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Biomedical subjects

A G Herman

Publications and source records attributed to A G Herman.

At least 163 records · Page 9Linked to original sources
PubMed1989

Kinetics of serotonin uptake in isolated rabbit lungs.

The single-pass, bolus-injection method was used to study the effect of serotonin (5-HT) concentration on the extraction of 5-HT by isolated perfused rabbit lungs. The extraction pattern suggested that an uptake model, which includes multiple parallel uptake processes, provided a better representation of the data than the simple Michaelis-Menten equation, which has commonly been used to fit the saturable uptake data in previous studies. In particular, the rabbit lung data could be fit with two such parallel pathways. Since the 5-HT uptake could virtually be completely blocked by imipramine, both pathways can be considered to be carrier-mediated processes. The high-affinity pathway was saturable within the range of concentrations studied, with a Km and Vmax of approximately 0.84 microM and 0.21 nmol.s-1.g wet lung wt-1. The Km for the low-affinity pathway was larger than concentrations for which accurate uptake measurements are practical in the perfused organ. Thus, for the low-affinity pathway, only Vmax/Km was identifiable. Vmax/Km values for the high- and low-affinity pathways were approximately 2.87 and 0.35 ml/s, respectively. The results suggest that it will be worthwhile to investigate the behavior of these uptake parameters in response to changes in lung physiology and endothelial function in future studies.

Animals↗
PubMed1989

Interaction between SIN-1 and prostacyclin in inhibiting platelet aggregation.

SIN-1, the metabolite of molsidomine, caused a dose-dependent inhibition of the aggregation of rabbit platelets induced by adenosine diphosphate (ADP) and the stable thromboxane mimetic U-46619. Molsidomine was inactive in this respect. In the presence of a threshold concentration of prostacyclin, the antiaggregating activity of SIN-1 became more pronounced. As a result, the dose-response curve of SIN-1 was shifted to the left. These findings suggest that SIN-1 could be of therapeutic value to suppress platelet aggregation during atherosclerotic disease when the endogenous supply of endothelium-derived relaxing factor is compromised.

Animals↗
PubMed1989

Granulocyte chemotactic protein/interleukin-8 induces plasma leakage and neutrophil accumulation in rabbit skin.

Granulocyte chemotactic protein/Interleukin-8 (GCP/IL-8), purified to homogeneity from endotoxin- or mitogen-stimulated human mononuclear cells, was injected intradermally into rabbits to evaluate the proinflammatory properties of this novel cytokine. In the presence of a vasodilator substance, pmol amounts of GCP/IL-8 induced neutrophil accumulation that was fast in onset, relatively short of duration (half life 60 to 70 minutes), and was associated with a parallel time course of plasma protein extravasation. GCP/IL-8-induced edema formation was found to be neutrophil dependent. These data provide evidence that GCP/IL-8 fulfills two important criteria for consideration as an inflammatory mediator. It is possible that endogenous GCP/IL-8, if produced locally by tissue macrophages, may contribute to the initiation of the inflammatory response to infection.

Animals↗
PubMed1988

Prostacyclin biosynthesis and reduced 5-HT uptake after complement-induced endothelial injury in the dog isolated lung.

1. Pulmonary prostacyclin (PGI2) biosynthesis was evaluated in relation to endothelial integrity before and after complement activation in isolated plasma-perfused lung lobes of the dog. 2. The plasma was activated with zymosan (ZAP, n = 4), yeast cells (YAP, n = 4) or yeast with 3 microM indomethacin (Indo + YAP, n = 3). Immunoreactive 6-oxo-prostaglandin F1 alpha (i-6-oxo-PGF1 alpha) and thromboxane B2 (iTXB2) were measured to monitor PGI2 and TXA2 biosynthesis. 3. The kinetic parameters Km and Vmax of 5-hydroxytryptamine (5-HT) uptake were calculated on the basis of multiple indicator diffusion data to evaluate endothelial integrity. 4. YAP and ZAP induced a biphasic increase of the arterial perfusion pressure. The immediate pressure peak was partly mediated by TXA2 and the TXB2 was subsequently cleared by the lung. 5. The apparent Vmax of 5-HT uptake remained constant throughout the experiment. Thus, complement activation did not affect the number of endothelial 5-HT carrier sites available to the perfusate. 6. The apparent Km of 5-HT uptake was enhanced in 9 lungs exposed to activated plasma complement for 20 min. This decreased affinity for 5-HT probably reflects endothelial injury. It was transient as the apparent Km had returned to the baseline value after 60 min. 7. PGI2 clearance and biosynthesis were virtually absent in the control period. PGI2 formation increased drastically after infusion of ZAP or YAP and was proportional to the endothelial injury expressed as elevated Km or pulmonary oedema. Thus, PGI2 biosynthesis might be a marker of severe endothelial distress.

Animals↗
PubMed1988

Platelet inhibition by endothelium-derived relaxing factor from the rabbit perfused aorta.

1. The platelet inhibiting activity of endothelium-derived relaxing factor (EDRF) released by the perfused thoracic aorta of the rabbit was investigated. 2. The aortic effluent superfused a ring of the abdominal aorta without endothelium in order to bioassay EDRF. Aliquots of effluent were collected on rabbit washed platelets and aggregation induced by U-46619 was measured after 1 min. Prostacyclin (PGI2) was monitored by radioimmunoassay of 6-oxo-prostaglandin F1 alpha. 3. Acetylcholine (ACh) caused a dose-dependent secretion of EDRF, PGI2 and anti-aggregating activity. Plasma and methylene blue suppressed the platelet inhibition by the effluent. 4. The PGI2 content of the effluent was not sufficient to account for all the anti-aggregating activity. However, the platelet inhibition disappeared when PGI2 formation was blocked with indomethacin. 5. Compression of the thoracic aorta increased the EDRF content in the effluent. A transient secretion of anti-aggregating activity was then observed in aortic effluent in the absence of PGI2. This activity coincided with the presumed EDRF peak in the effluent. 6. Superoxide dismutase enhanced the ACh-induced EDRF content and revealed secretion of an anti-aggregating substance when PGI2 formation was blocked. Pretreatment of the platelets with subthreshold concentrations of PGI2, or the cyclic GMP phosphodiesterase inhibitor RX-RE 56, also revealed the release of a labile platelet inhibitor in response to ACh. 7. The results indicate that EDRF released by fresh aortic endothelium may suppress platelet aggregation, particularly when PGI2 is present.

Acetylcholine↗
PubMed1988

The beta adrenoceptor blocker tertatolol causes vasodilatation in the isolated perfused vasoconstricted rat kidney.

The activity of the beta adrenoceptor antagonist tertatolol on renal vasoconstrictions was investigated. Infusion of increasing concentrations of tertatolol (10(-8) to 10(-5) M) progressively inhibited the constrictor responses to bolus injections of norepinephrine and to electrical stimulation in isolated perfused kidneys of both normotensive and spontaneously hypertensive rats. Also, in kidneys of normotensive rats the vasoconstrictions caused by serotonin and barium chloride were inhibited by tertatolol. During sustained vasoconstrictions induced by infusion of norepinephrine (6 X 10(-7) M) increasing doses of tertatolol (2.5 X 10(-7) g to 2 X 10(-5) g) caused rapid, reversible dilatations in the rat kidneys. The inhibitory responses caused by tertatolol were not antagonized by propranolol, atropine, hexamethonium, SCH23390, metoclopramide, mepyramine, cimetidine, naloxone, cocaine or indomethacin. During constrictions caused by norepinephrine, methylene blue significantly inhibited the renal vasodilatations caused by tertatolol, acetylcholine, papaverine and nitroglycerin but not those caused by atrial natriuretic factor. Unlike the other vasodilators, tertatolol did not inhibit the constrictions induced by prostaglandin F2 alpha (5 X 10(-6) M) in the rat kidneys. In canine renal arteries with endothelium, tertatolol (10(-9) to 10(-5) M) did not cause relaxations during contractions induced by norepinephrine, electrical stimulation or prostaglandin F2 alpha. Our data illustrate that tertatolol has potent vasodilator properties in the isolated perfused vasoconstricted rat kidney. The dilator response to the beta blocker cannot be inhibited by a variety of classical receptor blockers but ultimately seems to depend on the formation of cyclic GMP.

Adrenergic beta-Antagonists↗
PubMed1988

The endothelium inhibits the penetration of serotonin and norepinephrine in the isolated canine saphenous vein.

Serotonin can accumulate in the adrenergic nerves of vascular tissues. We have determined whether in the isolated perfused dog saphenous vein 1) luminal administration of serotonin can result in its accumulation in the adrenergic nerves and 2) endothelium can interfere with the transport of the amine into the vessel wall. Saphenous veins were perfused with medium containing [3H]serotonin, [3H]norepinephrine or [3H]epinephrine; after washout, significant amounts of 3H were detected in the veins. The 3H-accumulation was augmented when the endothelium was removed mechanically; the augmented accumulation was only observed when the [3H]amines reached the tissues from the intimal side. In coronary arteries perfused with [3H]serotonin, similar results were obtained. No increased 3H-accumulation was noted in veins without endothelium perfused in the presence of cocaine. Nerve stimulation of veins labeled with [3H]serotonin caused an augmented release of 3H from the tissues without endothelium. Pargyline augmented the accumulation of [3H]serotonin and [3H]norepinephrine and decreased the difference between tissues with or without endothelium only for norepinephrine. Perfusion of venous segments with platelets, labeled with [3H]serotonin, resulted in a 3H-content which was significantly higher in the veins without endothelium. Our experiments show that serotonin and other amines, applied luminally to perfused blood vessels, can accumulate in the adrenergic nerves and that the endothelium can reduce this accumulation. Serotonin, originating from aggregating platelets, can penetrate the vessel wall much easier at sites of endothelial denudation and this serotonin also can enter the adrenergic nerves.

Animals↗
PubMed1986

Effects of Iskedyl and its two constituents raubasine and dihydroergocristine on the release of [3H]noradrenaline and [3H]serotonin in canine basilar arteries.

In strips of isolated canine basilar arteries, previously labeled with 3 X 10(-7) M of either [3H]noradrenaline or [3H]serotonin, three consecutive periods of electrical stimulation (2 Hz) evoked a reproducible overflow of the respective [3H]amine. Increasing concentrations of raubasine (7.5 X 10(-7)-7.5 X 10(-6) M) did not influence the spontaneous 3H efflux but increased the stimulation-induced 3H overflow in a concentration-dependent way. The highest concentration of raubasine used (2.5 X 10(-5) M) caused an increased spontaneous 3H efflux but no longer augmented the stimulation-induced 3H overflow. Dihydroergocristine (5.4 X 10(-8)-1.8 X 10(-6) M) did not affect the spontaneous 3H efflux; the compound slightly but significantly reduced the stimulation-evoked 3H overflow concentration dependently. High concentrations of Iskedyl (mixtures of raubasine and dihydroergocristine in a 14:1 molar ratio) augmented the spontaneous 3H efflux and moderately decreased the stimulation-induced 3H overflow. Although some quantitative differences were noted, the compounds exerted similar effects on arteries labeled with either [3H]noradrenaline or [3H]serotonin. The most important difference detected was that DHEC decreased the stimulation-induced release of [3H]serotonin more than that of [3H]noradrenaline. Our results allow a comparison of [3H]noradrenaline and [3H]serotonin release in the dog basilar artery: the basal fractional release of [3H]serotonin was higher than that of [3H]noradrenaline while the stimulation-induced overflow was equal in both groups of tissues. The constituents of Iskedyl can profoundly affect the release of the neurotransmitters. Raubasine, a presynaptic alpha-receptor antagonist, increases the stimulation-induced release of the neurotransmitters and both DHEC, a presynaptic receptor agonist, and the combination of the compounds, Iskedyl, decrease the release of the neurotransmitters.

Animals↗
PubMed1986

Inhibition of rabbit platelet activation by lipoxygenase products of arachidonic and linoleic acid.

The hydroperoxy fatty acids, 15-hydroperoxyeicosatetraenoic acid (15-HPETE), 13-hydroperoxy and 9-hydroperoxyoctadecadienoic acid (13- and 9-HPODE) and the corresponding hydroxy compounds (15-HETE and 13-HODE) were synthesized and purified. Washed rabbit platelets were incubated with these fatty acid derivatives before aggregation was induced. Arachidonic acid-induced aggregation, as well as the secretion of ATP and the formation of thromboxane B2 (TXB2) were dose-dependently inhibited by these compounds. Low thrombin-, collagen- and ADP-induced aggregations were also suppressed by 15-HPETE. Platelet activation induced by the calcium ionophore A23187 and by high thrombin concentrations were not affected by 15-HPETE. In addition, doses of 15-HPETE which were inactive by themselves, potentiated the anti-aggregating activity of prostacyclin (PGI2). It is suggested that the hydroperoxy and hydroxy compounds suppress platelet activation by interference with the rise in cytoplasmic calcium in addition to the inhibition of cyclo-oxygenase.

Adenosine Triphosphate↗
PubMed1986

Modulation of prostacyclin biosynthesis by calcium entry blockers and extracellular calcium.

The influence of variations in the availability of extracellular Ca2+ and of Ca2+-entry blockers on prostacyclin production by mesothelial cells in culture was studied. The Ca2+-entry blockers nifedipine and verapamil suppressed the basal, as well as the thrombin-, bradykinin-, and ionophore A23187-stimulated biosynthesis by about 50-60%, but high concentrations were required and the inhibition was never complete. Basal prostacyclin formation was unaffected by a Ca2+-poor buffer, but showed 50% reduction in the Ca2+-free buffer. Although the thrombin-stimulated prostacyclin formation was not significantly influenced by a Ca2+-poor or a Ca2+-free buffer, prostacyclin release stimulated by A23187 and bradykinin was diminished in the presence of these modified incubation media; the reduction of bradykinin stimulated biosynthesis was rather small (30%). These results suggest that the Ca2+ from intracellular stores is sufficient for half maximal stimulation of the phospholipases involved in the biosynthetic pathway of prostacyclin and that--depending on the nature of the stimulus--different phospholipases are activated with varying requirements for free Ca2+.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Dexamethasone and prostacyclin biosynthesis by serosal membranes of the rabbit peritoneal cavity.

The effect of 2.5 microM dexamethasone on prostacyclin biosynthesis in isolated peritoneal serosa of the rabbit was studied. Pretreatment with dexamethasone for 90 min or more led to suppression of the subsequent prostacyclin biosynthesis in the absence of dexamethasone. This inhibition and the formation of extracellular non dialysable inhibitors were dependent on protein biosynthesis. These results indicate that glucocorticoids can partly suppress prostacyclin biosynthesis, probably via formation of lipocortin-like activity.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Biphasic response of intimal prostacyclin production during the development of experimental atherosclerosis.

Feeding a cholesterol rich diet (0.3%) to rabbits for up to 10 weeks resulted in morphological changes of the vascular wall. Microscopic evaluation of the aorta revealed a lipid infiltration and an intimal thickening containing foam cells, which both became more pronounced as the cholesterol feeding was more prolonged. The intimal prostacyclin production showed a transient increase after 2 weeks, but was significantly decreased after 6 weeks of diet and remained at this low level during the rest of the experiment. No significant changes in formation of thromboxane B2 by the platelets could be observed, whereas the production of 12-HETE was enhanced.

Animals↗
PubMed1986

Vitamin C increases the prostacyclin production and decreases the vascular lesions in experimental atherosclerosis in rabbits.

Feeding a cholesterol-rich diet (0.3%) to rabbits resulted in an intimal thickening and lipid infiltration of the aorta. The prostacyclin production by the vascular endothelium was significantly decreased, after a transient increase after 2 weeks of diet. The arachidonic acid metabolism in platelets was hardly changed. Addition of a low dose vitamin C (150 mg/day) to the cholesterol rich diet resulted in decreased lipid infiltration and intimal thickening and the transient increase of the prostacyclin production was postponed to the 4th week. Although this dose of vitamin C could not restore the decreased prostacyclin production observed after 6 weeks diet, a higher dose of vitamin C (600 mg/day), besides its beneficial effect on the lipid infiltration and the intimal thickening in the thoracic aorta, kept the intimal prostacyclin production at normal levels for at least 8 weeks.

Animals↗
PubMed1986

Effects of dexamethasone on prostacyclin biosynthesis in rabbit mesothelial cells.

We investigated whether glucocorticoids reduce the formation of arachidonic acid metabolites in a non myeloid cell type, the mesothelial cell, which is functionally and embryologically related to the vascular endothelial cell and which forms almost exclusively prostacyclin from arachidonic acid. Preincubation of rabbit mesothelial cells with 2.5 microM dexamethasone suppressed basal as well as bradykinin- or thrombin-stimulated prostacyclin biosynthesis. In further experiments bradykinin was selected as stimulus. The inhibition by dexamethasone was dose-dependent between 0.025 and 2.5 microM. The minimum contact period required for expression of this effect was 30 min and after a contact period of 60 to 120 min the inhibition reached a maximum, but was never complete. After 240 min, sufficient activity was secreted in the extracellular medium for inhibition of the prostacyclin formation in untreated cells. Experiments with cycloheximide were somewhat confused by its direct effects on prostacyclin biosynthesis, but still suggested that the anti-prostacyclin effect of dexamethasone required de novo protein biosynthesis. Our experiments indicate that glucocorticoids induce the formation of lipocortin-like factor(s) in non-phagocytic mesothelial cells, thereby suppressing the formation of prostacyclin, their main arachidonic metabolite.

Animals↗
PubMed1986

Cyclo-oxygenase blockers influence the effects of 15-lipoxygenase metabolites of arachidonic acid in isolated canine blood vessels.

In canine saphenous veins both the 15-hydroxy- and 15-hydroperoxy derivatives of arachidonic acid, 15HETE and 15HPETE, caused endothelium-independent contractions which were not affected by a variety of classical receptor antagonists. These contractions were markedly augmented by cyclooxygenase blockers; nifedipine, which did not influence the contractions induced by lipoxygenase products, inhibited the potentiating effect of indomethacin. In the veins, 15HETE and 15HPETE also induced spontaneous rhythmic contractions which persisted after several washings but could be blocked by inhibitors of cyclooxygenase. In coronary, splenic, renal and femoral arteries, 15HETE and 15HPETE caused contractions which were also augmented by indomethacin and were dependent on the influx of extracellular calcium as they were inhibited by verapamil. Both 15-lipoxygenase metabolites evoked relaxations during contractions induced by prostaglandin F2 alpha or the thromboxane-mimetic U46619. These relaxations were not endothelium-dependent but were inhibited by indomethacin; they did not occur when the initial contractions were caused by K+, norepinephrine or 5-HT. Our results illustrate multiple vascular actions of 15HETE and 15HPETE in dog blood vessels.

Animals↗