Biomedical subjects

C A Paterson

Publications and source records attributed to C A Paterson.

At least 19 recordsLinked to original sources

PubMed2006

Modulation of ocular inflammatory responses by EP1 receptors in mice.

The purpose of the study was to investigate the role of EP1 receptors in intraocular inflammation and to determine possible interplay between EP1, EP2 and EP4 receptors. The eyes of separate groups of EP1 receptor knockout and wild type mice were: 1) treated topically with prostaglandin E2 (PGE2) or the EP2 receptor selective agonist, butaprost; 2) given intravitreal injection of LPS; or 3) paracentesis performed. Another group of knockout mice were pretreated topically with an EP4 receptor selective antagonist prior to paracentesis or LPS treatment. Results demonstrated a significant increase (50% or more) in the protein levels of aqueous humor of the EP1 knockout mice in response to PGE2, paracentesis or LPS. The leukocyte infiltration in the aqueous humor of the knockout mice was 47% higher when compared with that in the wild type controls in response to LPS injection. No significant change was observed in the protein levels in response to butaprost. Pretreating the knockout mice with an EP4 receptor antagonist prior to paracentesis and LPS treatment substantially reduced the aqueous humor protein levels. Also, the leukocyte count in the aqueous humor of the knockout mice in response to LPS was reduced 4 fold after pretreatment with EP4 receptor antagonist when compared with the findings in knockout mice receiving LPS only. We concluded that EP1 receptor has no modulatory effect on EP2 receptors but there is definitely cross-talk between EP1 and EP4 receptors.

Alprostadil↗

PubMed2006

Ocular inflammatory responses in the EP2 and EP4 receptor knockout mice.

PURPOSE: To examine the role of EP2 and EP4 receptors in murine ocular inflammation. METHODS: Prostaglandin EP2 and EP4 receptor knockout and wild-type mice were treated topically with prostaglandin E2, SDF-1, and RANTES and lipopolysaccharide by intravitreal injection. Paracentesis was performed by puncturing the cornea. The increase in the level of aqueous humor protein and the number of leukocytes were measured and the vascular leakage of protein was visualized using fluorescein angiography. RESULTS: In the EP2 receptor knockout mice, there was significant inhibition of the disruption of the blood-aqueous barrier caused by lipopolysaccharides, paracentesis, prostaglandin E2, SDF-1, and RANTES. Reductions in the disruption in the blood-aqueous barrier and leukocyte infiltration after lipopolysaccharide injection and paracentesis were significant, but there was no increase in the aqueous humor protein level after prostaglandin E2 treatment in EP4 receptor knockout mice. CONCLUSIONS: The results of the present experiments suggest that EP2 and EP4 receptors partly mediate the disruption of the blood-aqueous barrier and leukocyte infiltration induced by prostaglandin E2, SDF-1, RANTES, and lipopolysaccharides.

Animals↗

PubMed2005

Plasma membrane Ca2+-ATPase expression in the human lens.

The focus of the study was to characterize plasma membrane calcium-ATPase pump (PMCA) isoform expression in the human lens and cultured lens epithelial cells as a basis for future studies of calcium homeostasis in the lens. Proteins and mRNA expression were analysed using Western Immunoblotting and reverse transcription polymerase chain reaction (RT-PCR), respectively. Clear human lenses from the Kentucky Lions Eye Bank and an immortalized human lens epithelial cell line (HLE B-3) were used. RT-PCR products of PMCA1, PMCA2, and PMCA4 primers were detected at 429, 557, and 849bp, respectively. All these products were identified as PMCA isoforms by sequence analysis. Protein bands at approximately 130, 115, and 135kDa were detected by Western blot analysis for PMCA1, PMCA2 and PMCA4, respectively. PMCA3 was not detected at protein or mRNA level in any human lens sample or cell culture, but was detected in the rat brain cortex used as a control. Several bands with lower molecular weights, especially for PMCA2, were detected in the epithelial samples and probably represent break down products of PMCA2. No PMCA proteins or breakdown products were detected in the nuclear or cortical fractions from human lenses. PMCA1, 2, and 4 proteins and mRNAs are expressed in human lens epithelium and cultured epithelial cells; PMCA3 is not. PMCA was not detected at all in the lens fibre cells. The calcium pump must be selectively processed, independent of other membrane proteins such as the Na-K-ATPase pumps, because the distribution of the Na-K-ATPase pump is asymmetrical in the epithelium and present throughout the lens whereas the calcium pumps are not. The findings of this study provide a basis for further studies to examine the role and modulation of PMCA isoforms in calcium homeostasis and in the development of cataract.

Animals↗

PubMed2004

Independent predictors of morbidity and mortality in blunt colon trauma.

We sought to determine the impact of (1) grade of the colon injury, (2) the formation of an ostomy, and (3) associated injuries on outcomes such as morbidity and mortality after blunt colon injuries. We retrospectively reviewed 16,814 cases of blunt abdominal trauma. Patients with colonic injuries were selected and charts reviewed for demographic, clinical, and outcomes data. Injuries were grouped by the Colon Injury Scale (grades I-V). Independent risk factors of morbidity included spine and lung injuries, as well as increased age. A higher grade of colon injury trended toward a significant association with intra-abdominal complications. Independent risk factors of mortality included liver, heart, and lung injuries, as well as intracerebral blood and female gender. The grade of colon injury, the formation of an ostomy, and management of the colon trauma did not independently predict increased intra-abdominal complications, morbidity, or mortality. These results indicate that patients afflicted with blunt colon trauma experience a high rate of morbidity and mortality from associated injuries and or increased age. Treatment regimens directed at these factors will be most helpful in reducing the high morbidity and mortality after blunt colon trauma. Factors such as ostomy formation and management strategy are not associated with increased morbidity or mortality after blunt colon trauma.

Adolescent↗

PubMed2002

Regulation of sarco/endoplasmic Ca2+ -ATPase expression by calcium in human lens cells.

Maintenance of cellular calcium levels is critical to cell function. Loss of calcium homeostasis might be a contributing factor to the development of cataract in the lens. In lens epithelium, calcium is involved in cell signaling and its precise regulation is vital. In this study, we investigated the regulation of sarco/endoplasmic reticulum Ca(2+)-ATPase2b (SERCA2b) and SERCA3 isoform expression in cultured epithelial B-3 cells from human lenses. Both mRNA and membrane proteins samples were collected for semi quantitative RT-PCR using GAPDH as a control. Western blot analyses were performed on membrane samples.Thapsigargin, a SERCA isoform inhibitor which causes increased cytosolic levels elicited dose-and time-dependent up-regulation of SERCA3 at both mRNA and protein levels; SERCA2b expression was unaffected. Both EGTA and actinomycin partially inhibited the thapsigargin-induced SERCA3 up-regulation. These results indicate that the up-regulation of SERCA3 by thapsigargin is dependent on a calcium-mediated pathway that is likely to occur at the transcription level.

Blotting, Western↗

PubMed2001

Anaylsis of birefringence during wound healing and remodeling following alkali burns in rabbit cornea.

The use of synthetic inhibitors of metalloproteinases (SIMP) or medroxyprogesterone (MP) can prevent or significantly delay the ulceration of alkali-injured corneas by influencing collagen degradation. We have examined the remodeling of rabbit corneal stroma following alkali injury and have assessed the effect of SIMP and MP treatment. Following a defined alkali injury to the rabbit cornea, animals were divided into three subgroups, one group treated with topical beta-mercaptomethyl tripeptide (SIMP), one treated by subconjunctival injection of MP and one treated with a control solution. The corneal tissue was taken at 3 days, 1, 2, 3, 4, 9 and 26 weeks after alkali injury and prepared for light microscopy and transmission electron microscopy (TEM). A quantitative measurement of birefringence, in terms of the optical path difference (OPD), was made using a modified polarized microscopy technique based on the analysis of interference colours. The results showed that SIMP effectively prevented deep corneal ulceration. MP could delay the ulceration and the corneas treated with MP appeared to have better transparency than the other groups. There was a significant difference of the OPD between the anterior (5.8 +/-0.3 nm) and posterior (7.8 +/-0.4 nm) stroma of the normal cornea (P<0.001). The OPD values from the central corneas from alkali-injured eyes were generally lower than normal during the first 4 weeks and then gradually recovered to the normal level or above, except for the posterior stroma of the MP-treated eyes. We found that the OPD changes were very dependent on the presence of corneal lesions. The stroma near corneal ulceration, scar tissue, calcified stroma and the retro-corneal collagen layer showed a significant reduction of birefringence (lower OPD values). These OPD values remained much lower than normal up to the end of the experiment. TEM showed disrupted corneal stroma in all three groups, with thinner scar tissue in the MP group. The fibril diameters did not change significantly 3 days and 1 week after the alkali burns (27.1+/-2.3 nm in the control group, 27.3+/-2.2 nm in the SIMP group and 27.7+/-2.1 nm in the MP group) and there were no differences compared with 29.7+/-1.7 nm of the normal cornea (P>0.05). After 2 weeks of tissue remodeling, the fibril diameters in alkali-injured corneas showed a large variation (the range was between 11.5 and 80 nm) with a bimodal distribution, especially in the control group. The technique presented here for birefringence evaluation can provide an alternative way to monitor wound healing and tissue remodeling, both visually and quantitatively.

Animals↗

PubMed2001

Studies on receptor binding and signal transduction pathways of unoprostone isopropyl.

We examined the binding characteristics of unoprostone isopropyl and its metabolite, M1 (M1), in bovine corpus luteum membranes, mobilization of intracellular calcium in human ciliary muscle cells and cyclic AMP generation in rabbit iris-ciliary body. The ligand binding assay of 3H-unoprostone isopropyl and M1 did not demonstrate any specific binding of these compounds in the bovine corpus luteum membranes. However, there was a high specific binding of prostaglandin F2alpha. Competitive ligand binding studies showed that neither the docosanoid, unoprostone isopropyl, nor M1 binds to prostaglandin receptor sites. In human ciliary muscle cells that express EP1, EP2 and FP receptors, unoprostone isopropyl did not increase the mobilization of intracellular calcium nor was it able to generate cyclic AMP at low concentrations in rabbit iris-ciliary body. Similar observations were made with M1 on the above signal transduction pathways. From these results, it is concluded that unoprostone isopropyl and M1 do not bind to prostaglandin (PG) receptor sites in the bovine corpus luteum membranes and do not have affinity for PG receptors linked to intracellular calcium and cyclic AMP second messenger systems.

Adenylyl Cyclases↗

PubMed2000

Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia.

Vascular endothelial growth factor-B (VEGF-B) is closely related to VEGF-A, an effector of blood vessel growth during development and disease and a strong candidate for angiogenic therapies. To further study the in vivo function of VEGF-B, we have generated Vegfb knockout mice (Vegfb(-/-)). Unlike Vegfa knockout mice, which die during embryogenesis, Vegfb(-/-) mice are healthy and fertile. Despite appearing overtly normal, Vegfb(-/-) hearts are reduced in size and display vascular dysfunction after coronary occlusion and impaired recovery from experimentally induced myocardial ischemia. These findings reveal a role for VEGF-B in the development or function of coronary vasculature and suggest potential clinical use in therapeutic angiogenesis.

Aging↗

PubMed2000

Determinants of occurrence and volume of transpyloric flow during gastric emptying of liquids in dogs: importance of vagal input.

The precise factors and their relative contributions that lead to individual flow pulses across the pylorus during liquid gastric emptying remain unclear. Our objective was to determine the factors leading to individual flow pulses, their relative contributions and the role of the vagus nerve in their modulation. Proximal gastric tone had a strong positive correlation with the volume of the corresponding transpyloric flow pulse whereas pyloric tone had an inverse correlation. Antral contractions were associated with the presence but not the volume of the pulse. Acute vagal blockade retarded emptying via loss of proximal gastric tone and increased outflow resistance and loss of propagating antral pressure waves. In conclusion, the major determinants of the volume of pulsatile transpyloric flow are proximal gastric and pyloric tone. The vagus nerve plays a key role in regulating both proximal gastric and pyloric tone as well as moderating propagating antral contractions.

Animals↗

PubMed2000

Nitrergic and cholinergic vagal pathways involved in the regulation of canine proximal gastric tone: an in vivo study.

To better understand the relationship between cholinergic and nitrergic (NO) innervation in the regulation of proximal gastric (fundic) tone in vivo, the effects of nitric oxide synthase blockade on fundic tone were studied in conscious dogs using vagal cooling and an electronic barostat. Vagal cooling, atropine (0.05 mg kg-1 i. v. bolus) and hexamethonium (1 mg kg-1 i.v. bolus) all markedly decreased fundic tone as reflected by increased intragastric volume, indicating a significant contribution of vagal and enteric cholinergic pathways to the maintenance of canine fundic tone. Administration of L-NNA (10 mg kg-1 i.v. bolus) increased fundic tone and the effects of L-NNA were completely prevented by prior vagal cooling or atropine administration, but not by pretreatment with hexamethonium. The relaxation effects of neurally derived NO appear primarily related to inhibition of ongoing vagal cholinergic activity. The data are consistent with the primary site of action of nitrergic mechanisms on gastric fundic tone in conscious dogs being at a presynaptic site on vagal cholinergic efferent nerves.

Animals↗

PubMed1999

Pharmacological validation of a feline model of steroid-induced ocular hypertension.

OBJECTIVE: To validate pharmacologically the feline model of steroid-induced ocular hypertension. METHODS: Serial studies were conducted in domesticated adult female cats trained to accept topical ocular drug administration and pneumotonometry. To establish intraocular pressure (IOP) values for each study, measurements were performed at the same time of day for 6 consecutive days. Beginning on day 7, cats received either steroid or vehicle administered topically to both eyes three times a day for approximately 28 days. The IOP measurements were performed daily. RESULTS: After 5 to 7 days of treatment with 0.1% dexamethasone or 1.0% prednisolone acetate, IOP began to increase, reaching peak values within 2 weeks. These values were sustained throughout dosing but declined rapidly to baseline upon cessation of treatment. Maximum IOPs for the dexamethasone- and prednisolone-treated groups averaged 4.5 +/- 0.3 mm Hg (n = 12) greater than the mean IOP value obtained in vehicle-treated cats. Cats treated with 0.25% fluorometholone, 1.0% loteprednol etabonate, and 1.0% rimexolone exhibited increases of 0.6, 1.2, and 1.7 mm Hg, respectively. These values were significantly lower than those observed following treatment with dexamethasone or prednisolone. CONCLUSIONS: The ocular hypertensive effects of selected anti-inflammatory topical ocular steroids in this model are consistent with clinical findings. CLINICAL RELEVANCE: This feline model is a useful tool for assessing the potential IOP liability of novel anti-inflammatory steroids.

Administration, Topical↗

PubMed1999

Ca(2+)-ATPase activity and lens lipid composition in reconstituted systems.

Lens lipid composition and lipid hydrocarbon chain structure change with age, region and cataract. Since the lens Ca(2+)-ATPase pump is important to the maintenance of calcium homeostasis and lens clarity, muscle sarcoplasmic reticulum Ca(2+)-ATPase was reconstituted with bovine lens lipids and dihydrosphingomyelin, the rare and major phospholipid of the human lens. Ca(2+)-ATPase activity was found to be about 5 times lower when the pump was reconstituted into dihydrosphingomyelin or lens lipids compared to native sarcoplasmic reticulum lipids. The addition of cholesterol to levels ranging from 13-53 mole%, had no affect on reconstituted Ca(2+)-ATPase activity. Ca(2+)-ATPase activity correlated with the degree of hydrocarbon chain saturation. The greater levels of saturation are a consequence of the high sphingolipid content in the reconstituted systems. These data support the hypothesis that changes in lens lipid composition or structure could affect Ca(2+)-ATPase activity in human lenses. Because the mechanisms governing Ca(2+)-ATPase activity in vivo are much more complex than in these simple reconstituted systems, this study represents an initial step in the elucidation of the relationships of endogenous membrane lipid composition-structure and function.

Animals↗

PubMed1999

Basal cell carcinoma of the perianal region: 20-year experience.

INTRODUCTION: Although basal cell carcinoma remains the most common cutaneous malignancy, its occurrence in the perianal region is very rare. Earlier reports have suggested that basal cell carcinoma in this region may be more aggressive than basal cell carcinoma in other regions of the body. METHODS: A chart review of patients with perianal basal cell carcinoma who presented consecutively during a 20-year period (ending December 1996) was performed. Patients included were those with a histologically proven diagnosis of basal cell carcinoma in the perianal region. RESULTS: Twenty-one cases were identified (15 male) with a mean age at diagnosis of 67 (range, 43-81) years. Follow-up data were available on 19 patients with a mean follow-up time of 72 (range, 2-214) months. Seventeen patients were treated by local excision, one by electrocautery, and one by Moh's surgery. No patients developed a local recurrence. Seven patients (33 percent) had multiple basal cell carcinomas at other anatomic sites. Four patients died of other causes during the follow-up period. CONCLUSIONS: Perianal basal cell carcinoma is a rare tumor. Given the significant association with multiple lesions at other sites, a diagnosis of perianal basal cell carcinoma should prompt an examination of all cutaneous surfaces. It does not seem to be more aggressive in this region than in other areas. Local excision seems to provide adequate control.

Adult↗

PubMed1999

Effect of oxidation on Ca2+ -ATPase activity and membrane lipids in lens epithelial microsomes.

Membrane oxidation may contribute to cataractogenesis. In our pursuit to understand the etiology of cataracts, we assessed the effect of membrane oxidation products on the activity of the lens epithelium calcium pump. Microsome preparations from bovine lens epithelium were oxidized to varying degrees with a ferrous and ferric ascorbate system to generate hydrogen peroxide and superoxide. Ca2+ -ATPase activity was measured using a colorometric assay. Lipid oxidation was quantified by infrared spectroscopy. Ca2+ -ATPase activity decreased as a function of ascorbate concentration between 0 and 200 microM. The level of Ca2+ -ATPase inhibition was correlated to both the level of lipid oxidation and the degree of lipid hydrocarbon chain order. At 25 degrees C when lipids are more ordered, the Ca2+ -ATPase activity was similar to that observed in the oxidized system measured at 37 degrees C. Glutathione, mercaptoethanol, and iodoacetate were able to reverse the oxidative inhibition of the calcium pump, suggesting that the ascorbate/iron oxidant directly oxidized the protein sulfhydryl moieties. To further probe the mechanism of Ca2+ ATPase inhibition, hydrogen peroxide was used to oxidize muscle sarcoplasmic reticulum Ca2+ -ATPase reconstituted in its native lipid vesicles, egg phosphatidylcholine, and dihydrosphingomyelin, with saturated hydrocarbon chains. In these systems, oxidation inhibited the Ca2+ -ATPase pump by 60-80%. There was no statistical difference between the level of oxidative inhibition and the percentage of dihydrosphingomyelin. Because dihydrosphingomyelin cannot be oxidized, whereas egg phosphatidylcholine (PC) can, and because the percentage of inhibition was the same for reconstituted systems using either lipid, the mechanism of inhibition is likely not via a secondary process involving oxidation-induced lipid structural changes or products of lipid oxidation.

Animals↗

PubMed1999

Membrane lipid alpha-crystallin interaction and membrane Ca2+ -ATPase activities.

PURPOSE: To determine the effect of alpha-crystallin binding on lens membrane lipid characteristics and the stability of Ca2+ -ATPase activity when challenged with H2O2 or elevated temperatures. METHODS: Alpha-Crystallin binding to muscle sarcoplasmic reticulum membranes was quantified using a centrifugation protocol. Alpha-Crystallin binding to lens epithelial lipids was measured by a fluorescence energy transfer technique. Lipid phase transition temperature and lipid order was measured using fluorescence spectroscopy. Ca2+ -ATPase activity was measured using classical biochemical assays. RESULTS: The main phase transition temperatures of multilamellar vesicles composed of sphingomyelin or lipids extracted from bovine lens were 40 degrees C and 20 degrees C, respectively. In the presence of saturating amounts of alpha-crystallin, the phase transition temperature and lipid order of both sphingomyelin and lens lipid membranes remained almost the same as that without alpha-crystallin. The interaction of alpha-crystallin and lipid is likely to be restricted to the membrane surface. The binding of alpha-crystallin did not influence the oxidative or thermal inactivation of the Ca2+ -ATPase pump. CONCLUSION: Alpha-Crystallin-lens membrane binding does not protect the Ca2+ -ATPase pump from thermal derangement or oxidation by H2O2.

Animals↗

PubMed1999

Expression of sarco/endoplasmic reticular Ca(2+)-ATPase in human lens epithelial cells and cultured human lens epithelial B-3 cells.

PURPOSE: Sarco/Endoplasmic Reticulum Ca(2+ )-ATPase (SER-CAs) isoforms, SERCA2b (100Kd) and SERCA3 (97Kd), are co-expressed in some non-muscle tissues. Both types of SERCAs play important roles in Ca(2+) regulation in non-muscle tissues such as brain and platelets. We tested whether these two SERCAs are present in human lens epithelial cells, human lens epithelial B-3 cells (HLE B-3 cells) and rat lens epithelial cells providing a basis for further studies the role of SERCAs in cataract formation. METHODS: Lens epithelial cells from rat lens, human lens and cultured human lens epithelial B-3 cell line (HLE B-3) were used to extract mRNA and membrane proteins. Reverse transcription polymerase chain reaction (RT-PCR) was employed to detect SERCA3 and SERCA2b mRNA using SERCA2b and SERCA3 primers. Western blotting was used to detect SERCA3 and SERCA2b proteins using anti-SERCA2b and 3 antibodies. RESULTS: A 270 bp fragment was amplified with SERCA2b primers and a 186 bp fragment amplified with SERCA3 primer in human lens epithelial cells, human lens epithelial B-3 cells and rat lens epithelial cells. Both fragments are the expected SERCA2b and SERCA3 products. The sequences of these two fragments in human lens epithelial cells are 100% and 98% homologous to the published partial SERCA2b and SERCA3 mRNA sequence, respectively. The amino acid sequences translated from both PCR products are 100% homologous to the published SERCA2b and SERCA3 sequences in GeneBank. Western blotting confirmed that the expected 100 KDa and a 97 KDa proteins are recognized by anti-SERCA2b and anti-SERCA3 antibodies. CONCLUSION: Sarco/Endoplasmic Reticulum Ca(2+)-ATPase (SERCAs) isoforms 2b and 3 mRNAs are expressed in human lens epithelial cells, the cultured human lens epithelial B-3 cell line (HLE B-3) and rat lens epithelial cells. SERCA2b and SERCA3 may play an important role in the regulation of calcium homeostasis in lens epithelial cells.

Animals↗

PubMed1999

Bovine iris-sphincter muscle lacks FP receptor binding sites.

PURPOSE: To determine the affinity, density, and specificity of the binding sites of tritium-labeled prostaglandin F2alpha in membrane preparations of bovine iris-sphincter muscle and corpus luteum. METHODS: Membrane preparations were incubated with 0.312-40.0 nM 3H-prostaglandin F2alpha in saturation experiments, or 8 nM 3H-prostaglandin F2alpha in competition studies, in the presence or absence of varying concentrations of unlabeled prostaglandin F2alpha or other prostaglandin receptor agonists. The affinity (Kd) and the density of the binding sites (Bmax) of 3H-prostaglandin F2alpha in the bovine iris-sphincter muscle were determined by Scatchard analysis. Reverse transcription polymerase chain reaction was performed with bovine iris-sphincter muscle and corpus luteum total RNA and the PCR products were hybridized with specific 32P-labeled probe for further confirmation of FP receptor expression. RESULTS: Specific binding sites of 3H-prostaglandin F2alpha in the membranes of bovine iris-sphincter muscle are saturable with an affinity of 9.5 nM and a density of 596 fmoles/mg of protein. Prostaglandin E2, 17-phenyl trinor prostaglandin E2, and GR63799 (EP, EP1, and EP3 receptor agonists, respectively) inhibited 3H-prostaglandin F2alpha binding with an IC50 of 0.0048 microM, 0.0038 microM, and 0.044 microM, respectively. Fluprostenol, a specific FP receptor agonist did not inhibit 3H-prostaglandin F2alpha binding. In contrast, prostaglandin F2alpha and fluprostenol effectively inhibited 3H-prostaglandin F2alpha binding in the bovine corpus luteum with an IC50 of 0.031 microM and 0.037 microM, respectively. CONCLUSIONS: Our results demonstrate that in the bovine iris-sphincter muscle, FP receptors are not expressed and 3H-prostaglandin F2alpha binds to EP1 and EP3 receptor sites. RT-PCR results demonstrated that FP receptor mRNA, which is present in bovine corpus luteum, is probably absent in iris-sphincter muscle.

Animals↗

PubMed1999

Responses of intraocular pressure and the pupil of feline eyes to prostaglandin EP1 and FP receptor agonists.

PURPOSE: Previous studies suggested that FP receptors do not mediate the relaxation of the ciliary muscle and reduction of intraocular pressure in cats by prostaglandin (PG) F2alpha. The present study was undertaken to determine whether the reduction of intraocular pressure in cats induced by PGF2alpha is mediated by FP or other prostaglandin receptors. METHODS: One eye of each cat was treated topically with prostaglandin F2alpha, fluprostenol (FP receptor agonist), or 17-phenyl trinor PGE2 (EP1 receptor agonist) in a dose range of 12.5 to 50 microg. The effects of SC19220 and SC51089 (EP1 receptor antagonists), BWA868c, and SQ29548 (DP and TP receptor antagonists, respectively) on the intraocular response to PGF2alpha were also examined. At intervals up to 6 hours after treatment, intraocular pressure was measured with a pneumotonometer, and pupil diameters were measured with a millimeter ruler. RESULTS: In the dose ranges used, PGF2alpha and 17-phenyl trinor PGE2 decreased intraocular pressure and pupil diameter. The greatest reduction of intraocular pressure by 50.0 microg PGF2alpha was 5.0+/-1.4 mm Hg, whereas that by 50 microg 17-phenyl trinor PGE2 was 6.2+/-1.5 mm Hg. The isopropyl ester of PGF 2alpha at a dose of 1.25 microg reduced intraocular pressure by 3.75+/-0.25 mm Hg at 2 hours. At doses up to 100 microg, fluprostenol did not decrease intraocular pressure but did reduce pupil diameter. SC19220, a weak but selective EP1 receptor antagonist, inhibited the intraocular pressure response to both PGF2alpha and 17-phenyl trinor PGE2. The more potent EP1 receptor antagonist SC51089 had a greater inhibitory effect than SC19220 on the intraocular pressure response to PGF2alpha. Both of these antagonists had a small but non-dose dependent and statistically insignificant effect on the pupil response to PGF2alpha. These observations suggest that in cats, intraocular pressure and pupil responses to PGF2alpha, are mediated by EP1 and FP receptors, respectively. However, SC19220 significantly and dose-dependently inhibited the pupil response to 17-phenyl trinor PGE2alpha suggesting that EP1 receptors mediate pupil response to this agonist. DP and TP receptor antagonists at doses 5- to 20-fold greater than the IC50 values had no effect on the ocular hypotensive response to PGF2alpha. The concurrent administration of 12.5 microg of each of PGF2alpha and 17-phenyl trinor PGE2 did not produce an additive effect on intraocular pressure, indicating that in cats PGF2alpha and 17-phenyl trinor PGE2 act on the same receptor type. CONCLUSIONS: These results suggest that a significant proportion of the ocular hypotensive action of PGF2alpha in cats is mediated by EP1 but not by FP receptor. Evidence was also provided to show that 17-phenyl trinor PGE2 is an ocular hypotensive agent in cats.

Animals↗