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1.
Exp Eye Res ; 78(5): 973-85, 2004 May.
Article in English | MEDLINE | ID: mdl-15051478

ABSTRACT

The prostaglandin F2alpha derivative, latanoprost (LT), used in glaucoma treatment, can induce pigmentation in irises of patients with hazel or heterochromatic eye colour. The mechanism by which LT induces pigmentation in the iris is not yet established, although it does not appear to induce proliferation of iridial melanocytes. The purpose of this study was to develop an in vitro model in which to investigate this mechanism. The pigmentary responses to LT and prostaglandin F(2alpha) (PGF(2alpha)) were examined in human iridial melanocytes alone or in co-culture with epithelial cells (non-ocular human epidermal keratinocytes and iris pigment epithelial cells) or mesenchymal cells (non-ocular dermal fibroblasts or iridial fibroblasts). Melanogenesis was assessed after 4 days culture with prostanoids, using dopa oxidase activity. Prostaglandin FP expression on human iridial fibroblasts and melanocytes was investigated using an immunofluorescent technique employing antibody to PGF(2alpha) receptor and RT-PCR. Iridial melanocytes did not show a convincing increase in dopa oxidase when cultured alone but in the presence of fibroblasts (ocular or non-ocular) there was a significant increase (25-30%) in dopa oxidase activity in response to 10(-7)-10(-5)m LT and PGF(2alpha). Co-culture of melanocytes with epithelial cells, while leading to increased dopa oxidase activity, did not lead to any melanogenic response to LT or PGF(2alpha). FP receptor expression was detected on fibroblasts but not iridial melanocytes by immunocytochemistry and RT-PCR. The melanocyte/fibroblast co-culture model developed in this study also showed that LT and PGF(2alpha) increased dopa oxidase activity in melanocytes from donors with brown but not blue eyes. These results suggest that LT may be inducing pigmentation in the human iris indirectly through the FP receptor on adjacent fibroblasts.


Subject(s)
Antihypertensive Agents/pharmacology , Eye Color/drug effects , Fibroblasts/physiology , Melanocytes/drug effects , Prostaglandins F, Synthetic/pharmacology , Adult , Cells, Cultured , Coculture Techniques , Dinoprost/pharmacology , Eye Color/physiology , Humans , Indoles/metabolism , Latanoprost , Melanocytes/enzymology , Monophenol Monooxygenase/metabolism , Receptors, Prostaglandin/metabolism , Skin/cytology
2.
J Ocul Pharmacol Ther ; 17(3): 255-77, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11436946

ABSTRACT

The effects of locally administered brimonidine, clonidine, and p-aminoclonidine on microvessel caliber were compared in human retinal tissues grafted into the hamster cheek pouch. Clonidine and p-aminoclonidine, but not brimonidine, potently constricted human retinal microvessels over a broad concentration range. All three agonists elicited significant vasoconstriction in naive hamster cheek pouch microvasculature. The alpha2-adrenoceptor antagonist, rauwolscine, inhibited p-aminoclonidine-induced constriction in naive hamster cheek pouch microvessels, but not p-aminoclonidine-induced effects in retinal grafts. Selective alpha1-adrenoceptor agonists evoked vasoconstriction in retinal grafts only at relatively high concentrations. These differential effects on the retinal microvasculature could not be readily explained solely on the basis of alpha1- or alpha2-adrenoceptor involvement. Clonidine, p-aminoclonidine and brimonidine are also imidazoline derivatives that interact with putative non-adrenergic imidazoline-sensitive binding sites, the so-called I1-imidazoline binding site subtype implicated by some investigators in mediation of peripheral vasoconstriction. As with p-aminoclonidine, the potent vasoconstriction in human retinal microvasculature elicited by moxonidine, an alpha-adrenergic agonist that has also been reported to exhibit selectivity for putative I1-imidazoline binding sites, was not inhibited by the selective alpha-adrenoceptor antagonist, rauwolscine, nor by idazoxan, an antagonist characterized as having substantial activity at putative I2-imidazoline binding sites. These data suggest the possible involvement of an unconventional non-adrenergic imidazoline-sensitive pathway in regulation of microvascular responses in the inner retina, and that drug activity mediated via such an imidazoline-sensitive component could potentially evoke deleterious effects in the retinal microvasculature.


Subject(s)
Adrenergic alpha-Agonists/pharmacology , Clonidine/analogs & derivatives , Clonidine/pharmacology , Quinoxalines/pharmacology , Retinal Vessels/drug effects , Vasoconstriction/drug effects , Adrenergic alpha-Antagonists/pharmacology , Animals , Brimonidine Tartrate , Cheek/surgery , Cricetinae , Humans , Mesocricetus , Muscle, Smooth, Vascular/drug effects , Retina/transplantation
3.
Surv Ophthalmol ; 45 Suppl 4: S337-45, 2001 May.
Article in English | MEDLINE | ID: mdl-11434936

ABSTRACT

Bimatoprost (Lumigan) is a pharmacologically unique and highly efficacious ocular hypotensive agent. It appears to mimic the activity of a newly discovered family of fatty acid amides, termed prostamides. One biosynthetic route to the prostamides involves anandamide as the precursor. Bimatoprost pharmacology has been extensively characterized by binding and functional studies at more than 100 drug targets, which comprise a diverse variety of receptors, ion channels, and transporters. Bimatoprost exhibited no meaningful activity at receptors known to include antiglaucoma drug targets as follows: adenosine (A(1-3)), adrenergic (alpha(1), alpha(2), beta(1), beta(2)), cannabinoid (CB(1), CB(2)), dopamine (D(1-5)), muscarinic (M(1-5)), prostanoid (DP, EP(1-4), FP, IP, TP), and serotonin (5HT(1-7)). Bimatoprost does, however, exhibit potent inherent pharmacological activity in the feline iris sphincter preparation, which is prostamide-sensitive. Bimatoprost also resembles the prostamides in that it is a potent and highly efficacious ocular hypotensive agent. A single dose of bimatoprost markedly reduces intraocular pressure in dogs and laser-induced ocular hypertensive monkeys. Decreases in intraocular pressure are well maintained for at least 24 hr post-dose. Human studies have demonstrated that systemic exposure to bimatoprost is low and that accumulation does not occur. The sclera is the preferred route of accession to the eye. The high scleral permeability coefficient Papp is a likely contributing factor to the rapid onset and long-acting ocular hypotensive profile of bimatoprost.


Subject(s)
Antihypertensive Agents/pharmacology , Lipids/pharmacology , Amides , Animals , Antihypertensive Agents/pharmacokinetics , Bimatoprost , Cloprostenol/analogs & derivatives , Glaucoma/drug therapy , Intraocular Pressure/drug effects , Iris/drug effects , Lipids/pharmacokinetics , Muscle, Smooth/drug effects , Ocular Hypertension/drug therapy
4.
Adv Exp Med Biol ; 400B: 699-706, 1997.
Article in English | MEDLINE | ID: mdl-9547621

ABSTRACT

The effects of exogenous leukotrienes B4 and E4 (LTB4, LTD4) on the under-agarose motility of isolated normodense human eosinophils and neutrophils were examined using a novel sampling strategy for quantitation of leukocyte migration distance and vectorial orientation. Eosinophil chemotaxis to LTD4 was evident at a 10(-10)M threshold. The selective peptide-LT antagonist, SK&F 104353, abolished LTD4-induced eosinophil migration, indicating pharmacological specificity of the response. Neutrophil chemotaxis was apparent only with a very high (10(-5)M LTD4 concentration. LTB4 was a potent eosinophil and neutrophil chemoattractant over a 10(-9)M to 10(-4)M dose range. Analysis of leukocyte orientations provided evidence that chemokinetic responses were not being interpreted as indications of chemotactic behavior. LTB4 and LTD4 significantly altered neutrophil vectorial orientation. Comparison of migration distance and orientation at the leading edge and at the periphery of the well seeded with cells suggested that cell polarization appeared to be the earliest response to chemoattractive LTs. These results indicate that chemoattractant responses to LTs may be identified by utilizing the under-agarose technique and computer assisted analysis of cell orientation.


Subject(s)
Chemotaxis, Leukocyte/drug effects , Eosinophils/physiology , Leukotriene B4/pharmacology , Leukotriene D4/pharmacology , Neutrophils/physiology , Dicarboxylic Acids/pharmacology , Dose-Response Relationship, Drug , Eosinophils/drug effects , Humans , In Vitro Techniques , Kinetics , Neutrophils/drug effects , Structure-Activity Relationship
5.
J Pharmacol Exp Ther ; 272(2): 758-65, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7853191

ABSTRACT

The studies described herein characterize animal behavioral models for conjunctival and cutaneous itch. Histamine was used as the reference stimulus for model development because it is firmly established as a pruritogen in both conjunctiva and skin. Itching evokes the desire to scratch in human subjects, so hind limb scratching at the afflicted area was used to identify pruritogenic stimuli. Under optimized environmental conditions, hind limb scratching behavior yielded substantial and highly reproducible responses. The conjunctival itch-scratch response was delineated from pain and foreign body sensations by using appropriate stimuli. Examination of a large and diverse variety of autocoids revealed that only histamine, platelet-activating factor (PAF) and arachidonic acid and its cyclooxygenase metabolite prostaglandin E2 possessed meaningful pruritogenic activity. PAF-induced ocular pruritus did not involve histamine release, according to studies with appropriate antagonists. Thus PAF-induced ocular pruritus was unaffected by the histamine H1-receptor antagonist pyrilamine but was substantially attenuated by the PAF antagonists WEB 2086 and CV-6209 and was virtually abolished by E-6123. Similar itch-scratch behaviors were quantified in hairless guinea pig skin following the application of cowhage or the iontophoretic administration of histamine and PAF. Findings from these newly developed itching models suggest that PAF could be an important mediator of the pruritic sensation by activating a population of nerve endings responsible for encoding the itch sensation.


Subject(s)
Platelet Activating Factor/pharmacology , Pruritus/chemically induced , Animals , Azepines/pharmacology , Female , Guinea Pigs , Histamine/pharmacology , Male , Platelet Activating Factor/analogs & derivatives , Pyridinium Compounds/pharmacology , Triazoles/pharmacology
6.
J Ocul Pharmacol Ther ; 11(3): 339-47, 1995.
Article in English | MEDLINE | ID: mdl-8590266

ABSTRACT

The therapeutic utility of cyclooxygenase (CO) inhibitors, such as ketorolac, in reducing the inflammatory events associated with allergic conjunctivitis is not unexpected since prostanoids (PG) elicit conjunctival redness (PGD2, PGE2, PGF2 alpha), edema (PGD2, TxA2), eosinophil infiltration (PGD2, PGJ2) and mucous cell discharge (PGD2, PGJ2, TxA2). Recently, topically administered ketorolac has also been reported to alleviate the itching associated with allergic conjunctivitis. This was viewed as intriguing since CO inhibitors are not regarded as useful for treating itching dermatoses and PGs do not elicit itching when applied to the skin. In order to investigate the antipruritic activity of ketorolac, we developed a model for reproducibly measuring ocular surface itch responses. The model involves itch-scratch responses to pruritogens applied locally to the ocular surface. Painful and foreign body stimuli do not produce an itch-scratch response. Unlike reported skin studies, PGE2 was a potent itch-producing substances in the conjunctiva. PGD2 was weakly pruritogenic but PGF2 alpha and the TxA2-mimetic U-46619 were inactive. The PG precursor arachidonic acid was also a potent pruritogen and its effects were inhibited by ketorolac pretreatment. Ketorolac also dose-dependently inhibited the itching associated with experimental allergic conjunctivitis. It appears that PGs are potent itch-producing substances in the conjunctiva and the anti-itch efficacy of ketorolac in allergic conjunctivitis appears to involve inhibition of conjunctival PG biosynthesis from arachidonic acid.


Subject(s)
Conjunctiva/drug effects , Conjunctivitis, Allergic/prevention & control , Prostaglandins/pharmacology , Pruritus/prevention & control , Animals , Capillary Permeability , Conjunctiva/blood supply , Conjunctivitis, Allergic/etiology , Cyclooxygenase Inhibitors/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Eosinophils/metabolism , Female , Guinea Pigs , Humans , Ionophores , Ketorolac , Male , Prostaglandin Antagonists/pharmacology , Prostaglandins/therapeutic use , Pruritus/etiology , Tolmetin/analogs & derivatives , Tolmetin/pharmacology
7.
J Leukoc Biol ; 55(2): 183-91, 1994 Feb.
Article in English | MEDLINE | ID: mdl-8301215

ABSTRACT

The motility of isolated normal human peripheral blood eosinophils and neutrophils in response to exogenous leukotrienes B4 and D4 was examined by means of a modified under-agarose technique and a novel quantitative sampling strategy. Leukotriene D4 was a potent chemoattractant for eosinophils, with a significant threshold chemotactic effect evident at 10(-10) M. The abolition of eosinophil chemotaxis by the potent and selective peptide-leukotriene-antagonist SK&F 104353 indicated the pharmacological specificity of the leukotriene D4-induced response. The chemokinetic response of eosinophils to leukotriene D4 generally did not differ significantly from spontaneous migratory activity of unstimulated cells. Leukotriene D4 did not, however, alter directed neutrophil motility until a very high concentration (10(-5) M) was achieved, although significant neutrophil chemokinesis relative to unstimulated movement was observed over the tested concentration range. Directional emigration of both eosinophils and neutrophils was induced by leukotriene B4 at concentrations as low as 10(-8) M. Analysis of leukocyte orientations provided evidence that chemokinetic responses were not being interpreted as indications of chemotactic behavior. These studies suggest that leukotriene D4 may behave as a potent and selective chemoattractant for human eosinophils at physiologically relevant concentrations.


Subject(s)
Chemotaxis, Leukocyte/drug effects , Eosinophils/physiology , Leukotriene B4/pharmacology , Leukotriene D4/pharmacology , Neutrophils/physiology , Cell Adhesion , Cell Separation , Dicarboxylic Acids/pharmacology , Dose-Response Relationship, Drug , Eosinophils/cytology , Eosinophils/drug effects , Humans , In Vitro Techniques , Neutrophils/cytology , Neutrophils/drug effects , SRS-A/antagonists & inhibitors
8.
J Leukoc Biol ; 55(2): 201-8, 1994 Feb.
Article in English | MEDLINE | ID: mdl-8301217

ABSTRACT

The effects of leukotriene (LT) B4 and D4 on the motility of human peripheral blood neutrophils were investigated employing a novel analytical method. Using the under-agarose technique, migration distance and vectorial orientation of neutrophils in response to selected LT concentrations were determined with the aid of digital image processing. Neutrophil polarization induced by a chemotactic gradient was very apparent even at fields taken adjacent to the cell seeding well where little directional cell motility had occurred. Thus, cell polarization appeared to be the earliest response to chemoattractive LTs. Cell motility occurred in a dose-dependent manner to LTB4 according to determination of the leading edge. LTD4 produced similar effects on neutrophil polarization and motility, but these occurred only at very high concentrations. These data support the view that vectorial orientation is a prerequisite for directional migration of cells and it is also feasible that these are separately regulated events. Furthermore, our studies confirm that LTB4 and, to a much lesser extent, LTD4 are chemotactic for human peripheral blood neutrophils.


Subject(s)
Chemotaxis, Leukocyte/drug effects , Leukotriene B4/pharmacology , Leukotriene D4/pharmacology , Neutrophils/physiology , Humans , In Vitro Techniques , Kinetics , Microscopy/instrumentation , Microscopy/methods , Neutrophils/cytology , Neutrophils/drug effects
9.
Eur J Pharmacol ; 230(3): 327-33, 1993 Jan 19.
Article in English | MEDLINE | ID: mdl-8440310

ABSTRACT

Prostaglandin D2 (PGD2) and the selective DP receptor agonist BW 245C have been previously shown to lower intraocular pressure in rabbits, while PGD2, but not BW 245C, caused plasma extravasation, eosinophil infiltration, and goblet cell depletion. In these present studies definition of the ocular pharmacology of prostaglandin D2 (PGD2) has been extended by using a further selective DP receptor agonist SQ 27986 and a potent and selective DP receptor antagonist BW A868C. In cats and rabbits SQ 27986 caused ocular hypotension. The ocular hypotensive effect of PGD2 in rabbits was blocked by pretreatment with the DP receptor antagonist BW A868C, whereas the activities of PGE2 and PGF2 alpha remained unaltered. The singular involvement of the DP receptor in changes in rabbit intraocular pressure evoked by PGD2 was thereby verified by using the antagonist BW A868C. In terms of effects on the ocular surface, SQ 27986 caused no increase in conjunctival microvascular permeability, no eosinophil infiltration, and no depletion of the goblet cell population. These findings reinforce the concept that selective DP receptor agonists may be useful for lowering intraocular pressure without causing ocular surface pathology. PGD2 induced increases in conjunctival microvascular permeability were inhibited by BW A868C, despite the fact that DP receptor agonists failed to evoke a plasma exudation response. This finding was unexpected and suggests a possible subdivision of the DP receptor designation.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic , Eye/drug effects , Prostaglandin D2/pharmacology , Receptors, Immunologic , Receptors, Prostaglandin/drug effects , Animals , Bridged Bicyclo Compounds/pharmacology , Capillary Permeability/drug effects , Cats , Conjunctiva/blood supply , Dinoprost/pharmacology , Dinoprostone/pharmacology , Fatty Acids, Unsaturated/pharmacology , Female , Guinea Pigs , Hydantoins/pharmacology , Intraocular Pressure/drug effects , Male , Rabbits
10.
Drugs Exp Clin Res ; 17(12): 543-8, 1991.
Article in English | MEDLINE | ID: mdl-1841046

ABSTRACT

The effects of LTD4 on eosinophil motility were studied in order to indicate its potential role as an eosinophil chemoattractant. The guinea pig was selected as a suitably sensitive species for in vivo studies. Eosinophil infiltration was quantified by digital image analysis of 6 microns paraffin ocular and cutaneous tissue sections stained by Luna's method. LTD4, applied topically to the ocular surface, caused pronounced eosinophil infiltration into the conjunctival epithelium and was more potent and efficacious than a variety of other putative mediators of allergy. Pretreatment with the LT-antagonist SK&F 104353 (i.v. 1 mg/kg) abolished LTD4-induced eosinophil infiltration into the conjunctiva. Eosinophil infiltration did not occur in other ocular anterior segments structures such as the cornea, iris and ciliary body after either topical application or intracameral injection. LTD4 did not cause eosinophil emigration into skin following intradermal injection, despite causing an increase in cutaneous microvascular permeability at identical doses. These studies indicate that LTD4 may cause eosinophil emigration in vivo according to tissue-dependent regulation.


Subject(s)
Chemotactic Factors, Eosinophil/pharmacology , SRS-A/pharmacology , Administration, Cutaneous , Animals , Chemotactic Factors, Eosinophil/administration & dosage , Chemotactic Factors, Eosinophil/antagonists & inhibitors , Conjunctiva/drug effects , Dicarboxylic Acids/pharmacology , Female , Guinea Pigs , Histamine/pharmacology , Male , Prostaglandin D2/pharmacology , SRS-A/administration & dosage , SRS-A/antagonists & inhibitors
11.
Invest Ophthalmol Vis Sci ; 31(1): 138-46, 1990 Jan.
Article in English | MEDLINE | ID: mdl-2298534

ABSTRACT

Prostaglandin D2 (PGD2) exerts a variety of biologic actions in the eye; these include ocular hypotension and inflammatory effects on the conjunctiva. The profile of activity of PGD2 in ocular tissues was compared to that of BW 245C, a selective agonist for the PGD2-sensitive (DP) receptor, and to that of the biologically active metabolites of PGD2, 9 alpha,11 beta-prostaglandin F2 (9 alpha,11 beta-PGF2) and prostaglandin J2 (PGJ2). PGD2 produced a dose-dependent decrease in intraocular pressure and in the conjunctiva it caused increased conjunctival microvascular permeability, eosinophil infiltration and goblet cell depletion. Although BW 245C was equipotent to PGD2 as an ocular hypotensive agent, it did not cause pathological effects in the conjunctiva. Thus, the ocular hypotensive effect of PGD2 may be separated from inflammatory effects on the conjunctiva by employing a selective DP-receptor agonist such as BW 245C. 9 alpha,11 beta-PGF2 was a weak ocular hypotensive and did not cause conjunctival inflammation. PGJ2 produced no significant effect on intraocular pressure. PGJ2 did not elicit a microvascular permeability response in the conjunctiva, but was inflammatory in other respects and caused eosinophil infiltration and goblet cell depletion similar to PGD2. Thus, both the ocular hypotensive actions and the conjunctival pathology of PGD2 may be replicated individually by employing PGD2 analogues and metabolites.


Subject(s)
Dinoprost/pharmacology , Eye/drug effects , Intraocular Pressure/drug effects , Animals , Aqueous Humor/drug effects , Capillary Permeability/drug effects , Chemotaxis, Leukocyte/drug effects , Conjunctiva/blood supply , Conjunctiva/drug effects , Dinoprost/analogs & derivatives , Eosinophils/drug effects , Evans Blue , Female , Guinea Pigs , Hydantoins/pharmacology , Inflammation/etiology , Male , Prostaglandin D2/pharmacology , Rabbits
12.
Eur J Pharmacol ; 168(1): 23-30, 1989 Sep 01.
Article in English | MEDLINE | ID: mdl-2555201

ABSTRACT

Platelet-activating factor (PAF) (1-O-hexadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) produced dose-dependent depletion of the goblet cell population associated with the conjunctival epithelium. Reductions in goblet cell numbers did not correspond to leukocyte infiltration and were consistent with a direct effect of PAF. In contrast, LTD4 and LTE4 did not affect the goblet cell population although they caused massive eosinophil infiltration into the conjunctival epithelium. Histamine also produced conjunctival goblet cell depletion, but this appeared secondary to eosinophil degranulation and resultant epithelial desquamation. In addition to goblet cell expulsion, PAF produced an increase in conjunctival microvascular permeability over an identical dose-range. PAF-induced leukocyte emigration was small or absent and comprised a neutrophil infiltrate which exhibited no clear dose-dependent relationship. Lyso-PAF produced effects only at the highest dose employed where pathological changes and a distinct increase in conjunctival microvascular permeability were evident. Lyso-PAF- and PAF-induced increases in conjunctival microvascular permeability were virtually abolished by the PAF antagonist CV-6209. The pronounced inhibitory activity of CV-6209 suggests that high doses of lyso-PAF may either weakly stimulate conjunctival PAF receptors or that there may be sufficient conversion of lyso-PAF to biologically active levels of PAF.


Subject(s)
Conjunctiva/cytology , Platelet Activating Factor/pharmacology , Animals , Capillary Permeability/drug effects , Conjunctiva/drug effects , Conjunctiva/metabolism , Guinea Pigs , Histamine/pharmacology , In Vitro Techniques , Leukocytes/drug effects , Leukotriene E4 , Male , Neutrophils/drug effects , Platelet Activating Factor/antagonists & inhibitors , Pyridinium Compounds/pharmacology , SRS-A/pharmacology
13.
J Lipid Mediat ; 1(1): 63-73, 1989.
Article in English | MEDLINE | ID: mdl-2562432

ABSTRACT

The time course of extravascular albumin accumulation responses elicited by the leukotrienes LTC4, LTD4, LTE4, and histamine in the skin were compared in the conscious guinea pig. During the initial 15-min period, comparison of the dose-response curves revealed that histamine produced a much larger increase in extravascular albumin content than any of the leukotrienes. One hour after intradermal injection and at subsequent time intervals, the response to LTD4 had increased in magnitude so that it equaled the response produced by histamine. This was apparent from comparison of the time courses of extravascular albumin accumulation for intermediate doses of LTD4 and histamine and also from comparison of dose-response relationships at 4 h post intradermal injection. In contrast to LTD4, the magnitude of the microvascular permeability responses to LTC4 and LTE4 remained relatively small even over an extended time scale. Although histamine produced a large initial response, this also remained essentially unchanged over a 4-h period. It appears that LTD4 may produce a unique, time-dependent cutaneous microvascular permeability response and measurements over 15-30-min periods may underestimate its activity as a vasopermeability factor. The time-dependent effects of LTD4 on albumin extravasation cannot be ascribed to leukocyte infiltration into the skin since LTC4, LTD4, and LTE4 were entirely without effect in this regard.


Subject(s)
Capillary Permeability/drug effects , Leukotrienes/pharmacology , Albumins/metabolism , Animals , Dose-Response Relationship, Drug , Female , Guinea Pigs , Histamine/pharmacology , Leukotriene E4 , Leukotrienes/administration & dosage , SRS-A/analogs & derivatives , SRS-A/pharmacology , Skin/blood supply , Skin/drug effects , Time Factors
14.
Am J Pathol ; 130(2): 354-68, 1988 Feb.
Article in English | MEDLINE | ID: mdl-2829632

ABSTRACT

Leukotrienes (LT) B4 and D4, alone and in combination, were topically applied to the eyes of guinea pigs, and their effects on conjunctival leukocyte infiltration studied. LTD4 potentiated the neutrophil response to LTB4, even though no neutrophil emigration was evoked by LTD4 itself over a dose range of 10-1000 ng. LTB4 alone at the 1-ng and 10-ng doses failed to evoke any leukocyte emigration, but significant numbers of neutrophils were observed at these concentrations when LTD4 (1-1000 ng) was present. Although a dose-dependent increase in neutrophil infiltration was observed for the 100-ng and 1000-ng doses of LTB4, cell counts were substantially higher with these doses in the presence of LTD4. Eosinophil numbers increased in a dose-related manner in response to LTB4 and LTD4 alone, with a greater response to LTD4. The addition of either 10 ng or 100 ng of LTB4 to graded doses of LTD4 (10-1000 ng) caused increased eosinophil numbers, the lower dose of LTB4 potentiating the response to LTD4 and the higher LTB4 dose showing no significant effect. The effects on leukocyte infiltration that were evoked by the LT combinations could not be explained simply on the basis of an increase in vascular permeability. Bradykinin (BK), a potent conjunctival microvascular permeability factor that does not elicit any leukocyte infiltration, did not significantly potentiate LTB4-induced eosinophil or neutrophil emigration. The synergistic effects of LTs on leukocyte emigration are also difficult to ascribe to hyperemia (ie, increased blood volume in the conjunctiva), because both LTB4 and LTD4 caused only very modest increases in conjunctival blood content, and BK, which did not potentiate the leukocytic responses to LTB4, caused marked increases in tissue blood content. High-dose LT combinations caused eosinophils, but not neutrophils, to migrate into the conjunctival epithelium and fragment, resulting in overt tissue damage. These results further suggest a synergistic interaction between LTB4 and LTD4 that directly alters leukocyte function. The relevance of these observations to a number of disease and trauma states is discussed.


Subject(s)
Conjunctiva/cytology , Leukocytes/physiology , Leukotriene B4/pharmacology , SRS-A/pharmacology , Animals , Blood Volume , Bradykinin/pharmacology , Capillary Permeability , Cell Count , Cell Movement/drug effects , Conjunctiva/blood supply , Dose-Response Relationship, Drug , Drug Synergism , Eosinophils/drug effects , Eosinophils/physiology , Female , Guinea Pigs , Leukocytes/cytology , Leukocytes/drug effects , Leukotriene B4/administration & dosage , Neutrophils/drug effects , Neutrophils/physiology , SRS-A/administration & dosage
15.
Invest Ophthalmol Vis Sci ; 27(10): 1495-503, 1986 Oct.
Article in English | MEDLINE | ID: mdl-2875975

ABSTRACT

The present histological studies have demonstrated that histamine causes dose-dependent eosinophil infiltration into the conjunctiva. A highly directional movement toward the conjunctival epithelium was observed, and the presence of large numbers of degranulating eosinophils appeared to result in epithelial cell damage and goblet cell discharge. Blockade of H2-receptors by systemic cimetidine pretreatment significantly inhibited the eosinophil infiltration elicited by an intermediate histamine dose, whereas the H1-receptor blockade produced by systemic pyrilamine pretreatment markedly reduced the response to all histamine doses. The pyrilamine-insensitive residual eosinophil infiltrate was not affected by administering a cimetidine-pyrilamine combination. In animals presensitized to ovalbumin, antigen challenge evoked extensive and directional emigration of eosinophils toward the conjunctival epithelium with resultant exfoliation and depletion of goblet cell populations. In conjunctival immediate hypersensitivity, neither cimetidine nor pyrilamine alone produced an inhibitory effect, but a cimetidine-pyrilamine combination caused a significant reduction in the number of infiltrating eosinophils and prevented epithelial damage and goblet cell depletion. These results suggest that histamine may participate in the recruitment of eosinophils during immediate hypersensitivity reactions. The differential effect of pyrilamine on the eosinophil infiltration evoked by histamine or immediate hypersensitivity may, perhaps, reflect the importance of increased microvascular permeability in facilitating eosinophil emigration.


Subject(s)
Conjunctival Diseases/pathology , Eosinophils/physiology , Histamine H1 Antagonists/pharmacology , Histamine H2 Antagonists/pharmacology , Histamine/physiology , Hypersensitivity, Immediate/pathology , Animals , Cell Movement/drug effects , Cimetidine/pharmacology , Female , Guinea Pigs , Male , Pyrilamine/pharmacology
16.
Prostaglandins ; 31(4): 795-809, 1986 Apr.
Article in English | MEDLINE | ID: mdl-3014611

ABSTRACT

The ability of LTB4, LTC4, the 5S,6R and 5R,6S LTD4 stereoisomers, and LTE4 to evoke leukocyte infiltration into the conjunctiva was demonstrated in the guinea pig by histological and light microscopy techniques. LTD4 and LTE4 demonstrated a dose-dependent and predominantly eosinophilic infiltrate over the selected dose range (10 ng to 1000 ng), while there was only a minimal response to LTC4. LTB4 produced marked eosinophil infiltrates only at the highest dose; scattered neutrophil infiltrates were also noted at the high dose of LTB4. The 5R,6S LTD4 stereoisomer did not evoke any leukocyte infiltration. The SRS-A antagonist, FPL 55712, abolished peptidoleukotriene-induced eosinophil emigration, and indomethacin pre-treatment had no inhibitory effect, indicating direct mediation of this response by LTs. Histamine caused a comparable eosinophilia over a dose range of 10 micrograms to 1000 micrograms. LT-induced eosinophil emigration was directed to the conjunctival epithelium; the cells appeared intact and no tissue damage was observed. These results may have relevance in the areas of allergic conjunctivitis and asthma research.


Subject(s)
Conjunctiva/drug effects , Eosinophils/physiology , Leukotriene B4/pharmacology , SRS-A/pharmacology , Animals , Cell Movement/drug effects , Chemotaxis, Leukocyte/drug effects , Chromones/pharmacology , Conjunctiva/cytology , Dose-Response Relationship, Drug , Epithelial Cells , Female , Guinea Pigs , Histamine/pharmacology , Indomethacin/pharmacology , Male
17.
Agents Actions ; 17(2): 121-5, 1985 Dec.
Article in English | MEDLINE | ID: mdl-4096302

ABSTRACT

Several substances alter eosinophil motility, but the relative importance of these putative mediators in immediate hypersensitivity remains unclear. The present study has re-investigated the role of histamine in type I allergic eosinophil infiltration, and the temporally associated microvascular events, by examining the effect of H1- and H2-receptor antagonist pretreatment. A combination of cimetidine and pyrilamine significantly reduced eosinophil accumulation, whereas neither antagonist alone was effective. Similarly, cutaneous hyperemia, measured indirectly as ear surface temperature, was reduced only by the cimetidine-pyrilamine combination. Pyrilamine partially attenuated the increase in microvascular permeability, but the addition of cimetidine provided no further reduction. It appears that histamine participates significantly in mediating both the microvascular changes and the eosinophil infiltration evoked by cutaneous anaphylaxis. The histaminergic component of increased microvascular permeability appears to be an H1-receptor mediated phenomenon. However, blockade of both H1- and H2-receptor subtypes is required to inhibit the hyperemia and eosinophil infiltration responses.


Subject(s)
Capillary Permeability/drug effects , Eosinophils/physiology , Passive Cutaneous Anaphylaxis/drug effects , Receptors, Histamine H1/physiology , Receptors, Histamine H2/physiology , Receptors, Histamine/physiology , Animals , Cell Movement/drug effects , Cimetidine/pharmacology , Drug Combinations , Guinea Pigs , Male , Pyrilamine/pharmacology , Receptors, Histamine H1/drug effects , Receptors, Histamine H2/drug effects , Skin/blood supply
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