O3-induced mucosa-linked airway muscle hyperresponsiveness in the guinea pig.

We investigated the effects of ozone exposure (3.0 ppm, 2 h) on the responsiveness of guinea pig airway muscle in vitro from animals developing bronchial hyperreactivity. Muscarinic reactivity in vivo was determined by measuring specific airway resistance (sRaw) in response to increasing concentrations of aerosolized acetylcholine (ACh) administered before and 30 min after exposure. Immediately after reactivity testing, multiple tracheal rings from ozone- and air-exposed animals were prepared and the contractile responses to increasing concentrations of substance P, ACh, or KCl were assessed in the presence of 10 microM indomethacin with or without 1 microM phosphoramidon, an inhibitor of neutral endopeptidase. Isometric force generation in vitro was measured on stimulation by cumulative concentrations of the agonists, and force generation (in g/cm2) was calculated after determination of muscle cross-sectional area. The smooth muscle of mucosa-intact airways from guinea pigs with ozone-induced bronchial hyper-reactivity proved to be hyperresponsive in vitro to substance P and ACh but not to KCl. Pretreatment with phosphoramidon abolished the increase in substance P responsiveness but had no effect on muscarinic hyperresponsiveness after ozone exposure. Furthermore, substance P responsiveness was not augmented in ozone-exposed airways in which the mucosa had been removed before testing in vitro. Likewise, muscarinic hyperresponsiveness was not present in ozone-exposed airways without mucosa. Our data indicate that airway smooth muscle responsiveness is increased in guinea pigs with ozone-induced bronchial hyperreactivity and suggest that this hyperresponsiveness may be linked to non-cyclooxygenase mucosa-derived factors.     

Variation in guinea pig responsiveness.

Over the years, many reports have been published in which mention has been made of the variation in guinea pig responsiveness due to a number of different influences. In this review, we have attempted to summarize these findings with respect to genetic factors, age, sex, diet, season of the year, infection, and stress.     

Innovar-Vet-induced pathologic changes in the guinea pig.

High doses of Innovar-Vet administered im induced pathologic changes in tissues at the site of drug deposition. The onset and extent of the changes were dose related. Distal self-mutilation occurred coincidentally to the peak of pathologic changes in the ischiatic nerve.     

The metabolism in vivo of 3 alpha, 5 beta-tetrahydroaldosterone in the guinea pig

Analysis of urinary metabolites of [1, 2-3H]-3 alpha, 5 beta-tetrahydroaldosterone was performed in male guinea-pigs. Separation of urinary metabolites was carried out by means of DEAE-Sephadex A-25 column chromatography and four fractions (fraction A to fraction D) were detected. 46-50% of fraction A was extractable with ethyl acetate. When ethyl acetate extract was submitted to reversed phase high pressure liquid chromatography, a number of peaks were present and one of these peaks cochromatographed with 3 alpha, 5 beta-tetrahydroaldosterone. Fraction B, fraction C and fraction D were incubated with enzyme and the free steroid released was identified on the basis of retention time on reversed phase high pressure liquid chromatography. Thus, fraction B contained monoglucosiduronate of 3 alpha, 5 beta-tetrahydroaldosterone, whereas identification of fraction C was not successful. Fraction D was characterized as a monosulphate; 3 beta, 5 beta-tetrahydroaldosterone, 3 alpha, 5 beta-tetrahydroaldosterone and 3 beta, 5 alpha-tetrahydroaldosterone were identified as aglycones. It is probable that 3 beta, 5 alpha-tetrahydroaldosterone is converted from other tetrahydroisomers by intestinal bacteria of the guinea-pig, since mammalian tissues do not contain enzymes that introduce a double bond into ring A.     

Characterization of guinea pig cytomegalovirus DNA.

The genome of guinea pig cytomegalovirus (GPCMV) was analyzed and compared with that of human cytomegalovirus (HCMV). GPCMV and HCMV DNAs were isolated from virions and further purified by CsCl centrifugation. Purified GPCMV DNA sedimented as a single peak in a neutral sucrose gradient and was infectious when transfected into guinea pig embryo fibroblast cells. The cytopathology was characteristic of that seen after infection with GPCMV. Virus DNA purified from virions isolated from infected GPEF or 104C1 cells had a CsCl buoyant density of 1.713 g/cm3, which corresponds to a guanine plus cytosine content of 54.1%. The CsCl buoyant density of GPCMV DNA was slightly less than that of HCMV DNA (1.716 g/cm3), but sufficiently different so that the two virus DNA peaks did not coincide. GPCMV DNA cosedimented with T4 DNA in a neutral sucrose gradient. Restriction endonuclease cleavage of GPCMV or HCMV DNAs with HindIII, XbaI, or EcoRI yielded fragments easily separable by agarose gel electrophoresis and ranging from 1.0 X 10(6) to 25.8 X 10(6) daltons. The number, size, and molarity of GPCMV DNA fragments generated by restriction enzymes were determined. Hybridization of restriction endonuclease-cleaved GPCMV DNA with radioactively labeled HCMV DNA and, conversely, hybridization of restriction endonuclease-cleaved HCMV DNA with radioactively labeled GPCMV DNA indicated sequence homology between the two virus DNAs.     

Population pharmacokinetics of methotrexate in the guinea pig.

The population pharmacokinetics of an antitumoral and antiinflammatory agent, methotrexate (MTX), a folic acid antagonist, was studied in guinea pigs. Animals received an acute intraperitoneal injection of 0.25, 1 or 5 mg/kg MTX. Blood sampling was carried out for 12 hrs. after MTX administration and plasma drug concentrations were measured by fluorescence polarization immunoassay. The pharmacokinetic (PK) parameters were computed using the bayesian population model. MTX reached the level of detection at 3 hrs. for the animals injected with the lowest dose (0.25 mg/kg), at 3.5 hrs. for those animals which had the intermediate dose (1 mg/kg) and more than 6 hrs. for animals having received the highest dose (5 mg/kg). Each kinetic parameter (half life, total clearance - CLt, volume of distribution at steady state - VDSS, mean residence time - MRT - and area under curve - AUC) didn't show any significant difference between doses. MTX kinetic was linear for the first two doses (0.25 and 1 mg/kg MTX) and non-linear thereafter. MTX presented a one compartment distribution.     

Biochemical properties of the bromodeoxyuridine-induced guinea pig virus.

The biophysical and biochemical properties of the virus particles released by guinea pig embryo cells treated with 5-bromo-2'-deoxyuridine (BUdR) have been compared to those of the B-type mouse mammary tumor virus (MMTV) and the C-type Rauscher murine leukemia virus. The high-molecular-weight (60 to 70S) RNA of the BUdR-induced guinea pig virus (GPV) has a molecular weight of 8 X 106 when measred by mixed agarose polyacylamide gel electrophoresis. The virus particles isolated from the tissue culture medium of BUdR-induced guniea pig cells have the following properties in common with MMTV: (i) a buoyant density of 1.18 g/ml in sucrose and 1.21 g/ml in CsCl, and (ii) a DNA polymerase that prefers Mg2+ over Mn2+ in an assay using the synthetic template poly(rC):oligo(dG). No nucleic acid sequence homology between GPV RNA and the viral RNAs of the MMTV, murine leukemia virus, hamster sarcoma virus, or Mason-Pfizer monkey virus could be observed in a competition hybridization assay using the radioactive-labeled GPV 60 to 70S RNA. By this same competition by hybridization assay the frequency of GPV proviral sequences was estimated to be at least 83 per haploid cellular genome of guniea pig cells. No nucleic acid sequences related to be GPV RNA were detected in the DNA of normal tissues of mice, rats, cats, dogs, baboons, or humans by direct RNA-DNA hybridization using radioactive GPV60 to 70S RNA.     

Estrogen sulfotransferase distribution in tissues of mouse and guinea pig: steroidal inhibition of the guinea pig enzyme.

The highest total activity of estrogen sulfotransferase in guinea pig is in liver and the highest specific activities are in the adrenal and the midgestational chorion. Guinea pig gonads contain scarcely detectable activities. In CD-1 mice the highest specific activity is in testis and the highest total activity is in late placenta. Adrenals from both sexes and ovaries contain minimal activities, while liver and fetal membrane activities are remarkably low. In CD-1, DBA, C57BL, and BALB mice, qualitative patterns are similar. Purified or partially purified estrogen sulfotransferase from guinea pig adrenal and chorion were used to study the effect of a number of possible steroidal inhibitors. Considerable structural specificity is evident within a range of steroids, even among some which are not substrates. Pregnenolone is the most effective 21-carbon inhibitor and, in general, more highly hydroxylated forms are less inhibitory. Within a series of 21-, 19- and 18-carbon steroids, the structure of the A ring appears to be extremely important in regard to inhibitory effects.