Biomedical subjects

D F Woodward

Publications and source records attributed to D F Woodward.

At least 19 recordsLinked to original sources

PubMed2006

Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin-ethanolamides) in the feline iris.

BACKGROUND AND PURPOSE: The prostamides (prostaglandin-ethanolamides) and prostaglandin (PG) glyceryl esters are biosynthesized by COX-2 from the respective endocannabinoids anandamide and 2-arachidonyl glycerol. Agonist studies suggest that their pharmacologies are unique and unrelated to prostanoid receptors. This concept was further investigated using antagonists. EXPERIMENTAL APPROACH: The isolated feline iris was used as a key preparation, where prostanoid FP receptors and prostamide activity co-exist. Activity at human recombinant FP and other prostanoid receptors was determined using stable transfectants. KEY RESULTS: In the feline iris, AGN 204396 produced a rightward shift of the dose-response curves for prostamide F2alpha and the prostamide F2alpha analog bimatoprost but did not block the effects of PGF2alpha and synthetic FP receptor agonists. Studies on human recombinant prostanoid receptors confirmed that AGN 204396 did not behave as a prostanoid FP receptor antagonist. AGN 204396 exhibited no antagonism at DP and EP1-4, but was a highly effective TP receptor antagonist. Contrary to expectation, the FP receptor antagonist AL-8810 efficaciously contracted the cat iris. AGN 204396 did not affect AL-8810 induced contractions, demonstrating that AL-8810 and AGN 204396 are pharmacologically distinct. Unlike AL-8810, the ethylamide derivate of AL-8810 was not an agonist. Al-8810 did not block prostamide F2alpha activity. Finally, AGN 204396 did not block PGE2-glyceryl ester activity. CONCLUSIONS AND IMPLICATIONS: The ability of AGN 204396 to selectively block prostamide responses suggests the existence of prostamide sensitive receptors as entities distinct from receptors recognizing PGF2alpha and PGE2-glyceryl ester.

Animals↗

PubMed2006

Changes in endocannabinoid and palmitoylethanolamide levels in eye tissues of patients with diabetic retinopathy and age-related macular degeneration.

Cannabinoid receptors and the endocannabinoids (anandamide (N-arachidonoylethanolamine--AEA) and 2-arachidonoylglycerol (2-AG)), as well as the AEA congener, palmitoylethanolamide (PEA), are involved in ocular physiology. We measured endocannabinoid and PEA levels by isotope-dilution liquid chromatography-mass spectrometric analysis in post-mortem eye tissues of patients with diabetic retinopathy (DR) or age-related macular degeneration (AMD). In eyes with DR, significantly enhanced levels of AEA were found in the retina ( approximately 1.8-fold), ciliary body ( approximately 1.5-fold) and, to a lesser extent, cornea ( approximately 1.3-fold). Surprisingly, 2-AG levels were significantly higher ( approximately 3-fold) only in the iris, whereas PEA levels only slightly increased ( approximately 1.3-fold) in the ciliary body. In eyes with AMD, significantly enhanced levels of AEA were found in the choroid ( approximately 1.3-fold), ciliary body ( approximately 1.4-fold) and cornea ( approximately 1.4-fold), whereas in the retina only a trend towards an increase ( approximately 1.5-fold) was observed. The tissue- and disease-selective nature of the changes observed suggests that the compounds analyzed here may play different roles in the control of eye function under different pathological conditions.

Amides↗

PubMed2006

Effect of the oestrous cycle, pregnancy and uterine region on the responsiveness of the isolated mouse uterus to prostaglandin F(2alpha) and the thromboxane mimetic U46619.

Previous studies in this laboratory have suggested that the isolated uterus from non-pregnant mice has a prostaglandin F and a thromboxane receptor population similar to that found in human myometrium. The aim of this study was to investigate any regional variation in myogenic activity ) and the and responsiveness to prostaglandin F(2alpha) (PGF(2alpha) thromboxane mimetic U46619 in the mouse uterus taken during different stages of the oestrous cycle and during pregnancy. Uterine samples from BKW mice were taken from different anatomical segments along the length of each uterine horn and set up for superfusion at 2 ml/min with Krebs solution (containing 1 microM indometacin) at 37 degrees C, and gassed with 95%O(2)/5%CO(2). Responses (area under the curve) are expressed as a percentage of the final contraction induced by hypotonic shock. Data are expressed as the means +/- s.e.m. of n=5-12 and were analysed using Student's paired t-test or two-way ANOVA with a Bonferroni post hoc test. Regional variation in myogenic activity was observed in all tissues studied except those taken during labour. These tissues displayed significantly greater myogenic activity than tissues taken at late gestation and at all stages of the oestrous cycle. Tissues from pregnant animals were generally more responsive to U46619 and PGF(2alpha) than tissues taken from non-pregnant animals. Tissues taken from the upper segment of the uterine horn were more responsive to both agonists during the oestrous cycle. The findings demonstrated that the hormonal milieu and site of excision are important for myogenic activity and responsiveness.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2004

Prostaglandin ethanolamides (prostamides): in vitro pharmacology and metabolism.

We investigated whether prostaglandin ethanolamides (prostamides) E(2), F(2alpha), and D(2) exert some of their effects by 1) activating prostanoid receptors either per se or after conversion into the corresponding prostaglandins; 2) interacting with proteins for the inactivation of the endocannabinoid N-arachidonoylethanolamide (AEA), for example fatty acid amide hydrolase (FAAH), thereby enhancing AEA endogenous levels; or 3) activating the vanilloid receptor type-1 (TRPV1). Prostamides potently stimulated cat iris contraction with potency approaching that of the corresponding prostaglandins. However, prostamides D(2), E(2), and F(2alpha) exhibited no meaningful interaction with the cat recombinant FP receptor, nor with human recombinant DP, EP(1-4), FP, IP, and TP prostanoid receptors. Prostamide F(2alpha) was also very weak or inactive in a panel of bioassays specific for the various prostanoid receptors. None of the prostamides inhibited AEA enzymatic hydrolysis by FAAH in cell homogenates, or AEA cellular uptake in intact cells. Furthermore, less than 3% of the compounds were hydrolyzed to the corresponding prostaglandins when incubated for 4 h with homogenates of rat brain, lung, or liver, and cat iris or ciliary body. Very little temperature-dependent uptake of prostamides was observed after incubation with rat brain synaptosomes or RBL-2H3 cells. We suggest that prostamides' most prominent pharmacological actions are not due to transformation into prostaglandins, activation of prostanoid receptors, enhancement of AEA levels, or gating of TRPV1 receptors, but possibly to interaction with novel receptors that seem to be functional in the cat iris.

Amides↗

PubMed2004

Latanoprost-induced pigmentation in human iridial melanocytes is fibroblast dependent.

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.

Adult↗

PubMed2003

Pharmacological characterization of a novel antiglaucoma agent, Bimatoprost (AGN 192024).

Replacement of the carboxylic acid group of prostaglandin (PG) F(2alpha) with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF(2alpha) analog, where the carboxylic acid is replaced by a neutral ethylamide substituent. Bimatoprost potently contracted the feline lung parenchymal preparation (EC(50) value of 35-55 nM) but exhibited no meaningful activity in a variety of PG-sensitive tissue and cell preparations. Its activity seemed unrelated to FP receptor stimulation according to the following evidence. 1) Bimatoprost exhibited no meaningful activity in tissues and cells containing functional FP receptors. 2) Bimatoprost activity in the cat lung parenchyma is not species-specific because its potent activity in this preparation could not be reproduced in cells stably expressing the feline FP receptor. 3) Radioligand binding studies using feline and human recombinant FP receptors exhibited minimal competition versus [(3)H]17-phenyl PGF(2a) for Bimatoprost. 4) Bimatoprost pretreatment did not attenuate PGF(2alpha)-induced Ca(2+) signals in Swiss 3T3 cells. 5) Regional differences were apparent for Bimatoprost but not FP agonist effects in the cat lung. Bimatoprost reduced intraocular pressure in ocular normotensive and hypertensive monkeys over a 0.001 to 0.1% dose range. A single-dose and multiple-dose ocular distribution/metabolism studies using [(3)H]Bimatoprost (0.1%) were performed. Within the globe, bimatoprost concentrations were 10- to 100-fold higher in anterior segment tissues compared with the aqueous humor. Bimatoprost was overwhelmingly the predominant molecular species identified at all time points in ocular tissues, indicating that the intact molecule reduces intraocular pressure.

Amides↗

PubMed2001

A functional study on prostanoid receptors involved in cultured human iridal melanocyte stimulation.

The effects of various prostanoids on the growth, melanogenesis and dendrification of cultured iridal melanocytes were studied. Iridal melanocytes were isolated and cultured with medium supplemented with cAMP elevating agents and basic fibroblast growth factor (bFGF) (complete medium). The iridal melanocytes were plated into multiple well plates and cultured with complete medium or various deleted media with or without various prostanoids at different concentrations. After 6 days, the numbers of cells and dendrites were counted and melanin content was measured and compared with controls. Prostaglandin E(2), an EP(2)receptor agonist (AH 13205) and AGN 192093 (thromboxane mimetic) stimulated growth, melanogenesis and dendrification of cultured iridal melanocytes in cAMP-deleted medium. A mixed EP(1)and EP(3)receptor agonist (sulprostone), a EP(4)receptor agonist (ONO-AE1-329), IP receptor agonists (cicaprost or iloprost) and a TP receptor agonist (U-46619) showed no effect. Prostaglandin D(2)showed stimulating effects. However, these stimulating effects could not be blocked by the addition of a DP receptor antagonist (BW A868C). Furthermore, a DP receptor agonist (BW 245C) showed no effects, indicating that the effect of prostaglandin D(2)may involve receptors other than the DP receptor subtype. The present study indicates that: (1) among various EP receptor agonists, only an EP(2)receptor agonist has stimulating effects on iridal melanocytes; (2) DP, IP and TP receptor agonists do not have stimulating effects; and (3) the mechanisms of action of prostaglandin D(2)and AGN 192093 need further study.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2001

The pharmacology of bimatoprost (Lumigan).

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.

Amides↗

PubMed2001

Cellular and hormonal regulation of pigmentation in human ocular melanocytes.

The purpose of this study was to examine some of the factors that may be relevant to regulating pigmentation in the human eye, specifically whether choroidal and iridial melanocytes are sensitive to regulation by epithelial and stromal cells and alpha-melanocyte stimulating hormone (alpha-MSH). Human choroidal and iridial melanocytes were established in culture and co-cultured with epithelial cells and stromal cells derived both from skin and from eye in order to determine their influence on choroidal and iridial melanocyte dopa oxidase activity. In all cases, co-culture of melanocytes with either epithelial cells or fibroblasts led to an increase in dopa oxidase activity during 5 days of co-culture. The extent of the increase ranged from 60% (non-significant) to as much as 185% when both fibroblasts and keratinocytes were present. The optimal ratio of fibroblasts to melanocytes was 1:10 (for dermal fibroblasts) or 1:2 (for iridial fibroblasts) and 1:1 for all epithelial cells to melanocytes. Both choroidal (three out of three cultures) and iridial (two out of three cultures) melanocytes showed increases in dopa oxidase activity to alpha-MSH when cultured in Green's media but the same cells cultured in MCDB153 were unresponsive to alpha-MSH. These in vitro studies suggest that ocular melanocytes have the capacity to be influenced by adjacent epithelial and stromal cells with respect to pigmentation.

Adult↗

PubMed2001

Differential effects of alpha-adrenoceptor agonists on human retinal microvessel diameter.

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.

Adrenergic alpha-Agonists↗

PubMed2001

Naturalized salmonid populations occur in the presence of elevated trace element concentrations and temperatures in the Firehole River, Yellowstone National Park, Wyoming, USA.

We investigated the effects of geothermally influenced waters on the distribution of rainbow trout, Oncorhynchus mykiss, and brown trout, Salmo trutta, in the Firehole River and its tributaries in Yellowstone National Park (WY, USA) from June 1997 to June 1998. Geothermal features in the Firehole River basin elevate mineral content and temperature in portions of the river and its tributaries. We found concentrations of boron and arsenic to be elevated in geothermally influenced areas compared with upstream sites. Boron concentrations occasionally exceeded 1,000 microg/L, a proposed limit for the protection of aquatic organisms. Arsenic concentrations occasionally exceeded 190 microg/L, the chronic ambient water quality criterion. Temperatures in geothermally influenced sites ranged up to 30 degrees C and were consistently 5 to 10 degrees C higher than upstream sites unaffected by geothermal inputs. Rainbow trout occurred at sites with elevated concentrations of boron, arsenic, and other trace elements and elevated water temperatures. Rainbow trout inhabited and spawned at sites with the most elevated trace element concentrations and temperatures; however, brown trout were absent from these sites. Water temperature may be the major factor determining brown trout distributions, but we cannot exclude the possibility that brown trout are more sensitive than rainbow trout to boron, arsenic, or other trace elements. Further investigations are needed to determine species-specific tolerances of boron, arsenic, and other trace elements among salmonids.

Adaptation, Physiological↗

PubMed2000

Delayed reversal of shape change in cells expressing FP(B) prostanoid receptors. Possible role of receptor resensitization.

Prostaglandin F(2 alpha) (PGF(2 alpha)) receptors are G-protein-coupled receptors consisting of two alternative mRNA splice variants, named FP(A) and FP(B). As compared with the FP(A) isoform, the FP(B) isoform lacks the last 46 amino acids of the carboxyl terminus and, therefore, represents a truncated version of the FP(A). We recently found (Pierce, K. L., Fujino, H., Srinivasan, D., and Regan, J. W. (1999) J. Biol. Chem. 274, 35944-35949) that stimulation of both isoforms with PGF(2 alpha) leads to activation of a Rho signaling pathway, resulting in tyrosine phosphorylation of p125 focal adhesion kinase, formation of actin stress fibers, and cell rounding. Although the activation of Rho and subsequent cell rounding occur at a similar rate for both isoforms, we now report that following the removal of PGF(2 alpha) the reversal of cell rounding is much slower for cells expressing the FP(B) isoform as compared with the FP(A) isoform. Thus, in HEK-293 cells that stably express the FP(A) isoform, the reversal of cell rounding appears to be complete after 1 h, whereas for FP(B)-expressing cells there is essentially no reversal even after 2 h. Similarly, the disappearance of stress fibers and dephosphorylation of p125 focal adhesion kinase following removal of agonist are much slower in FP(B)-expressing cells than in FP(A)-expressing cells. The mechanism of this differential reversal appears to involve a difference in receptor resensitization following the removal of agonist. Based upon whole cell radioligand binding, agonist-induced stimulation of inositol phosphate formation, and mobilization of intracellular Ca(2+), the FP(B) isoform resensitizes more slowly than the FP(A) isoform. These findings suggest that the carboxyl terminus of the FP(A) is critical for resensitization and that the slower resensitization of the FP(B) isoform leads to prolonged signaling. This differential signaling distinguishes the FP(A) and FP(B) receptor isoforms and could be important toward understanding the physiological actions of PGF(2 alpha).

Calcium↗

PubMed2000

Influence of autonomic neurotransmitters on human uveal melanocytes in vitro.

The influence of autonomic neurotransmitters on the growth and melanogenesis of cultured uveal melanocytes was studied. Uveal melanocytes were cultured with medium supplemented with cAMP elevating agents and basic fibroblast growth factor (complete medium). The cells were plated into multiple well plates, and various concentrations of adrenergic and cholinergic agents were added to the media (complete medium or various deleted media). After 6 days, the cells were detached for cell counting and melanin measurement and compared to controls. Epinephrine, isoproterenol, salbutamol and metaproterenol (adrenergic agonists that can activate beta(2)-adrenoceptors) substantially stimulated growth and melanogenesis of cultured uveal melanocytes in cAMP-deleted medium. Methoxamine, clonidine, prenalterol and D-7114 (adrenergic agonists that do not activate beta(2)-adrenoceptors) showed no effect under similar experimental conditions. Muscarine (a cholinergic agonist) inhibited the growth and melanogenesis of uveal melanocytes in complete medium. It indicates that adrenergic agents (beta(2)-adrenoceptor agonists) stimulate growth and melanogenesis in uveal melanocytes, while cholinergic agonist has an inhibitory effect. This effect appears to involve the cAMP second messenger system. These studies suggest that homeostasis of the uveal melanocytes may be maintained, in part, by regulating the autonomic nervous system in vivo.

Adrenergic Agonists↗

PubMed2000

Replacement of the carboxylic acid group of prostaglandin f(2alpha) with a hydroxyl or methoxy substituent provides biologically unique compounds.

Replacement of the carboxylic acid group of PGF(2alpha) with the non-acidic substituents hydroxyl (-OH) or methoxy (-OCH(3)) resulted in an unexpected activity profile. Although PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) exhibited potent contractile effects similar to 17-phenyl PGF(2alpha) in the cat lung parenchymal preparation, they were approximately 1000 times less potent than 17-phenyl PGF(2alpha) in stimulating recombinant feline and human FP receptors. In human dermal fibroblasts and Swiss 3T3 cells PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) produced no Ca(2+) signal until a 1 microM concentration was exceeded. Pretreatment of Swiss 3T3 cells with either 1 microM PGF(2alpha) 1-OH or PGF(2alpha) 1-OCH(3) did not attenuate Ca(2+) signal responses produced by PGF(2alpha) or fluprostenol. In the rat uterus, PGF(2alpha) 1-OH was about two orders of magnitude less potent than 17-phenyl PGF(2alpha) whereas PGF(2alpha) 1-OCH(3) produced only a minimal effect. Radioligand binding studies on cat lung parenchymal plasma membrane preparations suggested that the cat lung parenchyma does not contain a homogeneous population of receptors that equally respond to PGF(2alpha)1-OH, PGF(2alpha)1-OCH(3), and classical FP receptor agonists. Studies on smooth muscle preparations and cells containing DP, EP(1), EP(2), EP(3), EP(4), IP, and TP receptors indicated that the activity of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) could not be ascribed to interaction with these receptors. The potent effects of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) on the cat lung parenchyma are difficult to describe in terms of interaction with the FP or any other known prostanoid receptor.

3T3 Cells↗

PubMed2000

Synthetic modification of prostaglandin f(2alpha) indicates different structural determinants for binding to the prostaglandin F receptor versus the prostaglandin transporter.

Several principles governing the binding of E series prostaglandins to EP receptors have emerged in recent years. The C-1 carboxyl group binds electrostatically to a conserved arginine residue in the seventh transmembrane segment of the receptor. Prostaglandin E analogs involving bioisosteric replacements of the carboxyl group, such as acylsulfonamide, are also active. In addition, structurally similar esters may also exhibit similar affinity, presumably by virtue of hydrogen bonding. Other regions of the substrate molecule appear to bind to other domains of EP receptors, either via hydrophobic interactions or by hydrogen bonding. Less information is available about the structural requirements for substrate binding to FP receptors. Prostanoids also bind to the prostaglandin transporter PGT. In this case, a conserved C-1 carboxyl group is critically important, since C-1 esters exhibit little affinity. Here we examined the binding of chemically diverse PGF(2alpha) structural analogs to the FP receptor and compared these with binding by the PG transporter. PGT recognized a wide range of anionic substituents. In contrast, the carboxylic acid group was essential for optimal binding to the FP receptor, since replacement by larger moieties with a similar pK(a), such as acylsulfonamide and tetrazole, substantially decreased binding affinity. Interestingly, insertion of cyclic substituents in the omega chain increased binding to the FP receptor but reduced affinity for PGT, and substitution for the 15-hydroxyl group produced only a modest reduction in FP receptor binding, but eliminated binding by PGT. Because extracellular PGF(2alpha) may compete for binding between FP receptors and PGT, these findings have implications for designing PGF(2alpha) analogs for treating disease states.

Animals↗

PubMed1998

Relationships between boron concentrations and trout in the Firehole River, Wyoming: historical information and preliminary results of a field study.

The Firehole River (FHR) in Yellowstone National Park (YNP) is a world-renowned recreational fishery that predominantly includes rainbow trout (RBT, Oncorhynchus mykiss) and brown trout (BNT, Salmo trutta). The trout populations apparently are closed to immigration and have been self-sustaining since 1955. Inputs from hot springs and geysers increase the temperature and mineral content of the water, including elevating the boron (B) concentrations to a maximum of approximately 1 mg B/L. Both RBT and BNT reside in warm-water reaches, except when the water is extremely warm (> or = approximately 25 degrees C) during midsummer. They spawn in late fall and early winter, with documented spawning of BNT in the cold-water reach upstream from the Upper Geyser Basin and of RBT in the Lower Geyser Basin reach, where water temperatures presumably are the warmest; however, successful recruitment of RBT in waters containing approximately 1 mg B/L has not been demonstrated conclusively. Thus, we began investigating the relationships among temperature, B concentrations, other water-quality parameters, and the distribution and reproduction of trout in the FHR in spring 1997. However, atypical high water flows and concomitant lower than historical temperatures and B concentrations during summer 1997 preclude conclusions about avoidance of high B concentrations.

Animals↗

PubMed1998

Concentrations of metals associated with mining waste in sediments, biofilm, benthic macroinvertebrates, and fish from the Coeur d'Alene River basin, Idaho.

Arsenic, Cd, Cu, Pb, Hg, and Zn were measured in sediments, biofilm, benthic macroinvertebrates, and fish from the Coeur d'Alene (CDA) River to characterize the pathway of metals transfer between these components. Metals enter the CDA Basin via tributaries where mining activities have occurred. In general, the ranking of food-web components from the greatest to smallest concentrations of metals was as follows: biofilm (the layer of abiotic and biotic material on rock surfaces) and sediments > invertebrates > whole fish. Elevated Pb was documented in invertebrates, and elevated Cd and Zn were documented in sediment and biofilm approximately 80 km downstream to the Spokane River. The accumulation of metals in invertebrates was dependent on functional feeding group and shredders-scrapers that feed on biofilm accumulated the largest concentrations of metals. Although the absolute concentrations of metals were the largest in biofilm and sediments, the metals have accumulated in fish approximately 50 km downstream from Kellogg, near the town of Harrison. While metals do not biomagnify between trophic levels, the metals in the CDA Basin are bioavailable and do biotransfer. Trout less than 100 mm long feed exclusively on small invertebrates, and small invertebrates accumulate greater concentrations of metals than large invertebrates. Therefore, early-lifestage fish may be exposed to a larger dose of metals than adults.

Animals↗

PubMed1998

Prostanoid-induced contraction of the rabbit isolated uterus is mediated by FP receptors.

Natural and synthetic prostanoid agonists were used to study the prostanoid receptors involved in contraction of the mature, isolated uterus of virgin rabbits. The prostanoids elicited contractile responses with a rank order of potency of PGF2 alpha, fluprostenol > PGD2 > U-46,619 > PGE2 > carbaprostacyclin with mean EC50 (nM) values of 4, 6, 34, 550, 1318 and > 10,000, respectively. Carbachol, a muscarinic agonist given after the prostanoids to elicit a reference contraction, had a mean EC50 value of 1.1 microM. The results show that the mature rabbit uterus is most sensitive to prostaglandin FP agonists and, thus, can be defined pharmacologically as an FP receptor preparation. These findings may facilitative investigations into the possibility of different prostanoid receptor populations. In the absence of useful competitive FP receptor antagonists, agonist potency data is particularly useful in systems where cross-species comparisons and tissue-related factors are not involved. The potent activities of the FP agonists, PGF2 alpha and fluprostenol, in the isolated jugular vein and uterus of the rabbit suggest that these tissues may be useful for intra-species comparisons.

Animals↗