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At least 541 records · Page 30Linked to original sources
PubMed1994

Role of R-type calcium channels in the response of the perfused arterial and venous mesenteric vasculature of the rat to platelet-activating factor.

1. The vasoactive properties of platelet-activating factor (PAF) were studied in the arterial and venous vasculature of the rat double-perfused mesenteric bed. Although PAF (0.01-0.3 pmol) induced a dose-dependent vasodilatation of the arterial mesenteric vasculature, it triggered only vasoconstrictions on the venous side, with an intact endothelium as bradykinin induced a significant venodilatation. 2. NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), a nitric oxide synthase inhibitor, markedly reduced the vasodilatation induced by PAF in the arterial mesenteric vasculature and potentiated the contractile responses of the venous side to the same agent. 3. The PAF antagonist, WEB-2170, markedly reduced the response to PAF on both sides of the mesenteric vasculature. However, the IC50 of WEB-2170 against PAF was reached at a much higher concentration (1 x 10(-8) M) on the arterial side than on the venous side (5.3 x 10(-11) M). Furthermore, a second antagonist of PAF receptors, SRI-63441, although being less potent on the venous vasculature than WEB-2170, was equipotent in antagonizing the venoconstriction and the arterial dilatation induced by PAF (IC50 of SRI-63441, arterial side: 2.9 x 10(-9) M; venous side: 3.1 x 10(-9) M). 4. The dual L- and R-calcium channel blocker, isradipine (PN 200-110), but not the L-type calcium channel blocker, nifedipine, markedly reduced the PAF-induced vasoactive properties on both sides of the mesenteric vasculature. 5. Our results illustrate the differential vasoactive properties of PAF in the mesenteric vasculature of the rat. These vasoactive responses occur following activation of specific receptors for PAF or,alternatively, through activation of R-type calcium channels.

Animals↗
PubMed1983

Effects of quinuronium sulfate pre-exposure on hepatic excretion of sulfobromophthalein (BSP) as measured by isolated perfused rat liver.

Effects of quinuronium sulphate pre-exposure on hepatic excretion of sulfobromophthalein (BSP) as measured by isolated perfused rat liver was investigated. Seventeen rats were used in the study. Rats were divided into controls (Group 1, n = 5), low quinuronium treated animals (Group 2, n = 6), and high quinuronium treated animals (Group 3, n = 6) receiving 0, 1.5 or 2.3 mg quinuronium sulphate/kg intraperitoneally, respectively. Each animal was dosed 30 min. before sacrifice. After 30 min. of equilibrium perfusion, BSP was introduced and the experiment continued for 2 hours. Perfusate and bile were collected at designated time intervals and the volume of bile was noted. BSP in perfusate and bile was assayed. Half-life in minutes (t 1/2 +/- S.E.) of BSP disappearance from perfusate in groups 1, 2 and 3 were 12.5 +/- 1.8, 13.7 +/- 1.0 and 16.8 +/- 3.3, respectively. Group 2 and 3 rats had a significant decrease of BSP excretion in bile (P less than 0.01) compared to group 1 rats. Bile volumes decreased in both quinuronium pre-exposed groups of rats compared to control rats. These observations indicate that quinuronium affects liver function.

Animals↗
PubMed2005

Inhibition of chemoattractant N-formyl peptide receptor trafficking by active arrestins.

Recent studies have highlighted the emergence of a class of G protein-coupled receptors that are internalized in an arrestin-independent manner. In addition to demonstrating that the N-formyl peptide receptor belongs in this family, we have recently shown that recycling of the receptor requires the presence of arrestins. To further elucidate mechanisms of arrestin-dependent regulation of G protein-coupled receptor processing, we examined the effects of altering the receptor-arrestin complex on ternary complex formation and cellular trafficking of the N-formyl peptide receptor by studying two active arrestin-2 mutants (truncated arrestin-2 [1-382], and arrestin-2 I386A, V387A, F388A). Complexes between the N-formyl peptide receptor and active arrestins exhibited higher affinity in vitro than the complex between the N-formyl peptide receptor and wild-type arrestin and furthermore were observed in vivo by colocalization studies using confocal microscopy. To assess the effects of these altered interactions on receptor trafficking, we demonstrated that active, but not wild-type, arrestin expression retards N-formyl peptide receptor internalization. Furthermore, expression of arrestin-2 I386A/V387A/F388A but not arrestin-2 [1-382] inhibited recycling of the N-formyl peptide receptor, reflecting an expanded role for arrestins in G protein-coupled receptor processing and trafficking. Whereas the extent of N-formyl peptide receptor phosphorylation had no effect on the inhibition of internalization, N-formyl peptide receptor recycling was restored when the receptor was only partially phosphorylated. These results indicate not only that a functional interaction between receptor and arrestin is required for recycling of certain G protein-coupled receptors, such as the N-formyl peptide receptor, but that the pattern of receptor phosphorylation further regulates this process.

Amino Acid Sequence↗
PubMed1991

Fluorescence energy transfer between dimethyldiazaperopyrenium dication and ethidium intercalated in poly d(A-T).

Dimethyldiazaperopyrenium is one of the largest known DNA intercalators. Fluorescence energy transfer occurred between dimethyldiazaperopyrenium (donor) and ethidium (acceptor) when these dyes were bound to a double-stranded polynucleotide such as poly d(A-T). The addition of increasing amounts of ethidium bromide led to a marked shortening of the fluorescence lifetime of the donor, whereas the excited state of the acceptor was progressively populated via energy transfer from the donor. Critical Förster distance between these two chromophores was calculated to be 3.8 nm. The observed transfer efficiency was lower than that calculated on the basis of this critical distance and a statistical distribution of bound drugs. These results are discussed taking into account the conformational change induced by intercalation of dimethyldiazaperopyrenium in the double-stranded polynucleotide.

Energy Transfer↗
PubMed1997

Factors affecting M13 bacteriophage inactivation by methylene blue photosensitization.

We have investigated the factors that affect the virucidal activity of methylene blue (MB) photosensitization. The M13 bacteriophage was more rapidly inactivated at higher temperatures (6 degrees C < 24 degrees C < 38 degrees C). Rate constants for inactivation were 0.072, 0.139 and 0.260 (log10 inactivation)/ (J/cm2) at 6 degrees C, 24 degrees C and 38 degrees C, respectively. On the other hand, dye penetration into virus particles, which was monitored by the fluorescence of YOYO-1, was unchanged with incubation temperature. These data suggest that temperature dependency of M13 inactivation was due to factors other than dye permeability. The pH of the virus suspension also affected the rate of M13 inactivation by MB. The M13 bacteriophage was inactivated faster in basic suspensions and slower in acidic suspensions compared with neutral buffers. These results suggest that temperature and pH are factors that influence the extent of MB photosensitization, and hence, the control of these factors will be necessary for MB phototreatment of plasma products in transfusion medicine.

Antiviral Agents↗
PubMed1993

Administration of a receptor antagonist for platelet-activating factor during equine endotoxaemia.

Platelet-activating factor (PAF) is an important mediator of endotoxaemia and various PAF receptor antagonists prevent many of the adverse effects of experimental endotoxaemia in laboratory animals. In this study a specific PAF receptor antagonist was used to investigate the role of PAF in equine endotoxaemia. At an interval of not greater than 10 days, 6 horses were each challenged with endotoxin and endotoxin with concurrent administration of SRI 63-441, a PAF receptor antagonist. The order of the treatments was randomised. Clinical signs, serum biochemical and coagulation profiles, and platelet aggregation in vitro were monitored in all horses for 24 h after treatment. Challenge with endotoxin increased maximal platelet aggregation induced by PAF. This response was blocked by administration of SRI 63-441 concurrently with endotoxin. No changes in percentage maximal platelet aggregation to ADP or collagen were noted after administration of endotoxin. The PAF receptor antagonist delayed the onset of fever, tachycardia, leucopenia and lactic acidaemia. Lack of more profound beneficial alterations of the horses' responses to endotoxin may have been due to the low dose of endotoxin administered in this model or to only partial effectiveness of SRI 63-441 in blocking the effects of endotoxin-induced PAF.

Animals↗
PubMed1994

Adrenaline-regulated Cl- transport in cultured single rat epididymal cells measured by an entrapped Cl-(-)sensitive fluorophore.

1. Isolated cells from primary cultures of rat epididymal epithelial cells were employed for the study of adrenaline-stimulated Cl- transport using a Cl-(-)sensitive fluorophore 6-methoxy-N-(3-sulphopropyl) quinolinium (SPQ). SPQ was loaded into the cells by the hypotonic shock method. 2. The resting intracellular Cl- concentration, estimated in the presence of nigericin and tributyltin in high-K+ solution, was 62.3 +/- 0.2 mM. This value was not altered in the presence of 1 microM adrenaline. When extracellular Cl- was replaced by NO3-, an increase in fluorescence corresponding to a decrease in intracellular Cl- was observed. The initial outward Cl- movement was estimated to be 0.54 +/- 0.08 mM s-1. This value was increased by incubating the cells with adrenaline. The stimulatory effect of adrenaline was reduced by 1 mM DPC. 3. Addition of Cl- to cells previously depleted of Cl- caused an instantaneous decrease in fluorescence due to the entry of Cl-. The initial rate of Cl- entry was -0.62 +/- 0.13 mM s-1. Adrenaline increased the rate of entry to -2.13 +/- 0.08 mM s-1. The adrenaline-stimulated rate of entry was reduced by DPC or frusemide (0.5 mM) and was completely blocked in the presence of both agents. 4. In Na(+)-free solution, the adrenaline-stimulated rise of rate of Cl- entry was reduced in the presence of DPC. Frusemide had no effect on the entry rate. 5. The stimulatory effect of adrenaline were abolished by propranolol (5 microM) but not by phentolamine (5 microM). Conversely, isoprenaline (1 microM) and forskolin (1 microM) mimicked the effects of adrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Small conductance Ca2+-activated K+ channels formed by the expression of rat SK1 and SK2 genes in HEK 293 cells.

The rat SK1 gene (rSK1) does not form functional Ca2+-activated potassium channels when expressed alone in mammalian cell lines. Using a selective antibody to the rSK1 subunit and a yellow fluorescent protein (YFP) tag we have discovered that rSK1 expression produces protein that remains largely at intracellular locations. We tested the idea that rSK1 may need an expression partner, rSK2, in order to form functional channels. When rSK1 was co-expressed with rSK2 in HEK 293 cells it increased the current magnitude by 77 +/- 34% (as compared with cells expressing rSK2 alone). Co-expression of rSK1 with rSK2 also changed the channel pharmacology. The sensitivity of SK current to block by apamin was reduced approximately 16-fold from an IC50 of 94 pM (for SK2 alone) to 1.4 nM (for SK2 and SK1 together). The sensitivity to block by UCL 1848 (a potent small molecule blocker of SK channels) was similarly reduced, approximately 26-fold, from an IC50 of 110 pM to 2.9 nM. These data clearly demonstrate that rSK1 and rSK2 subunits interact. The most likely explanation for this is that the subunits are able to form heteromeric assemblies.

Algorithms↗
PubMed2006

Metabolism of nomifensine to a dihydroisoquinolinium ion metabolite by human myeloperoxidase, hemoglobin, monoamine oxidase A, and cytochrome P450 enzymes.

Nomifensine is an antidepressant agent that was removed from use because of a high incidence of hemolytic anemia. It contains an N-methyl-8-aminotetrahydroisoquinoline ring which has the potential to be oxidized to quaternary dihydroisoquinolinium and isoquinolinium ions, albeit such a transformation had not been previously observed. In this report, we demonstrate the conversion of nomifensine to a dihydroisoquinolinium ion metabolite by several human enzymes. Human liver microsomes supplemented with NADPH generated the dihydroisoquinolinium ion metabolite along with other hydroxylated metabolites, whereas when supplemented with t-butyl peroxide, only the dihydroisoquinolinium ion metabolite was observed. Monoamine oxidase A, but not monoamine oxidase B, catalyzed this reaction, as well as human hemoglobin supplemented with H2O2. Human myeloperoxidase catalyzed this reaction in the presence of H2O2, and activation of the reaction was observed when incubations were conducted in the presence of acetaminophen at concentrations relevant to those measured in humans. The reaction was also observed in human whole blood. The equilibrium between the dihydroisoquinolinium ion and carbinolamine was shown to have a pK of about 11.7. The dihydroisoquinolinium ion was shown to react with cyanide and borohydride, but not glutathione. These findings suggest that the electrophilic nomifensine dihydroisoquinolinium metabolite, which can be generated by several enzymes, could be behind toxic responses to nomifensine such as hemolytic anemia and hepatotoxicity.

Cytochrome P-450 Enzyme System↗
PubMed2003

Pharmacological and biophysical properties of the human P2X5 receptor.

We constructed a full-length human P2X5 purinoceptor cDNA by incorporating a sequence corresponding to exon 10, which is missing in cDNAs cloned previously from human tissues. We studied the functional properties by patch-clamp recording and fluorescence imaging after expression in human embryonic kidney 293 cells. ATP (1-100 microM; half-maximal current at 4 microM) elicited inward currents at -60 mV; these persisted during brief (2 s) applications but declined during longer applications. The peak current was dependent on the holding potential and showed little rectification; however, both the desensitization during the application and the decline in the current when ATP was washed out were slower at +30 mV than at -60 mV. 2',3'-O-(4-Benzoyl)-benzoyl-ATP and alphabeta-methylene-ATP mimicked the action of ATP (half-maximal concentrations 6 and 161 microM, respectively). The currents were inhibited by suramin, pyridoxal-5-phosphate-6-azo-2',4'-disulfonic acid and Brilliant Blue G, with half-maximal inhibition at 3, 0.2, and 0.5 microM, respectively; 2',3'-O-(2',4',6'-trinitrophenol)-ATP (1 microM) was ineffective. Removing divalent cations did not significantly alter ATP concentration-response curves. Reversal potential measurements showed that the human P2X5 receptor was permeable to calcium (PCa/PNa = 1.5) and N-methyl-d-glucamine (NMDG) (PNMDG/PNa = 0.4); it was also permeable to chloride (PCl/PNa = 0.5) but not gluconate (Pgluc/PNa = 0.01) ions. The permeability to NMDG developed as quickly as the channel opened, in contrast to the P2X7 receptor where the NMDG permeability develops over several seconds. Cells expressing human P2X5 receptors also rapidly accumulated the propidium dye YO-PRO-1 in response to ATP.

Adenosine Triphosphate↗
PubMed1999

Protamine-induced condensation and decondensation of the same DNA molecule.

The DNA in sperm and certain viruses is condensed by arginine-rich proteins into toroidal subunits, a form of packaging that inactivates their entire genome. Individual DNA molecules were manipulated with an optical trap to examine the kinetics of torus formation induced by the binding of protamine and a subset of its DNA binding domain, Arg6. Condensation and decondensation experiments with lambda-phage DNA show that toroid formation and stability are influenced by the number of arginine-rich anchoring domains in protamine. The results explain why protamines contain so much arginine and suggest that these proteins must be actively removed from sperm chromatin after fertilization.

Arginine↗
PubMed1993

Derivation and characterization of a quinapyramine-resistant clone of Trypanosoma congolense.

Over a period of 208 days a quinapyramine-resistant population was derived in vivo from a quinapyramine-susceptible clone of Trypanosoma congolense: IL 1180. While the dose of quinapyramine sulfate required to cure 50% of mice infected with the parental clone was 0.23 mg/kg of body weight, the 50% curative dose for the resistant derivative, IL 1180/Stabilate 12, was greater than 9.6 mg/kg. This approximately 40-fold increase in resistance to quinapyramine was shown to be associated with an 8-fold increase in resistance to isometamidium, a 28-fold increase in resistance to homidium, and a 5.5-fold increase in resistance to diminazene. Cross-resistance to homidium and diminazene was also demonstrated in goats. Two clones derived from the drug-resistant derivative underwent cyclical development in Glossina morsitans centralis, producing mature infection rates of 39.6 and 23.9%. Thus, induction of resistance to quinapyramine in T. congolense IL 1180 was associated with cross-resistance to isometamidium, homidium, and diminazene and did not compromise the population's ability to undergo full cyclical development in tsetse flies.

Animals↗