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Several immunochemical homologs of hepatic cytochromes P450 (CYPs) capable of steroid catabolism have been identified in the guinea pig adrenal cortex. Their predominance in males suggests a role in sex-differentiated metabolism of androgens. Therefore, we examined the ability of microsomes from male guinea pig adrenals and liver to metabolize androstenedione. Microsomes were incubated in the presence of radiolabeled steroids, the products of the reaction extracted, separated by TLC, and visualized by autoradiography. Metabolites were identified by comigration with commercially available standards in several solvent systems, in one and two dimensional TLC. Microsomes from both tissues metabolized androstenedione. However, the products formed differed markedly in the two tissues. Liver microsomes formed one major metabolite, testosterone. It represented 85% of the metabolized androstenedione. 6 beta-Hydroxylated androstenedione and testosterone each comprised 3-4% of the liver metabolites. In addition, at least 10 other products were formed, but taken together they constituted less than 8% of the metabolized androdostenedione. Adrenal microsomes, on the other hand, produced several major metabolites: 16 alpha-, 16 beta-, and 6 beta-hydroxy-androstenedione, plus one unidentified product constituted 93% of the metabolized androstenedione. 16 alpha-Hydroxylation of androstenedione was 60 fold, 16 beta-hydroxylation 12 fold, and 6 beta-hydroxylation 2.5 fold greater in adrenal than in liver microsomes. The unidentified product, which was the least polar, was formed exclusively by adrenal microsomes. The hydroxylation reactions performed by adrenal tissue are consistent with the presence in adrenal microsomes of immunochemical homologues of members of the CYP1A, 2B, 2C and 3A families which have known steroid hydroxylation functions in liver. The Kms of the formation of 16 alpha-, 16 beta- and 6 beta-hydroxyandrostenedione by adrenal microsomes are in the range reported for steroid hydroxylation reactions in rat liver tissue. Their distinct values suggest that these hydroxylation steps are performed by different CYPs. However, assignment of site-specific steroid hydroxylation reactions to individual hepatic CYP homologs in the adrenal requires further investigation and is being pursued using combined techniques of biochemistry and molecular biology.
Direct comparison of experimental data for drugs commonly used in the treatment of overactive bladder is difficult because of possible species differences. In this study, we compare the effects of atropine, propiverine, oxybutynin and tolterodine in strips of pig, guinea pig and mouse detrusor muscle. In the three species, we observed slight differences in potency of carbachol-induced biphasic contractile responses between the species (guinea pig>pig>mouse). Cumulative concentration-response curves for carbachol were shifted to the right by atropine, propiverine, oxybutynin and tolterodine. However, at higher concentrations of the latter three antagonists, the maximum response to carbachol was also reduced. Therefore, propiverine, oxybutynin and tolterodine must have additional pharmacological actions beyond competitive antagonism at muscarinic receptors. Electric field stimulation (30 Hz) of detrusor strips led to contraction amplitudes, which remained constant over time (210 min) in pig, decreased by 17+/-5% in guinea pig, and increased by 28+/-9% in mouse detrusor muscle. Electric field stimulation-evoked contractions were suppressed to 18% of pre-drug control by high concentrations of atropine (10 microM) in pig, but to a much lesser extent in guinea pig and mouse (to 46% and 70%, respectively). In all three species, a myogenic component of contraction was observed in the presence of tetrodotoxin (1 microM). Compared to atropine, the bladder spasmolytic agents propiverine, oxybutynin and tolterodine also reduced electrically evoked contractions in the three species, though higher concentrations were required. The differences in the reported effects of the spasmolytic agents commonly used for treating overactive bladder suggest that drug action is strongly dependent on the species. Thus, a comparison of drug effects is only feasible in the same animal model and the results cannot easily be transferred to humans.
Proteolysis of corneodesmosin, a 52- to 56-kDa basic protein located in the extracellular part of the modified desmosomes (corneodesmosomes) of human cornified epithelia, is thought to be a key event of desquamation. Three monoclonal antibodies specific for human corneodesmosin were used to search for the expression of the protein in other mammals. Cryosections of pig, guinea pig, rat, and mouse cornified tissues and proteins sequentially extracted from the corresponding epithelia were analyzed by immunofluorescence and immunoblotting, respectively. Two of the antibodies (F28-27 and B17-21) showed, on the epidermis of the four species and on the cornified epithelia of the rat tongue and esophagus, the same labeling as on human epidermis. Cytoplasmic in the lower granular layer, then pericellular microgranular, the labeling progressively disappeared in the lower cornified layer. By contrast, it persisted up to the surface in the rat tail epidermis. The two antibodies immunodetected basic proteins extracted with isotonic buffer from the epidermis of the pig (50 kDa), guinea pig (52 kDa), and mouse (75 kDa) and from the cornified epithelia of the rat (75 kDa). Immunoreactive proteins of lower Mr were also extracted partly with urea and partly with a reducing agent. The third antibody (G36-19) presented the same reactivities except on murine tissues, where it was unreactive. Our results show that the location, the biochemical characteristics, and the processing of corneodesmosin are similar in five mammals, including humans, suggesting an important role for this protein. They open the way to studies of its function in desquamation using various animal models.
Vertical transmission of Trichinella spiralis was evaluated in ferrets (n=21), foxes (n=11), pigs (n=12), guinea pigs (n=16), and mice (n=41). The placental barrier to be crossed by migratory Trichinella larvae varies structurally in different animal species. Ferrets and foxes have an endotheliochorial placenta structure, guinea pigs and mice a haemochorial, and pigs an epitheliochorial placenta. The non-encapsulating Trichinella pseudospiralis larvae have an extended muscle migration prior to entering a muscle cell. To evaluate if T. pseudospiralis was more likely to be transmitted to offspring, an additional group of foxes (n=11) infected with T. pseudospiralis was included. Two different dose levels were used for ferrets, pigs, guinea pigs, and mice. In pigs and guinea pigs, infection was given at different times of the gestation period. Vertical transmission, measured as recovery of muscle larvae in the offspring, was demonstrated in both ferrets groups, in all four guinea pig groups, and in the high dose mouse group, but not in any fox or pig groups.
OBJECTIVE: Cardiac injury, related to ischaemia and reperfusion, may be caused by the action of oxygen free radicals. Xanthine oxidoreductase activity may be an important free radical source. During cardiac ischaemia, the native dehydrogenase form may be converted to the oxidase form, which uses molecular oxygen to form superoxide radicals. Superoxide dismutase converts the radicals to H2O2, which is detoxified by catalase and glutathione peroxidase. In view of the large differences in xanthine oxidoreductase in various species, the activity of these antioxidant enzymes was investigated. METHODS: Normal rodent and porcine as well as explanted human hearts were perfused according to Langendorff. After a 30 minute stabilisation period, hypoxanthine was added to the perfusion buffer to estimate xanthine oxidoreductase. Hearts or biopsies were freeze clamped after 90 minutes. Effluent xanthine and urate were assayed with high performance liquid chromatography; tissue reduced glutathione content and the activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were determined spectrophotometrically. Apparent xanthine oxidoreductase was calculated as xanthine +2 x urate production. RESULTS: Xanthine oxidoreductase was (mU.g-1 protein, mean(SEM), n = 5-7): rat, 470(40); guinea pig, 270(41); pig < 1.5; and human, 5.4(1.0). Superoxide dismutase activities were (U.g-1 protein): rat, 13,370(1030); guinea pig, 10,100(1110); pig, 12,800(450); and human, 7400(450). Catalase activity (k < or = 10.g-1 protein) was low in all species studied. Glutathione peroxidase activity was 93(7) U.g-1 protein in rat heart, and 10 x lower in the other species. Glutathione reductase activity was (U.g-1 protein): rat, 15.0(1.6); guinea pig, 10.4(1.3); pig, 16.0(1.5); and human, 26.6(2.0). Tissue reduced glutathione concentrations were (mumol.g-1 protein): rat, 13.5(0.8); guinea pig, 18.5(0.9); pig, 11.1(2.9); and human 17.2(1.7). CONCLUSIONS: Considerable species differences in xanthine oxidoreductase activity exist, contrasting with the smaller variations in antioxidant enzyme activities. In the species examined catalase activities were very low. Rat hearts are far better protected against H2O2 than the other three species. Xanthine oxidoreductase induced free-radical damage probably plays a minor role in pig and human hearts. Human myocardium seems less protected against superoxide radicals.
Galanin, a newly discovered peptide isolated from porcine intestine, is known to cause contraction in rat smooth muscle preparations and to induce hyperglycaemia in dogs. By the use of radioimmunoassay and immunohistochemical techniques the concentration and distribution of galanin immunoreactivity were determined in several areas of the respiratory tract of five dogs, five guinea pigs, five rats, and two pigs. Antibodies were raised in rabbits to whole unconjugated natural porcine galanin. The highest galanin concentrations were found in the bronchus and the trachea of the dog, guinea pig, rat (2 pmol/g in each case), and pig (less than 1 pmol/g). The lowest galanin concentrations were found in the lung parenchyma. Gel chromatographic analysis in the pig showed one molecular form of galanin coeluting with the porcine galanin standard. By means of the indirect immunofluorescence technique on sections of tissues fixed in benzoquinone solution, galanin was found to be confined to nerve fibres in different regions of the respiratory tract. In the nasal mucosa of the pig nerve fibres containing galanin were distributed around seromucous glands and blood vessels and beneath the epithelium. In the trachea, bronchus, and major intrapulmonary airways of the pig, dog, and guinea pig galanin immunoreactive fibres were detected predominantly in smooth muscle, as well as around seromucous glands and in the adventitia of blood vessels. Rarely, galanin immunoreactive nerve fibres were found in the lung parenchyma. A few galanin immunoreactive ganglion cells also containing vasoactive intestinal polypeptide were found in the adventitia of the tracheobronchial wall of the pig and dog. The distribution of galanin suggests that it may have some influence on airway, vascular, and secretory functions in the mammalian respiratory tract.
We isolated and purified xanthine oxidase by Sephadex gel filtration and assayed the activity of the enzyme by urate production which we measured by HPLC and UV absorption at 290 nm. We applied this method to extracts of liver and heart of rats, guinea pigs, rabbits, and pigs and to heart of dogs and humans. We found that pig hearts do not exhibit xanthine oxidase activity and that human and rabbit hearts produced small amounts of urate only after hours of incubation. We conclude that xanthine oxidase does probably not play an important part in the mechanisms leading to myocardial infarction using the free radical generating pathway, because it is absent in one species (pig) and barely detectable in two others (rabbit and man) that are known for their rapid and complete infarction following acute coronary occlusion.
Galanin was measured by radioimmunoassay in whole thickness extracts of the gastrointestinal wall from four species and in extracts from separate layers of human small intestine. The immunoreactivity was characterized using gel chromatography and high-pressure liquid chromatography. Two antibodies were employed, which were characterized as non-C-terminal (Gal 8) and C-terminal (Gal 9) using a C-terminal galanin 10-29 fragment. Substantial quantities of galanin immunoreactivity were found, mainly localized at the muscle layer. Both intramolecular and intermolecular heterogeneity was apparent. Two molecular forms exist in humans (Kav 0.58, 0.69). The molecular heterogeneity in humans, rats, and guinea pigs may be localized near the C-terminus of the galanin molecule. A C-terminal extension of one human galanin form is likely (Kav 0.58). These findings give radioimmunologic evidence for a neurocrine origin of galanin. The chromatographic variations suggest that extrapolation of experimental results between species should be treated with caution.
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The involvement of the M2 muscarinic receptor in contractile responses of the guinea pig trachea, guinea pig esophagus, and rat fundus was investigated. In the standard assay, oxotremorine-M elicited contractions of the trachea with an EC50 value of approximately 73 nanoM.--2- -(Diethylamino)methyl- -1-piperidinyl-acetyl--5,11- dihydro-6H-pyrido-2,3-b--1,4- benzodiazepine-6-one (AF-DX 116) at 1 and 10 microM antagonized these contractions by 2.1- and 9.0-fold increases in the EC50 value for oxotremorine-M. These effects are consistent with antagonism of an M3-mediated contractile response. In subsequent experiments, the M3 receptors were first inactivated selectively by incubation with N-(2-chloroethyl)-4- piperidinyl diphenylacetate (4-DAMP mustard) (40 nanoM) for 1 hr in the presence of AF-DX 116 (1 microM) followed by extensive washing. In 4-DAMP mustard treated trachea, oxotremorine-M elicited contractions with an EC50 value of 0.31 microM in the presence of histamine (10 microM) and forskolin (4 microM). Under these conditions, AF-DX 116 at 1 and 10 microM antagonized contractions to oxotremorine-M by 8- and 59-fold increases in the EC50, respectively, while para- fluorohexahydrosiladiphenidol(p-F-HHSiD) (0.1 microM) had no effect. These effects are consistent with a contraction being mediated by an M2 receptor. In the guinea pig esophagus and rat fundus, AF-DX 116 and p-F-HHSiD blocked contractions measured under similar conditions with magnitudes intermediate between what would be expected from an M2 and an M3 receptor, suggesting that perhaps both subtypes contribute to the overall contractile response under these conditions. In addition, contractions of the guinea pig trachea measured in the presence of histamine and forskolin were pertussis toxin sensitive. These results that, in the trachea, M2 receptors can dominate the contractile response after a majority of the M3 receptors have been inactivated, whereas in the guinea pig esophagus and rat fundus, M2 receptors may contribute to, but do not play a dominant role in the overall response.
Fifty-four bacterial and 10 yeast isolates were screened to identify strains that were consistently bound by peripheral blood lymphocytes (PBL) of guinea pigs. None of the yeast isolates examined was bound by guinea pig PBL. Of 54 bacterial isolates, 10 were bound by greater than 5% of PBL. Potential lymphocyte markers from these bacteria were chosen for further study. Sodium azide inhibited the binding of bacteria by PBL. Preparations of T lymphocytes indicated that Salmonella schottmuelleri was bound by most T lymphocytes; Yersinia enterocolitica was bound by a subpopulation of T lymphocytes. Patterns of binding of bacteria by lymphocytes from thymus, lymph node, or spleen differed from binding patterns obtained using PBL. Aflatoxin did not affect the total WBC, differential leukocyte count, absolute lymphocyte count, or relative percentage of PCV of guinea pigs given as much as 0.060 mg of aflatoxin B1 equivalents/kg of body weight/day for 3 weeks. Changes in absolute numbers of peripheral blood T lymphocytes were not observed in guinea pigs given aflatoxin when immunofluorescence or bacterial binding was used to identify lymphocyte populations, except that the number of S schottmuelleri-binding lymphocytes (tentatively identified as T lymphocytes) in guinea pigs given the highest dose of aflatoxin (0.060 mg of aflatoxin B1 equivalents/kg/day) was less than the number of T lymphocytes identified by immunofluorescence.
The changes occurring in the oral mucosa, gingivae and periodontium of guinea pigs fed a vitamin C-deficient diet were determined by means of histological comparison with animals on a normal diet. The following results were obtained from the scorbutic guinea pigs: --detachment of the horny layer from the underlying epithelium, --bullous cells in the spinose and the granular layer, --formation of periodontal pockets, --reduction in number and disorientation of collagenous fibres of the periodontium associated with loosening of the molars.
Paralytical form of chronic intoxication was caused by single intracutaneous administration of tri-O-cresyl phosphate (TOCP)/2=2.2 ml/kg/ into guinea pigs. Within the first 27--33 days after the treatment, the animals with pronounced symptoms of neurotoxic effect of TOCP were subcutaneously administered with 2-14C-acetate/100 mu Ci per 100 g of body weight/2 hrs before decapitation. Purified cerebrosides, gangliosides and acid-soluble fraction, containing 14C-precursors, were isolated and their specific radiactivity was measured in a gas-flow counter. The rate of 14C incorporation into cerebrosides and gangliosides in spinal cord was found to exceed that in brain stem. In paralytical stage of disease, caused by TOCP, synthesis of cerebroside was depressed in spinal cord and in brain stem, according to calculated value for relative specific radioactivity. In spinal cord the rate of 14C incorporation into gangliosides was also decreased. These data suggest that neurtoxic drug TOCP affects metabolic processes both in oligodendroglial cells and in neurons, where ganglioside biosynthesis occurs.
Guinea pigs under 8 days of age generally are unable to develop fever (viz., deltaTre greater than 0.5 degrees C) in response to a standardized dose of endotoxin (2 mug/kg iv of Salmonella enteritidis [SE]). This study was undertaken to determine whether this lack of responsiveness might be due to an incapacity of leukocytes from young neonates to produce sufficient leukocytic pyrogen (LP). Three series of experiments were performed at Ta = 27 degrees C: guinea pigs aged 0-2, 4, and 8 days were injected iv with: a) 2, 4, 8, or 16 mug/kg of SE, b) 0.1, 0.5, or 1.0 ml of LP generated by 8 mug of SE/25 X 10(6) leukocytes from adult guinea pigs (LPa), or c) 0.1 or 1.0 ml of LP generated by 8 mug of SE/25 X 10(6) leukocytes from 0-5-, 6-12-, and 13-16-day-old guinea pigs (LPn). Adult guinea pigs received iv 1.0 ml of LPa or LPn. The results revealed that fever could be induced in these animals from birth, but the required doses of SE, LPa and LPn were greater the younger the guinea pigs. Under these conditions, LPn, regardless of the donors' ages, produced fever in all the recipients. It is concluded that the pyrogenic unresponsiveness of newborn guinea pigs to endotoxin may be related not to an inability of leukocytes from these neonates to elaborate LP, but rather to an insensitivity of, presumably, their hypothalamic febrogenic mechanisms to low levels of LP.
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Guinea pigs and Sprague-Dawley rats were intracerebroventricularly (icv) infused with various doses of angiotensin II (AII) in order to investigate central control of and species differences in cochlear blood flow (CBF) and blood pressure (BP). The results indicated a positive dose-response relationship between icv infusions of AII for BP and CBF in members of both species. This relationship was more predictable in the guinea pig than in the rat. In addition, responses to similar AII doses between species indicated that: a) BP elevations were significantly greater in the rat than in the guinea pig, b) CBF elevations were not significantly different between the rats and guinea pigs, and c) CBF was more highly correlated with BP in the guinea pig than in the rat. These results suggest that different relationships may exist between BP and CBF in rats and guinea pigs.
Guinea pig prostate was found to actively participate in the biosynthesis and catabolism of ascorbic acid. The key ascorbic acid biosynthetic enzyme L-gulono-gamma-lactone oxidase and the other two lactonases were found to be present in guinea pig prostate. The activities of dehydroascorbatase and diketogulonate decarboxylase, the enzymes for ascorbic acid degradation, were also detected in guinea pig prostate. Male guinea pigs kept under scorbutic condition for 7, 14, 21 and 28 days, were examined for prostatic metabolism of ascorbic acid. A significant but gradual decrease in the concentration of L-ascorbic acid was observed in prostate, total blood and leukocytes with the progression of scorbutic condition. There was an appreciable decrease in the rate of lipid peroxidation under the scorbutic condition. In the tissue fraction of scorbutic guinea pigs, the activities of biosynthesizing enzymes, measured in vitro, under optimum conditions were found to be higher with no significant alterations in the catabolizing enzymes. The implications of these findings are discussed in this paper.