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Antibodies obtained from guinea pigs injected with rabbit pancreatic trypsin together with antibodies raised in rabbits against bovine acrosin or bovine pancreatic trypsin were reacted against various mammalian trypsins and acrosins in double diffusion tests. The results of immunodiffusion analyses reveal antigenic dissimilarity between rabbit acrosin and rabbit trypsin.
The purpose of this study is to assess the permeability of acyclovir (ACV) prodrugs through the rabbit corneal cell line (SIRC) as well as the cornea, and characterize the SIRC cell line for transport and metabolism studies of ester prodrugs. Prodrug derivatization of an acycloguanosine antiviral agent, acyclovir, was employed to improve its permeability across the cornea. New Zealand albino rabbits were used as an animal model for corneal studies. The SIRC cell line grown on polyester membranes was used for transport of these prodrugs. SIRC cells grown on the membrane support for 10 days developed four to six layers of epithelial cells, and this is comparable to the normal rabbit corneal epithelial layer. Transport experiments were conducted across the rabbit cornea and confluent SIRC cells using side-by-side diffusion-cell apparatus. Enzymatic hydrolysis of these compounds was evaluated in SIRC cell lysates. Appropriate reversed phase HPLC method(s) were employed for quantitation of both the prodrug and ACV simultaneously. Corneal permeabilities of some of these prodrugs (Malonyl ACV and Acetyl ACV) were higher relative to ACV. The SIRC cell line permeability values of all the prodrugs were higher compared to that of the intact cornea. The total amount of ACV-prodrugs transported, i.e., unhydrolyzed prodrugs and regenerated ACV, across the SIRC cell line was more relative to ACV. Hydrolytic studies in the SIRC cell line homogenate demonstrated the bioreversion potential of the prodrugs and the presence of enzymes, particularly the cholinesterase in the SIRC cell line. It may be concluded that the SIRC cell line is leakier compared to the cornea. Keeping in mind the limitations, the SIRC cell line after further characterization may be used for transport and metabolism studies of ester prodrugs.
Erythropoietin (EPO) cDNA was cloned from kidney total RNA of a NZW rabbit. The cDNA comprises a 588-bp open reading frame encoding a 195 amino acid protein with distinguishable regions of high of homology to other mammalian EPOs. Intramuscular injection of mice with a rabbit EPO expression plasmid resulted in a significant hematocrit increase. A rabbit genomic DNA fragment was also cloned using the rabbit EPO cDNA. This 4312-bp genomic DNA fragment contains sequences homologous to the mouse EPO promoter and hypoxia-responsive enhancer. In addition, the genomic DNA also presents a high degree of conservation to other regions involved in hypoxia response. Sequence divergence in the 3' UTR may indicate differences in regulation of mRNA stability or response to low oxygen tension.
Methyl isocyanate (MIC) interaction with the rabbit erythrocyte membrane increased the fluidity of the membrane and decreased the osmotic fragility of erythrocytes both in vitro and in vivo in rabbits intoxicated with MIC subcutaneously. MIC inhibited both acetylcholinesterase (AChE) and adenosine triphosphatase (ATPase) activities of erythrocytes dose-dependently in vitro, while in vivo a decreased trend in ATPase activity with unaltered AChE activity was observed. MIC also caused significant decrease in plasma sodium level with corresponding increase in potassium level in rabbits. The observed effects are due to MIC, per se, as the hydrolysis products of MIC, methylamine and N,N'-dimethylurea did not affect the erythrocyte fluidity and enzymes activities both in vitro and in vivo while they increased the osmotic fragility of erythrocytes in vivo in rabbits administered subcutaneously in equimolar concentration to MIC dosage. Inhibition of Na(+)-K(+)-dependent ATPase with altered permeability to cations and also probably water transport of plasma membrane due to MIC interaction are envisaged.
During the development of proliferative arthritis in the knee joints of rabbits, there was a large increase in the ability of articular cartilage explants to produce latent collagenase in culture. In parallel, the normally high levels of collagenase inhibitor produced by cartilage in culture fell, but active collagenase was never detectable. Characterisation of the collagenase and other proteinase activities produced by rabbit articular cartilage in culture showed that two activities could be separated by gel filtration, one with activities on gelatin and cartilage proteoglycan and the other degrading collage. Under the conditions employed in this paper no resolution of the gelatin and proteoglycan activities could be achieved. All the activities were in a latent form, activated by 4-aminophenylmercuric acetate (APMA), and inhibited by 1,10-phenanthroline or EDTA, but not by di-isopropylfluorophosphate (DFP), indicating that they are metalloproteinases. Characterization of the collagenase inhibitor showed a single peak of activity of apparent molecular weight of 28,000 on gel filtration. The inhibitor was sensitive to APMA and also inhibited other rabbit metalloproteinases, analogous to the system described for rabbit bone. The physiological significance of the synthesis by articular cartilage of proteinases that destroy connective tissue macromolecules and the presence of an enzyme-inhibitor control system is discussed.
A newly isolated parvovirus of rabbits (F-7-9 strain) was inoculated into young female rabbits by the oral or intravenous route. Virus was recovered from the feces 3 to 13 days after inoculation. Viremia was demonstrated in orally inoculated rabbits. The virus was also isolated from tissue extracts of liver, pancreas, spleen, small intestine, appendix and mesenteric lymph node on days 10 and/or 14, and from the small intestine on day 30 after inoculation. Hemagglutination inhibiting antibody appeared in the serum after 8 days and neutralizing antibody was detected later. An 11S neutralizing antibody was demonstrated in fecal extracts between 15 and 30 days after inoculation. Infected rabbits showed very mild clinical signs of listlessness and inappetence lasting for a few days. Histologically, mild to moderate catarrhal enteritis was observed in the small intestine.
Rabbit lymphocytes from the mesenteric lymph nodes were stimulated with concanavalin A, goat anti-rabbit immunoglobulin, or the Ca2+ ionophore A 23187. The stimulated incorporation of labeled uridine into RNA as well as of labeled thymidine into DNA was suppressed within a dose range of 40-1000 ng/ml cyclosporin A in both Con A-stimulated T lymphocytes and in anti-immunoglobulin-stimulated B lymphocytes, without affecting the resting cells. A 23187-stimulated rabbit lymphocytes proved to be more sensitive to cyclosporin A. At 40 ng/ml the immunosuppressive drug was effective in inhibiting elevated incorporation of labeled nucleosides into macromolecules in ionophore-stimulated cells. Cyclosporin A, at the same concentrations that were effective in inhibiting stimulated RNA and DNA synthesis, suppressed one of the earliest events occurring in stimulated lymphocytes, i.e., enhanced incorporation of unsaturated fatty acids into membrane phospholipids. Whereas cyclosporin A significantly inhibited the incorporation of arachidonic acid into phosphatidylcholine and phosphatidylethanolamine in concanavalin A-, anti-immunoglobulin-, and A 23187-stimulated cells, it proved to be ineffective in inhibiting the incorporation of arachidonate into phosphatidylinositol. The data indicate that cyclosporin A inhibits both T- and B-cell stimulation by interfering with a common target, e.g., the early activation of membrane phospholipid metabolism of rabbit lymphocytes.
Two monoclonal antibodies against human apolipoprotein A-I were characterized to recognize rabbit apo A-I. By immunoblotting we determined that while neither antibody reacted with the other rabbit apolipoproteins they both recognized all rabbit apo A-I isoforms. Cotitration revealed that each antibody bound to different apo A-I epitopes. Then we developed a noncompetitive enzyme-linked immunosorbent assay (ELISA) to measure the concentration of total apolipoprotein A-I in rabbit serum. The ELISA curves of the different lipoprotein class and serum showed the similarity of the expression of the apo A-I epitopes recognized in each of them and in serum. This assay, as opposed to other techniques, offers several advantages such as sensitivity, specificity, and simplicity and avoids the use of radioisotope.
The metabolisms of the two glycoforms of rabbit plasminogen have been compared in rabbits. Plasminogen I and II (ratio in plasma, 1:2.2) differ only in glycan content: plasminogen I probably possesses one N-glycan and one O-glycan, and plasminogen II only one O-glycan. New Zealand White (NZW) rabbits were injected intravenously with 125I-plasminogen I and 131I-plasminogen II, and blood samples were taken at regular intervals over 5 days. Kinetic behaviors were determined from protein-bound radioactivities using a three-compartment model. Fractional catabolic rates for plasminogen II in the vascular space (2.42 d-1) and the total body (0.56 d-1) were significantly greater than those measured for plasminogen I (1.12 and 0.45 d-1); half-lives were 1.53 and 1.23 days for plasminogen I and II, respectively (P < .01). Fractional distributions among the vascular, noncirculating vascular, and extravascular compartments were 0.41, 0.13, and 0.46 for plasminogen I, and 0.23, 0.11, and 0.65 for plasminogen II. From these data, we determined that plasminogen II was catabolized 4.8 times more rapidly than plasminogen I and was quantitatively contained largely in the extravascular space. By comparison, perfusion of rabbit livers ex corpora showed that plasminogen II was synthesized and released 5.0 times faster than plasminogen I over a 5-hour period. The possible roles for these glycoforms in vivo with respect to their different turnover rates and compartmental distributions are discussed.
In three separate experiments albino rabbits, pigmented rabbits, and humans were tested following administration of acetazolamide and without acetazolamide. In all three experiments, we recorded electroretinograms (ERGs) under dark adapted and light adapted conditions and measured the b-wave amplitudes. Dark adapted ERG b-wave amplitudes were increased following administration of acetazolamide as compared to control conditions, in albino rabbits, pigmented rabbits and humans. Light adapted b-wave amplitudes showed no statistically significant changes as a function of acetazolamide administration although in all three experiments there was a trend toward light adapted b-wave amplitude reduction following administration of acetazolamide. In the human experiments, ERG a-wave amplitudes were also measured. Light adapted a-wave amplitudes were reduced following administration of acetazolamide. In the human experiments, several behavioral tests were performed, including L'Anthony desaturated D-15, Farnsworth-Munsell 100 hue, Cogan-Gunkel chromatograph, Nagel anomaloscope, Goldmann-Weekers dark adaptometry. There were no consistent changes in the human dark adaptation thresholds or color discrimination, although several measures approached significance.
The catalytic subunit of protein phosphatase-1 (PP1) isolated from rabbit liver had the same electrophoretic mobility as, and yielded peptide maps identical to those of the 33 kDa form of rabbit skeletal muscle PP1. The predicted amino-acid sequences of PP1 obtained from three rabbit liver cDNA clones were identical to that of PP1 alpha from rabbit skeletal muscle. These findings suggest that the distinctive substrate specificities and regulatory properties of hepatic and skeletal muscle type-1 protein phosphatases are not conferred by the catalytic subunits themselves, but by regulatory subunits that are complexed to the catalytic subunits in vivo.
Testicular androgen-binding proteins (ABP) in rabbit testis, caput epididymis and efferent duct fluid (EDF) were compared to a similar androgen-binding protein TeBg) in rabbit serum. The affinity of these proteins for 5alpha-dihydrotesterone (DHT) at 0 degrees C (KaABP = 1.6 X 10(9) M-1 and KaTeBG = 1.9 X 10(9) M-1) and their steroid specificities were similar (DHT greater than androstanediol greater than progesterone and androstenedione). ABP and TeBG had also almost identical Stokes radii (42.8 +/- 1.2 and 43.9 +- 0.8 A, respectively), sedimentation coefficients (4.7 +/- 0.2 S and 4.4 +/- 0.2 S, respectively) and electrophoretic mobility (Rf = 0.4 in 6 1/2% polyacrylamide gels). Calculation of molecular weights from Stokes radii and sedimentation rates indicated a molecular weight of 74,000 (69,000-78,000) for TeBG and 76,000 (71,000-82,000) for ABP. The corresponding frictional ratios were 1.61 for TeBG and 1.55 for ABP assuming a partial specific volume (v) of 0.70 cm3/g. Polyacrylamide gel electrophoresis (PAGE) at different gel concentrations gave a mean molecular radius of 2.74 nm, also indicating a molecular weight of about 75,000 (v = 0.70 cm3/g. ABP and TeBG could not be separated by PAGE; however, partial separation of ABP and TeBG was achieved by isoelectric focusing and ion-exchange chromatography on DEAE-cellulose. TeBG focused at pH 5.4, whereas ABP formed a distinct peak of bound radioactivity at pH 4.7. Also by ionexchange chromatography, ABP in both testis and epididymal supernatants was shown to have an apparently higher surface charge than TeBG in rabbit serum. The concentration of ABP in efferent duct fluid (2 X 10(-7) M = 60 pmol/mg protien) was much higher than TeBG in male rabbit serum (5.2 X 10(-8) M = 0.7 pmol/mg protein). These findings ruled against the possibility that ABP in the testis and epididymis could have been derived directly from serum. It is concluded that ABP and TeBG are very similar if not identical proteins both serving as transport and carrier proteins in their respective compartments.
Conditioned culture media from confluent rabbit articular chondrocytes maintained in serum-free monolayer culture contained metal-dependent neutral pH collagenolytic activity degrading Type I, II and III rabbit [125I]-labeled collagens. This collagenolytic activity degraded Type II collagen more slowly than Type I collagen and Type III collagen at 37 degrees C. By contrast, collagenolysis by chondrocyte cytosolic protein, lysosomal granule protein and residual lysosomal membrane protein was highly specific for Type II collagen. Although collagenolytic activity against all the collagen isotypes tested was predominantly in a latent form after 24 h of culture, increasing levels of constitutive collagenolytic activity was measured with increasing culture time. These results are consistent with a differential degradation of rabbit interstitial collagens by rabbit chondrocyte collagenase. The data suggest a cellular compartmentalization of collagenolytic activity with specificity toward Type II collagen.
In this work, we have studied the pharmacokinetics and milk penetration of verapamil following intravenous administration in lactating rabbits. Milk-to-serum drug concentration ratios (M/B(obs)) have been determined using area under the milk and serum concentration-time profiles, and the resulting values have then been compared with those obtained by theoretical classical diffusion milk transfer models that were described by Fleishaker et al. [J. Pharm. Sci. 76 (1987) 189.], Atkinson and Begg [Br. J. Clin. Pharmacol. 25 (1990) 495.], and Stebler and Guentert [Pharm. Res. 9 (1992) 1299.]. The pharmacokinetic profile of verapamil in lactating rabbits following endovenous administration is described in the form of a two-compartment model. Moreover, we detected an important milk transfer after endovenous administration of verapamil in lactating rabbits. M/B(obs) was near 15. The classical diffusional models mentioned were not able to predict this extensive transfer of verapamil into rabbit milk. However, when the classical Fleishaker equation was modified and a stepwise regression was carried out, we found that the M/B(obs) value could be predicted using the plasma and milk protein binding.
The 5' ends of five full-length LINE1 (L1) repeats from the rabbit genome (L1Oc) were mapped and their nucleotide sequences determined. Computer-generated alignments showed that these five L1Oc repeats can be divided into subfamilies, each of which has a characteristic sequence upstream of the first open reading frame (ORF1). These five L1Ocs range in size from 6.5 to 7.3 kb, with 5' ends located 76 to 1125 bp upstream of ORF1. Two of these subfamilies appear to have diverged from a common ancestor at least 66 million years ago. Comparisons of the 5' ends of L1s from rabbit, human, mouse, and rat show no common sequence 5' to ORF1, except for a 22-bp sequence that is found near the beginning of all characterized full-length L1s from rabbit and human. A statistical analysis indicates that this 22-bp aligned block is highly significant. Part of this 22-bp sequence matches the microE1 binding site in immunoglobulin gene enhancers. This strong conservation suggests that the microE1 binding site may be part of a transcriptional regulatory element at the 5' ends of rabbit and human L1 repeats.
Serum cholesterol in rabbits was elevated, by intravenous inoculation of 20% Tween 80, to amounts thought to have been sufficient to support growth of Mycoplasma gallisepticum when 20% of such serum was added to rabbit infusion broth.However, better growth of the organism was obtained with a supplement of 5% rabbit serum and commercial cholesterol. Investigation showed that normal rabbit serum may be inhibitory, which would explain these findings. The commercial cholesterol was not antigenic.
1. The European rabbit flea Spilopsyllus cuniculi (Dale) bred successfully in wild rabbits on three properties in New South Wales and, within two breeding seasons, almost every rabbit shot within a quarter of a mile of a release site was infested.2. It was demonstrated that the flea transmitted myxoma virus in the field.3. In areas where more than 75% of the rabbits shot at the beginning of the breeding season were flea-infested and myxoma virus was present, populations failed to show the expected summer build-up.
A rapid and sensitive liquid chromatographic assay for 2',3'-didehydro-3'-deoxythymidine (d4T) in plasma and urine is described. This assay uses thymidine oxetane (TO), a synthetic precursor of d4T, as internal standard. Sample preparation involves a simple extraction of plasma or urine with 5% isopropyl alcohol in methylene chloride. The method is specific and sensitive, allowing a linear response over a 2000-fold range of concentrations in human plasma (5 ng/ml to 10 micrograms/ml) and urine (50 ng/ml to 100 micrograms/ml). This assay, developed for human plasma and urine, is also applicable to rabbit samples with minor modification. Intravenous bolus doses of 10 mg/kg d4T to rabbits showed that the plasma concentration-time profile followed a biexponential decay. Estimates of the distribution and elimination half-lives were 6.7 +/- 0.9 and 51 +/- 6 min, respectively. The total-body and renal clearances were 23.4 +/- 3.6 and 8.82 +/- 3.9 ml/min.kg, respectively. That the renal clearance exceeds the glomerular filtration rate in the rabbit suggests that d4T is actively secreted in the renal tubule. The fraction excreted unchanged in the urine was 36 +/- 8%. Similar results were obtained in the same rabbits at steady state during constant-rate intravenous infusion. Noncompartmental analysis estimates of the MRT and Vdss were 46 +/- 5 min and 1.08 +/- 0.13 L/kg, respectively.