dye. The permeability of pulmonary parenchyma, liver and pancreas was not affected significantly by endothelin-1 treatment. 4. Pretreatment of animals with the specific PAF receptor antagonist, WEB 2086 (1 mg kg-1, i.v.) or BN 52021 (10 mg kg-1, i.v.) reduced the endothelin-1 (1 nmol kg-1)-induced rise in haematocrit by about 50 and 30%, respectively. Both antagonists were highly effective at inhibiting protein extravasation in the stomach, duodenum and kidney. On the other hand, BN 52021, but not WEB 2086, significantly attenuated the effect of endothelin-1 on permeability in the lower bronchi and spleen. Neither WEB 2086 nor BN 52021 modified the changes in MABP evoked by endothelin-1.5. When low doses of endothelin-1 (0.1 nmolkg-')and PAF (0.19nmolkg-')were administered simultaneously, enhanced protein extravasation was detected in the upper and lower bronchi, whereas neither endothelin-1 nor PAF by themselves affected vascular permeability in these tissues. These changes occurred in the absence of significant changes in MABP.6. Combined administration of higher doses of endothelin-1 (1nmolkg-') and PAF (1.9nmolkg-') resulted in marked increases (up to 530%) in protein extravasation in the airways, pancreas, stomach and duodenum. The effect of endothelin-1 on permeability was not affected by PAF in the spleen, whereas it was completely inhibited by PAF in the kidney. Combined injection of endothelin-1 and PAF resulted in a slight, but significant increase in MABP.7. The present findings show that endothelin-1 is capable of increasing vascular permeability in selected vascular beds including the airways, gastrointestinal tract and kidney, and suggest that PAF may mediate, in part, its action on permeability, but not its hypotensive action. The present data also suggest that endothelin-1 and PAF can act in concert to increase vascular permeability in rat airways and gastrointestinal tract.

Animals↗
PubMed1991

Interactions between platelet-activating factor and prostanoids during mesenteric ischemia-reperfusion-induced shock in the anesthetized dog.

The effects of platelet-activating factor (PAF) on prostanoid release during mesenteric ischemia-reperfusion-induced shock were investigated in anesthesized dogs 1) by measuring plasma levels of prostaglandin (PG)F2 alpha, 6-keto-PGF1 alpha and thromboxane (TX)B2 in the superior mesenteric vein during reperfusion following 2 hr occlusion of the superior mesenteric artery; 2) by monitoring the effects of BN 52021, a specific PAF receptor antagonist and indomethacin on hemodynamic parameters and prostanoid levels; and 3) by studying circulatory responses to PAF and PGF2 alpha injected into the superior mesenteric vein in the presence of BN 52021 or indomethacin. Restoration of the blood flow following 2 hr ischemia resulted in an immediate dramatic decrease in mean arterial blood pressure, with a concomitant increase in mean portal venous pressure, hematocrit values, and plasma prostanoid levels. Pretreatment of the animals either with BN 52021 (4 mg.kg-1) or indomethacin (2 mg.kg-1 plus 3 mg.kg-1hr-1) prevented the circulatory collapse and the increase in prostanoid levels during reperfusion. Administration of exogenous PAF (0.1 micrograms.kg-1) or PGF2 alpha (10 micrograms.kg-1) into the superior mesenteric vein evoked hypotension similar to that observed during reperfusion. Pretreatment of the animals with BN 52021 completely prevented the effects of PAF but failed to modify the responses to PGF2 alpha. Indomethacin at a dose that inhibited prostanoid formation was highly effective to attenuate the hypotensive response to exogenous PAF. These data suggest that prostanoid formation may be secondary to PAF release in circulatory collapse evoked by intestinal ischemia-reperfusion and give further support to the notion of the importance of PAF prostanoid interaction during ischemia-reperfusion-induced shock.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Inhibition by calcium channel blockers of the binding of platelet-activating factor to human neutrophil granulocytes.

The inhibitory action of calcium channel blockers on platelet-activating factor (PAF)-induced activation of human polymorphonuclear granulocytes (PMNL) and on the binding of [3H]PAF to neutrophils was studied. Verapamil and diltiazem inhibited PAF (10(-8)-10(-15) M)-induced degranulation and superoxide production in a dose-dependent manner, with pA2 values of 5.6 and 6.1 for verapamil and 5.9 and 6.2 for diltiazem, respectively. Both channel blockers inhibited the specific binding of [3H]PAF to PMNL in dose-dependent fashion, with Ki values of 3.9 +/- 0.6 X 10(-5) M and 3.2 +/- 0.4 X 10(-5) M for verapamil and diltiazem, respectively. Scatchard analysis of the binding data revealed that both calcium channel blockers decreased the receptor binding affinity and slightly increased the number of high-affinity PAF receptors, whereas they did not affect the binding affinity and number of low-affinity receptors. These results indicate that calcium channel blockers can inhibit neutrophil responses elicited by PAF by a mechanism other than inhibition of calcium influx and suggest that the PAF receptor may be closely associated with calcium channels.

Binding, Competitive↗
PubMed1990

Endothelin-induced constriction of guinea pig airways: role of platelet-activating factor.

Endothelin-1 (ET-1, 1-100 nM) evoked a concentration-dependent contraction of guinea pig trachea and upper bronchi in vitro. The response was significantly attenuated by BN 52021 (ginkgolide B, 10 microM), a specific receptor antagonist to platelet-activating factor. Precontraction of the tissues with endothelin (50 nM) desensitized tissues to platelet-activating factor (200 nM), while preincubation of the tissues with platelet-activating factor slightly inhibited the response to endothelin. These findings suggest that platelet-activating factor may mediate endothelin-induced airway contraction in the guinea pig.

Animals↗
PubMed1990

Endothelin induces thromboxane release and contraction of isolated guinea-pig airways.

The possible role of thromboxane (TX) A2 in mediating the bronchopulmonary effect of endothelin (ET) was studied in isolated guinea pig airways (trachea, upper bronchi and parenchyma). ET (1-100 nM) evoked a concentration-dependent contraction of all three tissues. The contractile response was significantly attenuated by pretreatment of the tissues with the specific thromboxane receptor blockers, BM 13177 (10-50 microM) and BM 13505 (1-5 microM). Furthermore, ET caused a dose-dependent TXB2 release from trachea and parenchyma. These findings suggest that the bronchopulmonary action of ET is mediated, in part, by the release of TXA2.

Animals↗
PubMedDate not supplied

Endothelin derivatives showing potent effects in the guinea pig trachea.

Endothelin (ET-1) was synthesized by solid-phase peptide synthesis. To prevent side reactions with tryptophan residue, a formyl group was used to protect the beta-indole moiety. The two disulfide bridges were formed selectively using S-methylbenzyl for the cysteine residues in positions 3 and 11, and S-acetamidomethyl for positions 1 and 15. Crude synthetic ET-1 was obtained after deprotection and cleavage from the resin by HF, followed respectively by potassium ferricyanide and iodine oxidations, in order to generate sequentially the monocyclic and bicyclic forms of the peptide. Finally, Trp(For) was deprotected by a treatment with piperidine. After each step, a sample of peptide was isolated and purified by RP-HPLC. The biological activity of these synthetic peptides was evaluated on guinea pig tracheal strips. The results suggest that oxidation of Met-7 and/or formylation of Trp-21 do not affect the biological activity of ET-1 in the guinea pig trachea. Moreover, although a decrease of potency and intrinsic activity was observed, the monocyclic analog containing Cys(Acm) residues at positions 1 and 15 exhibited substantial constrictor activity. This result, contrasting with that observed with several vascular preparations, suggests that the guinea pig trachea contains a distinct ET receptor population.

Animals↗
PubMedDate not supplied

Effect of renin-angiotensin system blockade on the expression of the angiotensinogen gene and induction of hypertrophy in rat kidney proximal tubular cells.

Studies have shown that high levels of glucose and angiotensin II (Ang II) stimulate hypertrophy and the expression of matrix protein genes in mouse proximal tubular cells in vitro. The present study tested the hypothesis that blockade of the renin-angiotensin system (RAS) inhibits the stimulatory effect of high levels of glucose on the expression of the renal angiotensinogen (ANG) gene and the formation of Ang II and subsequently attenuates the induction of hypertrophy in kidney proximal tubular cells. Immortalized rat proximal tubular cells (IRPTC) were cultured in monolayer. The levels of expression of rat ANG and ANG mRNA in the IRPTC were quantified by specific radioimmunoassays for rat ANG (RIA-rANG) and by a reverse-transcription polymerase chain reaction (RT-PCR) assay, respectively. Hypertrophy of IRPTC was analyzed by flow cytometry (FACScan) and cellular protein assay. Our studies showed that losartan (an Ang II (AT(1))-receptor blocker), perindopril and captopril (inhibitors of angiotensin-converting enzyme) blocked the stimulatory effect of a high level of glucose (i.e. 25 mM) on the expression of the rat ANG gene and hypertrophy in IRPTC but not by the Ang II (AT(2))-receptor blocker. Our studies indicate that the blockade of RAS is effective in inhibiting the stimulatory effect of hyperglycemia on the expression of the ANG gene and hypertrophy in IRPTC, supporting the notion that the local formation of intrarenal Ang II may play a role in the development of renal hypertrophy during early diabetes.

Angiotensin II↗