Bronchoconstriction in nonhuman primates: a species comparison

Bronchoconstriction is a characteristic symptom of various chronic obstructive respiratory diseases such as chronic obstructive pulmonary disease and asthma. Precision-cut lung slices (PCLS) are a suitable ex vivo model to study physiological mechanisms of bronchoconstriction in different species. In the present study, we established an ex vivo model of bronchoconstriction in nonhuman primates (NHPs). PCLS prepared from common marmosets, cynomolgus macaques, rhesus macaques, and anubis baboons were stimulated with increasing concentrations of representative bronchoconstrictors: methacholine, histamine, serotonin, leukotriene D? (LTD?), U46619, and endothelin-1. Alterations in the airway caliber were measured and compared with previously published data from rodents, guinea pigs, and humans. Methacholine induced maximal airway constriction, varying between 74 and 88% in all NHP species, whereas serotonin was ineffective. Histamine induced maximal bronchoconstriction of 77 to 90% in rhesus macaques, cynomolgus macaques, and baboons and a lesser constriction of 53% in marmosets. LTD? was ineffective in marmosets and rhesus macaques but induced a maximum constriction of 44 to 49% in cynomolgus macaques and baboons. U46619 and endothelin-1 caused airway constriction in all NHP species, with maximum constrictions of 65 to 91% and 70 to 81%, respectively. In conclusion, PCLS from NHPs represent a valuable ex vivo model for studying bronchoconstriction. All NHPs respond to mediators relevant to human airway disorders such as methacholine, histamine, U46619, and endothelin-1 and are insensitive to the rodent mast cell product serotonin. Only PCLS from cynomolgus macaques and baboons, however, responded also to leukotrienes, suggesting that among all compared species, these two NHPs resemble the human airway mechanisms best.     

Social interaction in nonhuman primates: an underlying theme for primate research.

Social living is assumed to be a critical feature of nonhuman primate existence inasmuch as most primate species live in social groups in nature. Recent USDA legislation emphasizes the importance of social contact in promoting psychological well-being and recommends that laboratory primates be housed with companions when consistent with research protocols. Our goals were to examine the link between social housing and psychological well-being and to explore the idea that research may be compromised when primates are studied in environments that vary too greatly from their natural ecological setting (individual cage housing versus group housing). Three general points emerge from these examinations. First, providing companionship may be a very potent way in which to promote psychological well-being in nonhuman primates; however, social living is not synonymous with well-being. The extent to which social housing promotes psychological well-being can vary across species and among individual members of the same species (for example, high- and low-ranking monkeys). Secondly, housing conditions can affect research outcomes in that group-housed animals may differ from individually housed animals in response to some manipulation. Social interaction may be a significant variable in regulating the biobehavioral responses of nonhuman primates to experimental manipulations. Finally, a larger number of socially housed subjects than individually housed subjects may be necessary for some biomedical research projects to yield adequate data analysis. Thus, social living has significant benefits and some potential costs not only for the animals themselves, but for the research enterprise.     

Effect of fish oil diet on hepatic lipid metabolism in nonhuman primates: lowering of secretion of hepatic triglyceride but not apoB

African green monkeys were fed diets containing either 11% (by weight) fish oil or lard for 2.5 yr. To test the hypothesis that fish oil decreases hepatic secretion of triglyceride (TG) and apoB, livers from these animals were perfused with a fatty acid mixture [85% (w/w) oleate containing [14C]oleate and 15% n-3 containing [3H]eicosapentaenoic acid (EPA)] at a rate of 0.1 mumol fatty acid/min per g liver. Liver perfusate was sampled every 30 min during 4 h of recirculating perfusion. The concentration of triglyceride was similar for livers of animals of both groups and there was no difference between groups in the extent of incorporation of [3H]EPA or [14C]oleate into hepatic TG. While the secretion rate for the mass of TG was less in the fish oil-fed group (8.3 +/- 2.5 vs 18.3 +/- 4.4 mg/h per 100 g liver, P less than 0.05), the apoB secretion rate was similar (0.92 +/- 0.15 vs 1.01 +/- 0.13 mg/h per 100 g liver). Significantly less [3H]EPA was incorporated into secreted TG in the fish oil group (0.4 +/- 0.1 vs 1.0 +/- 0.1% infused dose/h; P less than 0.01). The rate of secretion of [14C]TG was similar for both groups (1.3 +/- 0.3 vs 1.4 +/- 0.1% infused dose/h for fish oil and lard groups, respectively). No significant diet-related differences in [3H]TG or [14C]TG fatty acid specific activity were observed for perfusate TG or hepatic TG. After perfusion, livers from fish oil-fed monkeys contained significantly more [3H]EPA in hepatic phospholipid than livers from lard-fed monkeys (19.5 +/- 1.8 vs 11.4 +/- 1.7% infused dose; P less than 0.01) although hepatic phospholipid mass concentrations were similar. The liver phospholipids of the fish oil group were enriched in n-3 fatty acid mass and were relatively depleted of oleate and linoleate. We conclude that although apoB secretion was unaffected, dietary fish oil significantly decreased hepatic TG secretion through relatively poor utilization of EPA for the synthesis of TG destined for secretion in VLDL; at the same time, increased incorporation of [3H]EPA into hepatic phospholipid accompanied the decreased incorporation into secreted TG and these events may be coupled.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ontogenetic plasticity in nonhuman primates: I. Secular trends in the Cayo Santiago macaques

Although secular trends toward increasing body size are apparent in many human populations, little is known about their occurrence in nonhuman primates. The Cayo Santiago skeletal collection of Macaca mulatta includes 101 adult animals (greater than or equal to 10 years of age) born at different times in the past 3 1/2 decades, so that variation in size may be examined relative to birth year. No secular trends in orbital height were observed in this sample, but in both sexes lengths of adult long bones increased significantly over time, while cranial dimensions and length of the second molar in female also showed significant variation with birth year. These changes were consistent with the history of provisioning of the animals and with fluctuations in population size. Low-order correlations were observed between birth year and body proportions, especially the crural index in males, a pattern that has also been observed in human populations. These findings argue that, in addition to biomechanics and heritage, diet may affect allometric relationships and that an inherent plasticity or malleability of the growth process may be characteristic of nonhuman as well as human primates.     

Use of genetic markers in the colony management of nonhuman primates: a review

Genetic markers in blood were used to identify paternity and reconstruct genealogical relationships in six captive breeding groups of rhesus monkeys (Macaca mulatta) using paternity exclusion analysis. The theoretical and observed incidence of inbreeding and its deleterious effects were discussed and colony management alternatives proposed for minimizing these effects. Genetic markers for disorders and both desirable and undesirable phenotypic characteristics have been sought so as to maximize the reproductive success and vitality of the colony by selective breeding. A sound genetic component such as that described here is a necessary adjunct to any successful long-term program for breeding nonhuman primates.     

Evaluation of bendectin embryotoxicity in nonhuman primates: II. Double-blind study in term cynomolgus monkeys

The embryotoxic and teratogenic potential of Bendectin was assessed in this double-blind study in the cynomolgus monkey (Macaca fascicularis). Bendectin was administered orally at doses approximately two, five, and 20 times the human dose equivalent from 22 +/- 2 through 50 days of gestation. Fetuses were delivered by cesarean section near term and examined for malformations. There was no maternal toxicity as evidenced by maternal weights and physical signs. There was no correlation between dosage and the number of prenatal deaths. No significant abnormalities related to treatment were observed in postdelivery physical examinations, placental evaluations, external and internal gross examinations, or from radiographs of the neonates. Under the conditions of this study the treatment of pregnant cynomolgus monkeys with Bendectin produced no evidence of teratogenicity or embryo-, or fetal-, or maternal toxicity.     

Tumors in nonhuman primates: observations during a six-year period in the Yerkes primate center colony

Tumors were observed in nine of 1,066 nonhuman primates submitted for postmortem examination during a six-year period at the Yerkes Primate Center. Six of these animals had malignant tumors, and one animal had two primary malignancies. Nonhuman primates with tumors included rhesus, squirrel, and pigtail monkeys. Tumors observed included a sarcoma of the stomach, a sarcoma of the thigh, a malignant lymphoma, a glioblastoma of the cerebrum, two renal cell carcinomas, a carcinoma of the endometrium, and three uterine leiomyomas. Two monkeys in the colony presently have malignant tumors, one a testicular seminoma, and the other an abdominal adenocarcinoma, probably of ovarian origin. Electron microscopy revealed virus-like particles in specimens from the thigh sarcoma. The only tumors observed in any of the great ape species during this period have been two surgically removed benign tumors in chimpanzees, a subcutaneous lipoma and a hemangioma of the skin.     

Embryotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate

Two sex steroid compounds which have been used clinically for parenteral supportive therapy of pregnancy were examined for embryotoxic effects in rhesus and cynomolgus macaques. Hydroxyprogesterone caproate (HPC) alone or in combination with estradiol valerate (EV) were administered intramuscularly (i.m.) to pregnant monkeys at 7-day intervals between 20 and 146 days of gestation and fetuses were examined following cesarean section at 150 +/- 2 days. HPC alone was tested in both species at doses ranging from 0.01 X to 10 X the human dose equivalent (HDE); only rhesus monkeys were exposed to the HPC + EV combination at 0.1 X to 10 X HDE. Total embryolethality resulted following the administration of HPC alone and combined with EV at 1 X and 10 X HDE in rhesus monkeys; the level of abortions in cynomolgus monkeys exposed to HPC (0.1 X to 1 X HDE) was comparable to controls. A small number of nonspecific malformations and developmental variations observed in cynomolgus fetuses after HPC exposure were considered to be incidental findings. No anomalies were found in surviving rhesus monkey fetuses treated with HPC + EV. The results indicate that long-term in utero exposure to the progestin, HPC, alone or in combination with EV in rhesus and cynomolgus monkeys, is embryolethal but not teratogenic at doses up to ten times the human therapeutic dose.     

The radial bias: a different slant on visual orientation sensitivity in human and nonhuman primates

It is generally assumed that sensitivity to different stimulus orientations is mapped in a globally equivalent fashion across primate visual cortex, at a spatial scale larger than that of orientation columns. However, some evidence predicts instead that radial orientations should produce higher activity than other orientations, throughout visual cortex. Here, this radial orientation bias was robustly confirmed using (1) human psychophysics, plus fMRI in (2) humans and (3) behaving monkeys. In visual cortex, fMRI activity was at least 20% higher in the retinotopic representations of polar angle which corresponded to the radial stimulus orientations (relative to tangential). In a global demonstration of this, we activated complementary retinotopic quadrants of visual cortex by simply changing stimulus orientation, without changing stimulus location in the visual field. This evidence reveals a neural link between orientation sensitivity and the cortical retinotopy, which have previously been considered independent.     

A tail of two monkeys: social housing for nonhuman primates in the research laboratory setting

Despite great adaptability, most nonhuman primates require regular tactile contact with conspecifics for their psychological well being. By illustrating the inherent value of social contact and by providing clues to the best ways of satisfying this need, behavioral studies are useful in designing social enrichment programs. Although group housing is ideal for most gregarious primates, space constraints and protocol requirements may preclude such environments for macaques housed indoors. Pair housing is an effective and practical alternative. Furthermore, such social experience facilitates integration into future social groups, including those in postresearch retirement facilities. This article references common research protocols that accommodate pair housing and includes scientific recommendations for institutional animal care and use committees (IACUCs) to facilitate providing physical social contact for nonhuman primates in laboratories.     

Plasma and hepatic apoE isoproteins of nonhuman primates. Differences in apoE among humans, apes, and New and Old World monkeys

We have used two-dimensional polyacrylamide gel electrophoresis (PAGE) to study the plasma and hepatic apoE isoproteins of nonhuman primates and have compared them with their human counterparts. We have found that apoE obtained from fresh monkey or ape plasma, as well as nascent apoE synthesized by perfused monkey livers, is composed of several isoproteins that resemble the homozygous (beta) apoE phenotype observed in humans. The nonhuman primate plasma apoE pattern of 90 animals from nine different species consisted of a major isoprotein designated apoE3 and a few minor isoproteins. A group of acidic apoE isoproteins is eliminated after treatment with C. perfringens neuraminidase and has been designated sialo apoE (apoEs). Nonhuman primate liver apoE isoproteins comigrate with their plasma apoE isoprotein counterparts on two-dimensional PAGE, but hepatic apoE is enriched in sialo apoE isoproteins when compared to plasma apoE. The apparent molecular weight of asialo and sialo apoE obtained from Old World monkeys and apes is identical to the molecular weight of the corresponding human isoproteins (E3 = 38K, Es = 38.5-39.5K). However, the apparent molecular weight of apoE isoproteins obtained from New World monkeys is increased by approximately 0.5K (E3 = 38.5K, Es = 39.0-40.0K) as compared to the molecular weight of human and Old World monkey and ape isoproteins. The isoelectric points of apoE3 obtained from Old World monkeys, New World monkeys, chimpanzees, and gibbons are 5.74, 5.76, 5.95, and 5.89, respectively. The entire New or Old World monkey, chimpanzee, and gibbon apoE pattern is shifted by approximately -2.0, -0.5, and -1.0 charges, respectively, relative to the pattern of the corresponding human E3/3 phenotype. The molecular weight difference in apoE observed among New and Old World monkeys, as well as the molecular weight and/or charge differences observed among monkey, ape, and human apoE are consistent with structural changes in the apoE gene which have occurred following the divergence of the different species. The observation of only the homozygous apoE phenotypes in all animals studied suggests that the common apoE genetic polymorphism recently described in humans may not be present in nonhuman primates.     

Evaluation of bendectin embryotoxicity in nonhuman primates: I. Ventricular septal defects in prenatal macaques and baboon

Cynomolgus monkeys, rhesus monkeys and baboons were administered 10 to 40 times the human dose equivalent of Bendectin throughout the major period of organogenesis (22(+/-3)-50 days of gestation). In animals examined prenatally (100 +/- 2 days gestation) the total incidence of ventricular septal defects (VSD) was 40% in cynomolgus monkeys, 18% in rhesus monkeys, and 23% in baboons. The majority of VSD involved the muscular portion of the septum. No dose response was evident and there were no other cardiac or extracardiac defects found except for one baboon fetus with multiple defects. No defects were observed in cynomolgus monkeys administered Bendectin for 4-day periods between 22 and 41 days of gestation. There was no association of Bendectin treatment with any noncardiac defect. In cynomolgus and rhesus monkeys examined at term there was one mitral valve defect and no incidence of VSD. The increased incidence of VSD observed prenatally in all three species and the absence of defects in macaques at term suggests a delay in closure of the ventricular septum in treated animals. The Bendectin-treated monkey may be a suitable model for the study of the pathogenesis of VSD and the mechanism of spontaneous closure of the defect.     

Evaluation of [11C]metergoline as a PET radiotracer for 5HTR in nonhuman primates

Metergoline, a serotonin receptor antagonist, was labeled with carbon-11 in order to evaluate its pharmacokinetics and distribution in non-human primates using positron emission tomography. [¹¹C]Metergoline had moderate brain uptake and exhibited heterogeneous specific binding, which was blocked by pretreatment with metergoline and altanserin throughout the cortex. Non-specific binding and insensitivity to changes in synaptic serotonin limit its potential as a PET radiotracer. However, the characterization of [¹¹C]metergoline pharmacokinetics and binding in the brain and peripheral organs using PET improves our understanding of metergoline drug pharmacology.     

Breakage of yeast: a method for processing multiple samples.

A procedure is described for the rapid preparation of mitochondria and the soluble cell fraction of yeast. The method makes use of an adaptor for the Braun homogenizer which allows 16 samples to be processed at once.