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Biomedical subjects

B A Peskar

Publications and source records attributed to B A Peskar.

At least 37 records · Page 2Linked to original sources
PubMed1997

Dilatation by angiotensin II of the rat femoral arterial bed in vivo via pressure/flow-induced release of nitric oxide and prostaglandins.

1. The haemodynamic effects of angiotensin II (AII) and, for comparison, arginine vasopressin (AVP) in the femoral and superior mesenteric artery of urethane-anaesthetized rats were analysed with the ultrasonic transit time shift technique. 2. I.v. bolus injection of AII (0.1-3 nmol kg-1) and AVP (0.03-1 nmol kg-1) increased blood pressure which was accompanied by a decrease in blood flow through the superior mesenteric artery and an increase in femoral blood flow. The femoral hyperaemia was in part due to vasodilatation as indicated by a rise of femoral vascular conductance up to 200% relative to baseline. The femoral vasodilatation caused by AVP, but not AII, was followed by vasoconstriction. 3. Blockade of angiotensin AT1 receptors by telmisartan (0.2-20 mumol kg-1) prevented all haemodynamic responses to AII. 4. The femoral dilator responses to AII and AVP depended on the increase in vascular perfusion pressure since vasodilatation was reversed to vasoconstriction when blood pressure was maintained constant by means of a gravity reservoir. However, the AII-evoked femoral vasodilatation was not due to an autonomic or neuroendocrine reflex because it was not depressed by hexamethonium (75 mumol kg-1), prazosin (0.25 mumol kg-1) or propranolol (3 mumol kg-1). 5. The AII-induced femoral vasodilatation was suppressed by blockade of nitric oxide (NO) synthesis with NG-nitro-L-arginine methyl ester (L-NAME, 40 mumol kg-1) and reversed to vasoconstriction when L-NAME was combined with indomethacin (30 mumol kg-1), but was left unaltered by antagonism of endothelin ETA/B receptors with bosentan (37 mumol kg-1). 6. These results demonstrate that the effect of AII to increase systemic blood pressure and the resulting rise of perfusion pressure in the femoral artery stimulates the formation of NO and prostaglandins and thereby dilates the femoral arterial bed. This local vasodilator mechanism is sufficient to mask the direct vasoconstrictor response to AII.

Angiotensin II↗
PubMed1996

The prostacyclin stimulating plasma factor activity improves thromboresistance only if vascular PGI2-production is intact.

PGI2 is important in regulating platelet vessel wall interaction (1). In perfusion chamber experiments the amount of PGI2 formed was inversely related to the amount of platelets deposited (2). In 1978 a plasma factor was described which stimulates vascular PGI2-production (3). In later years, this activity has been monitored in different patient groups (for review see 4). Interestingly, it has been found that diseases associated with an increased bleeding tendency such as uraemia (5) or hepatic failure (6) were associated with an increased PF-activity while others with an enhanced thrombophilia sometimes show an absence of PF-activity (7). Recently, the PGI2 stimulating plasma factor has been purified and cloned (8). It was the aim of these experiments to assess whether PF-activity plays a role in local hemostasis regulation under in-vivo flow conditions and whether this is dependent on the presence of an intact PGI2-formation.

Adult↗
PubMed1996

Effect of a 5-lipoxygenase inhibitor on nerve growth factor-induced thermal hyperalgesia in the rat.

Intraplantar injection of mouse beta (2.5S) nerve growth factor (NGF) caused thermal hyperalgesia and stimulated release of immunoreactive leukotriene B4 from the rat paw skin. Both effects of NGF were prevented by the 5-lipoxygenase inhibitor, (R)-2-[4-quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid (BAY X1005). BAY X1005 did not affect bradykinin-induced thermal hyperalgesia. These results suggest the participation of 5-lipoxygenase products of arachidonate in NGF-induced local thermal hyperalgesia.

Animals↗
PubMed1996

Passive smoking and platelet thromboxane.

While active smoking is known to enhance platelet thromboxane production, no data on passive smoking is available yet. The influence of single and repeated exposure to passive smoke for 60 minutes in a 18 m3 room was assessed in non-smokers as compared to sex and age matched smokers. All the evaluated measures (malondialdehyde, plasma thromboxane B2, 11-dehydro-thromboxane B2, serum thromboxane B2, conversion of exogenous arachidonic acid to thromboxane B2 and to hydroxy-5, 8,10-heptadecatrienoic acid) were higher in smokers than non-smokers at baseline, immediately and 6 hours after passive exposure to cigarette smoke. Repeated exposure of non-smokers rendered their platelets more activated becoming close to the behaviour of smokers. These results indicate that passive smoking may activate thromboxane A2 release from the platelets, contributing to the development of hemostatic imbalance.

Adult↗
PubMed1996

Effects of single oral doses of lysine clonixinate and acetylsalicylic acid on platelet functions in man.

Lysine clonixinate is an analgesic drug with a so far unknown mechanism of action. We have determined its effect on platelet cyclooxygenase in man. Biosynthesis of thromboxane (TX)B2 and prostaglandin (PG)F2 alpha in clotting whole blood ex vivo as well as collagen-induced platelet aggregation measured before and at various time points after oral administration of 125 mg lysine clonixinate were compared to results obtained with 500 mg acetylsalicylic acid (ASA). While biosynthesis of both TXB2 and PGF2 alpha measured radioimmunologically was inhibited significantly 2.5 h, but not 6 h, after administration of lysine clonixinate, inhibition by ASA was much greater and still highly significant after 48 h. Similarly, collagen-induced aggregation of platelet-rich plasma was inhibited for a longer period and to a greater extent after administration of ASA than after lysine clonixinate. Our results indicate that lysine clonixinate is a cyclooxygenase inhibitor of moderate potency. It remains to be investigated whether mechanisms other than inhibition of cyclooxygenase contribute to the analgesic activity of lysine clonixinate.

Administration, Oral↗
PubMed1996

Inhibition of eicosanoid release from synovial organ culture by incubation with tepoxalin and its acid metabolite.

The pharmacological profile of a novel dual inhibitor, tepoxalin and of its carboxylic acid metabolite on cyclooxygenase and lipoxygenase pathways was evaluated by in vitro incubation with synovial tissue. Tissue specimens obtained at surgery in rheumatoid arthritis (RA, n = 10) or osteoarthritis (OA, n = 11) patients were incubated. Tepoxalin (10(-7), 10(-6), 10(-5) M) decreased eicosanoid release calculated in % of tyrode control for OA: LTC4 to 71-33%, 6-keto-PGF1a to 37-20%, PGE2 to 29-6%. For RA: LTC4 to 56-22%, 6-keto-PGF1a to 43-22%, PGE2 to 57-32%. Similarly, its metabolite (10(-7), 10(-5)M) decreased release in OA: LTC4 to 99 and 60%, PGE2 to 42 and 20%, 6-keto-PGF1a to 54 and 25%. In RA:LTC4 to 81 and 45%, PGE2 to 61 and 30%, 6-keto-PGF1a to 46 and 18%. Significance (P < 0.05) was achieved for all but 1 group (LTC4 metabolite at 10(-7)M vs tyrode). In summary a marked and dose dependent decrease of LT and PG release was obtained when incubating the dual inhibitor tepoxalin and its active carboxylic acid metabolite with synovial tissue at doses expected to be reached in the joint during therapy.

6-Ketoprostaglandin F1 alpha↗
PubMed1996

The effects on platelet aggregation and prostanoid biosynthesis of two parenteral analgesics: ketorolac tromethamine and dipyrone.

The pharmacokinetics and effects on platelet function of dipyrone (1.0 g; 2.5 g; i.v.) and ketorolac tromethamine (30 mg; i.m.) were studied in a three-way crossover study in twelve healthy subjects. The biosynthesis of thromboxane A2 in clotting whole blood ex vivo as well as collagen-induced platelet aggregation were determined before and up to 48 h after administration. Both prostanoid biosynthesis and platelet aggregation were inhibited by ketorolac tromethamine for a significantly longer period of time than by both doses of dipyrone. The changes in platelet functions correlated well with the serum concentrations of ketorolac or 4-methylaminoantipyrine and 4-aminoantipyrine. Using the sigmoidal Emax model the mean serum concentration (SD) of ketorolac, 4-methylaminoantipyrine and 4-aminoantipyrine inhibiting platelet TXB2 generation by 50% (EC50) in vitro was found to be 0.088 +/- 0.031, 1.2 +/- 0.3 and 10.2 +/- 3.4 micrograms ml-1, respectively. In conclusion the recovery of platelet function after dipyrone administration is faster as compared to ketorolac tromethamine. This is in line with clinical observations and may be an advantage when these drugs are given as postoperative analgesics at the doses tested.

Adult↗
PubMed1995

Interaction of 5-aminosalicylic acid with nitric oxide on rat aortic strips and human platelets.

We have examined the interactions of 5-aminosalicylic acid with nitric oxide (NO). Phenylephrine-precontracted rat aortic strips with intact endothelium were further contracted by 5-aminosalicylic acid (50-200 microM) in a concentration-dependent manner. Removal of endothelium, inhibition of guanylate cyclase by methylene blue, inhibition of NO biosynthesis by NG-nitro-L-arginine as well as in inactivation of NO by oxyhemoglobin abolished the effect of 5-aminosalicylic acid. The antiaggregatory effects of 3-morpholinosydnonimine and rat peritoneal neutrophils, which are due to release of NO, were diminished in a concentration-dependent manner by 5-aminosalicylic acid (50-250 microM). In both experimental models the effects of 5-aminosalicylic acid were significantly reduced by superoxide dismutase in a concentration which alone exhibited no effect. Since NO might act as a cytotoxic and vasodilating mediator, our results suggest that inactivation of NO by 5-aminosalicylic acid could contribute to the therapeutic activity of the drug in inflammatory bowel disease.

Aminosalicylic Acids↗
PubMed1995

A neutrophil-derived NO-synthase (NOS) inhibitor.

In the present work we have demonstrated that the low NOS activity of circulating blood neutrophils is related to an endogenous inhibitory factor. This factor inhibits constitutive NOS (cNOS) of cerebellum and inducible NOS (iNOS) of macrophages in a concentration-dependent manner. Boiling only partially diminished its activity. The inhibition of cNOS was specific, since to some degree NADPH (0.5-4 mM) and more effectively L-arginine (0.1-1 mM), but not D-arginine, reversed the inhibition.

Amino Acid Oxidoreductases↗
PubMed1995

Effects of lysine clonixinate and ketorolac tromethamine on prostanoid release from various rat organs incubated ex vivo.

The release of prostanoids from rat brain, gastric mucosa, lungs and kidneys incubated ex vivo has been investigated for up to 5 h after oral administration of 10 mg/kg lysine clonixinate or 1 mg/kg ketorolac tromethamine. Additionally, 60 min after drug administration, a time point of near-maximal inhibition of prostanoid release, the effects of 2.5, 10 and 30 mg/kg lysine clonixinate and of 0.0225, 0.15 and 1 mg/kg ketorolac tromethamine were compared. In all organs investigated both drugs inhibited fatty acid cyclooxygenase (COX) in a dose-dependent manner, but ketorolac tromethamine was more potent and had a longer-lasting effect than lysine clonixinate. While the ID50 values for lysine clonixinate were in the same order of magnitude for all 4 organs investigated, ketorolac tromethamine exhibited some organ selectivity with a particularly high activity in the kidneys. This effect might be related to the renal toxicity of ketorolac tromethamine. On the other hand, the difference in potency was smallest in brain suggesting that inhibition of central prostanoid biosynthesis could contribute to the rapid and effective inhibition of pain by both drugs. IC50 values for inhibition of purified COX-1 and COX-2 in vitro were slightly lower for lysine clonixinate (2.4 and 24.6 micrograms/ml, respectively) than for ketorolac tromethamine (3.7 and 25.6 micrograms/ml, respectively).

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Mediation by prostaglandins of the nitric oxide-induced neurogenic vasodilatation in rat skin.

1. Intraplantar administration of the nitric oxide (NO) donor, sodium nitroprusside (SNP), induces hyperaemia in the rat paw skin, which is in part due to release of calcitonin gene-related peptide (CGRP) from afferent nerve fibres. The present study examined whether prostaglandins or other inflammatory mediators participate in the neurogenic vasodilatation caused by SNP. Blood flow in the plantar hindpaw skin of urethane-anaesthetized rats was measured by laser Doppler flowmetry. 2. The hyperaemic responses to intraplantar administration of the NO donors SNP (150 pmol) and 3-morpholino-sydnonimine (SIN-1, 15 nmol) were attenuated by 45% and 61%, respectively, after injection of the CGRP antagonist, CGRP8-37 (50 nmol kg-1, i.v.) which did not significantly change baseline blood flow. 3. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 15 mg kg-1, i.v.), the bradykinin antagonist Hoc-140 (100 nmol kg-1, i.v.) and the histamine antagonists, pyrilamine (2 mg kg-1, i.v.) plus cimetidine (10 mg kg-1, i.p.) were without effect on baseline blood flow and the vasodilatation caused by SNP. 4. The cyclo-oxygenase inhibitors, indomethacin (10 mg kg-1, i.p.) and flurbiprofen (5 mg kg-1, i.p.) depressed the SNP-induced hyperaemia by 65% and 42%, respectively, without altering baseline blood flow. The ability of CGRP8-37 to inhibit the vasodilator response to SNP was lost in indomethacin-treated rats. 5. Intraplantar administration of prostaglandin E2 (PGE2, 15 pmol) evoked cutaneous vasodilatation which was attenuated by 66% after administration of CGRP8-37 but remained unaltered by indomethacin or L-NAME. 6. These data indicate that the neurogenic hyperaemia which in rat skin is induced by intraplantar administration of NO donors involves the formation of prostaglandins which in turn cause release of the vasodilator peptide, CGRP, from perivascular afferent nerve fibres.

Animals↗
PubMed1995

[Thrombocyte function of healthy probands taking 50 mg of acetylsalicylic acid per day].

The antithrombotic effect of acetylsalicylic acid (ASS) is attributed in part to its inhibitory action on platelet cyclooxygenase and, thereby, thromboxane A2 (TXA2) formation. The therapeutic goal of low-dose ASS regimens was the development of a preparation showing a high inhibitory capacity on platelet TXA2 generation whilst leaving vascular prostaglandin I2 (PGI2) synthesis unaffected, thereby minimizing side effects. The effect of a new acid-resistant preparation of 50 mg ASS (Thrombo-ASS 50 mg) on plasma levels of ASS, salicylate, TXB2, 11-dehydro-thromboxane B2, serum thromboxane B2 and malonyl dialdehyde, the conversion of exogenous 14C-arachidonic acid to TXB2 and hydroxy-5,8,10-heptadecatrienoic acid (HHT), as well as on the urinary metabolites 2,3-dinor-6-oxo-PGF1 alpha and 2,3-dinor TXB2, were compared in a crossover trial to those of a marketed preparation (Aspirin 100 mg) in healthy volunteers after a single dose and repeated administration of ASS. While platelet activity was inhibited by both the test and the reference substance to a comparable extent, vascular PGI2 production (as determined by urinary 2,3-dinor-6-oxo-PGF1 alpha excretion) was less affected by the test substance. These findings confirm the claim that a dosage of 50 mg ASS administered daily as an enteric coated or uncoated tablet is sufficient to almost completely block platelet cyclooxygenase, while the respective vascular enzyme is only minimally affected.

Adult↗
PubMed1995

PGE0 inhibits collagen and glycosaminoglycan-synthesis in the rabbit arterial wall.

The influence of 13,14-dihydro-PGE1 (PGE0), a biologically active metabolite of PGE1, on collagen and glycosaminoglycan synthesis by the rabbit arterial wall was assessed and compared with the effect of PGE1. Collagen (COL) and glycosaminoglycan (GAG) synthesis was measured using 14C proline- and 35S-incorporation respectively and both were subsequently quantified by autoradiography. PGE1 decreased GAG-synthesis by 40%, while PGE0 caused a 25% decrease. COL-synthesis after PGE1 treatment was diminished by 35%, while the biologically active metabolite caused a drop of 30%. Five and 15 micrograms/kg doses of both compounds were almost equally effective, 1 microgram was without effect. These findings indicate that PGE0 shares the inhibitory effect of PGE1 on COL and GAG biosynthesis. This metabolite has about 60 to 70% of the biological activity of its parent compound PGE1. These results suggest that part of the effects of PGE1 in inhibiting extracellular matrix production could be due to its metabolite PGE0.

Alprostadil↗
PubMed1994

Modulation of nitric oxide effects by flurbiprofen enantiomers and nefopam and its relation to antinociception.

We have examined the interactions of the analgesics, R- and S-flurbiprofen and nefopam, with nitric oxide (NO) in several experimental systems. Phenylephrine-precontracted rat aortic strips with intact endothelium were relaxed by R- and S-flurbiprofen and nefopam in a concentration-dependent manner. Removal of endothelium, inhibition of guanylate cyclase, inhibition of NO biosynthesis and inactivation of NO significantly reduced these relaxations. R- and S-flurbiprofen as well as nefopam enhanced the inhibition of platelet aggregation caused by rat peritoneal neutrophils or 3-morpholinosydnonimine. The antinociceptive effects of R- and S-flurbiprofen in the mouse writhing test as well as those of nefopam in the hot plate test were not significantly affected by administration of NO synthase inhibitors. We conclude that the increase in the biological activity of NO by R- and S-flurbiprofen and nefopam does not play a major role in the antinociceptive activity of the drugs, but might contribute to acute hypotension, a side-effect occasionally seen with flurbiprofen and nefopam.

Analgesics↗
PubMed1994

Isradipine decreases arterial thrombogenicity in rabbits. A morphometric and radioisotopic study.

The effect of isradipine, a calcium antagonist, on aortic and iliac wall thrombogenicity was examined in rabbits. After one week of dosing, the abdominal aortic and iliac artery endothelium was abraded using a Fogarthy catheter. One group of animals (n = 8) was dosed for one week with isradipine 0.3 mg/kg. A second group of animals received 10 mg acetylsalicylic acid (ASA)/kg daily in addition, while a third group received the vehicle only. Finally, a fourth group of animals (n = 8) was treated with ASA only. The percentage denuded surface covered with contact (unspread) platelets decreased significantly (p < 0.01) from 14.7 +/- 2.0 to 9.3 +/- 2.1 (6.2 +/- 0.8 to 3.7 +/- 0.4). The amount of contact and spread platelets was diminished from 84.9 +/- 5.6 to 71.4 +/- 4.4 (91.8 +/- 5.3 to 75.2 +/- 4.6). Platelet thrombi decreased from 7.4 +/- 0.9 to 4.6 +/- 1.4 (9.4 +/- 1.9 to 5.2 +/- 0.7) in the aortic and the iliac artery, respectively. In-platelet deposition decreased by 39.9 and 41.9%. Concomitant ASA therapy not only abolished the effect of isradipine but enhanced thrombogenicity, probably as a result of almost complete blockade of vascular PGI2-production.

Animals↗