Antihypertensive effects of vanadium compounds in hyperinsulinemic,hypertensive rats

Although considerable evidence lends credence to the association between insulin resistance, hyperinsulinemia and essential hypertension, the precise nature of this relationship remains unexplained. In the present investigation, we examined the proposition that these metabolic defects contribute causally to the development of high blood pressure. If these metabolic abnormalities were responsible for the development of hypertension, then drug interventions that improve these defects should also decrease high blood pressure. Since previous studies have demonstrated that vanadium compounds enhance insulin action and lower plasma insulin levels in nondiabetic rats, we examined the effects of these compounds on insulin sensitivity, plasma insulin concentration and blood pressure in two hyperinsulinemic models of experimental hypertension. The animal models studied were the genetically predisposed spontaneously hypertensive rat and the fructose-hypertensive rat, where hypertension is induced in normotensive rats by feeding them a high fructose diet. Vanadium compounds caused marked and sustained decreases in plasma insulin concentration and blood pressure in both the animal models studied. Furthermore, the effect of the drugs on blood pressure was reversed by restoring plasma insulin levels in the drug-treated rats to those observed in their untreated counterparts. These data suggest that either hyperinsulinemia contributes to the development of hypertension in both the spontaneously hypertensive and the fructose-hypertensive rats or that the underlying mechanism is closely related to the expression of both these disorders.     

Inbreeding in three captive groups of rhesus monkeys

Using electrophoretic and serological genetic markers each of 17 potentially inbred matings in three groups of rhesus monkeys could be classified as either inbred or noninbred matings. Although nine of these 17 matings involved either father-daughter or paternal half-sib matings, only 7.4 were expected by chance alone. At least two, and possibly as many as three, of the nine cases of inbreeding involved father-daughter matings. Thus, no evidence of avoidance of inbreeding was observed in the closed captive groups of rhesus monkeys studied. Colony management policies must be developed to minimize the opportunity for or the deleterious effects of both father-daughter and half-sib matings. Furthermore, kin selection theory should consider why kin recognition, if it occurs, does not lead to avoidance of inbreeding.     

Delayed dispersal and elevated monoaminergic activity in free-ranging rhesus monkeys

Male rhesus monkeys typically disperse from their groups of birth when they are between 3 and 5 years of age. Some males, however, delay dispersal from their natal groups until after they are 5 years old. The current study evaluated central monoaminergic neurotransmitter activity as a potential correlate of such “delayed” dispersal among 54 randomly selected adolescent and adult male rhesus monkeys (Macaca mulatta) captured on Cayo Santiago during an annual trapping season. Specifically, cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite), 3-methoxy-4-hydroxyphenylglycol (MHPG, a norepinephrine metabolite), and homovanillic acid (HVA, a dopamine metabolite) were compared in monkeys 60 months of age or more that had either dispersed (n = 33) or were still in their natal groups (n = 5). The monkeys still in their natal groups had higher CSF concentrations of both 5-HIAA and HVA (but not MHPG) than did the animals that had emigrated (Ps < 0.05). Subsequent analysis indicated that only 5-HIAA independently differentiated dispersing monkeys from delayed dispensers. Of monkeys less than 60 months of age (n = 16), only two had dispersed from their natal groups; in this age class, there were no significant differences between dispersing and natal individuals in any CSF monoaminergic metabolite (all Ps = NS). Finally, there was no difference in the CSF 5-HIAA concentrations of the five delayed dispersers and those of younger animals (P = NS), suggesting a failure to experience the frequently reported adolescent decline in serotonergic activity. In contrast, the CSF 5-HIAA concentrations of the dispersing animals were lower than those of the younger animals (P < 0.05), consistent with either an agerelated decline or an effect of dispersal per se. © 1995 Wiley-Liss, Inc.     

Sterilization and its behavioral effects on free-ranging female rhesus monkeys (Macaca mulatta).

In order to control population growth rates, a decision was made to sterilize most of the free-ranging, wild rhesus macaque females of Silver Springs, Florida. Between October 1987 and March 1988, the five females who had been sterilized and released in the fall of 1986 were matched with five intact females in a behavioral study. While there were differences between the behaviors of the sterilized and intact females, the differences can be attributed more to differences in age, rank, and other factors than to the sterilization. Clinical data collected and reported on the monkeys is unremarkable.     

Menopause in female rhesus monkeys

Fifteen female rhesus monkeys (Macaca mulatto), ranging in age from 8 to 34 years, were studied for one year to characterize the endocrine and menstrual changes associated with menopause in this species. Five monkeys were premenopausal; these younger monkeys, ages 8–11 years, menstruated and showed cyclic ovarian activity during the 12–month study period, as evidenced by menses and periodic elevations of serum estradiol (E₂) and luteinizing hormone (LH) concentrations. Four females, ages 24–26 years, were in transition to menopause. Two of these perimenopausal females menstruated and secreted E₂ and LH in a periodic fashion; the other two females showed elevated LH concentrations, consistently low E₂ levels, and no evidence of menstruation. Six females, ages 27–34 years, were clearly postmenopausal; LH concentrations were high, whereas E₂ concentrations were uniformly low. There was a significant inverse correlation between basal E₂ concentrations and age, and a significant positive correlation between age and LH concentrations across all 15 animals. Hormonal changes indicative of ovulation, when they occurred, were generally restricted to the winter and early spring months. Histological analysis of ovaries from four postmenopausal females revealed little or no evidence of active folliculogenesis. These data indicate that menopause in female rhesus monkeys does not occur until the second half of thethird decade of life. © 1995 Wiley-Liss, Inc.     

Carbon monoxide excretion as an index of bilirubin production in rhesus monkeys

The role of increased heme catabolism in neonatal hyperbilirubinemia was investigated in rhesus (Macaca mulatta) neonates through the measurement of carbon monoxide excretion rates (VECO), blood carboxyhemoglobin content (HbCO), and plasma bilirubin concentrations. Neonatal values were compared to those of adult rhesus monkeys. These indices of bilirubin production responded appropriately to administration of NEM-damaged erythrocytes and tin protoporphyrin. Our results indicate that VECO measurements are a valid index of changes in bilirubin production in the newborn rhesus monkey.     

Effect of testosterone on epididymal proteins in castrated rhesus monkeys

The effect of testosterone on regulation of epididymal protein synthesis has been investigated in castrated rhesus monkeys (Macaca mulatta). The proteins in the treated monkeys were characterized using polyacrylamide gel electrophoresis (under nondenaturing and denaturing conditions) and electrofocusing. At least four distinct proteins have been shown to be synthesized by the monkey epididymis under testosterone influence. Two of these proteins were detected following two days of testosterone treatment while the other two proteins were detected after a six-day treatment period. None of these proteins was detectable in monkeys treated with estradiol for six days. Electrofocusing of epididymal cytosol proteins from untreated and testosterone-treated and castrated monkeys also confirmed the presence of four androgen-dependent proteins in this species. The isoelectric points of these proteins were shown to range between 5.8 and 6.4. The molecular weights of these proteins were found to vary between 47,500 and 66,000. The in vitro incorporation of ³H-labeled amino acids was markedly greater in the androgen-primed epididymis as compared with the control tissue.     

恒河猕猴吗啡成瘾模型的初步建立

吗啡成瘾的非人灵长类动物恒河猕猴(Macaca mulatta)模型的实验结果表明,猕猴可建立吗啡条件化位置偏好(conditioned place preference,CPP),且其与吗啡线索相关的记忆可持续(36.3±1.3)月。该研究可以为药物成瘾研究提供有效的非人灵长类动物行为模型。     

Growth of rhesus monkeys during the first 54 months of life

As part of a study of the long-term effects of environmental conditions on the health and development of non-human primates, the growth of 60 rhesus monkeys (Macaca mulatta, 34 males and 26 females) was determined longitudinally with biweekly or triweekly measurements of eight body dimensions from one to 54 months of age. Our data showed similar growth to previous studies and provide additional data defining normal rhesus monkey growth under more precisely defined living conditions than were reported in previously published studies on this species.     

Glucose disappearance rate in rhesus monkeys: Some technical considerations

The intravenous glucose tolerance test (IVGTT) has been widely used as a tool to assist in the diagnosis of diabetes mellitus. Glucose disappearance rate (K_G) is calculated as an indicator of relative glucose tolerance; however, a standardized dose, consistent sampling times, and a consistent formula for the calculation of K_G have not yet been established for rhesus monkeys. Interpretation of results reported by different laboratories has, therefore, been rendered difficult. In the present study, 48 IVGTTs obtained from 33 male rhesus monkeys ranging widely in glucose tolerance have been analyzed. Various formulas for calculating K_G values have been tested in all experiments including a range of different pairs of time points, as well as the t_1/2. Regression analysis revealed that the log_e transformation of the plasma glucose levels obtained after an intravenous glucose load were best fitted with a straight line during the period between five and 20 minutes (R² = 0.97 ± 0.005). The use of time points prior to the five-minute value tended to produce spuriously larger K_G values, while sampling points that were later than 30 min occasionally produced an invalid K_G because in some monkeys the plasma glucose levels had already returned to basal levels. The advantages of using the five- and 20-minute glucose levels in calculating the K_G include (1) the optimal reflection of tissue uptake of glucose; (2) the relatively short sampling time required to obtain an accurate, consistent, and meaningful value for K_G; and (3) the relative ease in the calculation of K_G.     

Infant-directed behavior in young rhesus monkeys: Sex differences and effects of prenatal androgens

Young (3–4 years old) laboratory-reared rhesus monkeys were observed in five 15-minute tests with 1–15-day-old infants. Males and females were equally likely to investigate infants. Females communicated more with infants by grin-lipsmacking and gurgling–-gestures that were not shown by any males. More females presented the ventrum to infants than did males. Females contacted infants more than did males by grooming, crouching over, and having full body contact with them. To see whether prenatal androgens produced the male pattern of response, we conducted similar tests with pseudohermaphrodites (prenatally androgenized genetic females) and neonatally castrated males. On most sexually dimorphic behaviors, pseudohermaphrodites behaved more like females than like males. Castrated males, like females and pseudohermaphrodites, crouched over infants more than did intact males. Castrated males differed from females only on one infant-directed response, the grin-lipsmack. These comparisons showed that defeminization of the repertoire of infant-directed responses was measurable only in intact males. We conclude accordingly that prenatal androgens alone are not responsible for defeminization of this repertoire and that a contribution from postnatal androgens is likely to be necessary.     

Atresia of the dominant ovarian follicle in rhesus monkeys is detected within 24 hours of estradiol treatment

Following treatment with estradiol-17β (E₂) on day 6 of the menstrual cycle, degenerative alterations in the microenvironment of the dominant follicle (DF) (follicular fluid [FF], granulosa cells [GC], and oocyte) are readily apparent on day 10, or 96 h after E₂ administration. The present study was designed to determine how early such changes could be detected and which indices of atresia were observed first. The DF was identified during laparoscopy on day 5 or 6 of the cycle, and four capsules containing crystalline E₂ were inserted s.c. for 24 h. Contents of the DF were aspirated at 24, 48, and 72 h following initiation of E₂ treatment. General size and appearance of the DF did not change distinctly with E₂ treatment; however, by 48 h FF viscosity was increased markedly. GC viability was not altered with treatment. FF concentrations of estrogen (E) were dramatically reduced at 24 h. These differences were maintained at 48 h and at 72 h. E accumulation by cultured GC was significantly reduced by > eightfold. There appeared a similar trend for reduced progesterone (P) in FF and decreased P production by GC in vitro. These results demonstrate that degenerative alterations in the DF indicative of atresia can be detected as early as 24 h after initiation of E₂ treatment; the index of atresia appearing earliest is a reduction in FF concentrations of E, and the first morphological changes in the DF can be observed 24 h later. This study indicates that biochemical alterations precede morphologic changes with E₂-induced atresia, and should allow us to begin to determine the earliest events and putative initiation sites of atresia.     

Atretogenic action of estrogen in rhesus monkeys: Effects of repeated treatment

The effects of 17β-estradiol (E₂), administered in Silastic capsules for 24 hours at intervals of 10 or 14 days, on follicular development and menstrual cycle characteristics were studied in 13 rhesus monkeys. In seven monkeys receiving E₂ at l0-day intervals for 50 treatment periods, new follicles frequently developed between treatments but usually regressed. In seven instances, the follicles persisted longer than expected but were steroidogenically suppressed and regressed spontaneously. Ovulation occurred in only two instances. In six monkeys receiving E₂ at 14-day intervals, new follicles developed regularly, with seven ovulations occurring in 37 treatment periods. A persistent anovulatory follicle was noted in only one instance. Menstruation occurred with equal frequency, and the interval from treatment to onset of menstruation was not significantly different regardless of treatment or the occurrence of ovulation; the intervals between menstruation approximated those of normal menstrual cycles. In general, following termination of treatment, menstrual cycles returned to normal quickly. These data indicate that E₂ administered intermittently at 10-day intervals effectively suppresses ovulation, and they provide new insight into the actions of E₂ on folliculogenesis in primates.     

Temporal and endocrine sequelae of aspirating follicular contents in rhesus monkeys

Aspiration of ovarian follicular contents in humans is a well-established procedure used to obtain oocytes for fertilization in vitro (IVF). However, the effects of aspiration on the menstrual cycle and resulting luteal function have been incompletely characterized. The present study was designed to investigate alterations in the temporal and endocrine characteristics of menstrual cycles following aspiration of contents of the dominant preovulatory follicle (DF) on day 10 of the cycle in normal rhesus monkeys. When aspiration was performed prior to the preovulatory surge of luteinizing hormone (LH), cycle length was extended to 38.6 ± 8.6 [15] (x days ± SD, [n]), as compared to 29.5 ± 5.7 [8] days when the surge occurred before the time of aspiration. Mean and maximal amounts of progesterone (P) in the luteal phase and the number of days in which P-values were > 1 ng/ml were significantly greater when aspiration was performed prior to the surge of LH than for aspiration after this event. Laparoscopic observations made in the midluteal phase in animals of the former group demonstrated that the corpus luteum (CL was derived from a follicle other than the original DF which had been aspirated on day 10 of the menstrual cycle; observations in the latter group of animals indicated that the CL was derived from the DF.     

Colon cancer in aged captive rhesus monkeys (Macaca mulatta)

The age-related incidence of malignant neoplasia was surveyed from a total of 301 necropsy cases of rhesus monkeys ranging in age from 13–37 years performed in the Pathology Service Unit of the Wisconsin Regional Primate Research Center during the past 15 years. All our aged monkeys lived in indoor cages and were fed with monkey chow and supplemental fruits during the past decades. In this survey, we found a total of 51 malignant neoplasms, and among them 25 cases were colon cancer. The incidence of colon cancer increased with advancing age: 3.2% at 13–19 years, 9.2% at 20–25 years, 13.5% at 26–29 years, and 20.7% at 30–37 years. Most cancers were located in the cecum and transverse regions with a unicentric origin. Two multicentric cases were associated with chronic hypertrophic colitis. Precancerous polypous lesions were not found in all cases. Histologically, all cases were mucinous adenocarcinoma and had local invasion to the muscular wall. Metastasis to the mesenteric lymph nodes was found in only two cases. As in humans, colon cancer is a common outcome of aging in nonhuman primates. Am. J. Primatol. 44:19–27, 1998. © 1998 Wiley-Liss, Inc.     

Quantitative evaluation of Enterocytozoon bieneusi infection in simian immunodeficiency virus-infected rhesus monkeys

The association of the microsporidia Enterocytozoon bieneusi with chronic diarrhea and wasting in individuals with acquired immunodeficiency syndrome (AIDS) has been demonstrated. The disease caused by E. bieneusi has been linked to decreased levels of circulating CD4+ T lymphocytes. In this study, we investigated the relationship between the extent of excretion of E. bieneusi in feces of simian immunodeficiency virus (SIV)-infected juvenile macaques and the CD4+ T lymphocyte counts in the peripheral blood. Twelve juvenile rhesus monkeys (Macaca mulatta) were intravenously inoculated with the pathogenic molecular clone SIVmac239. Numbers of CD4+ T lymphocytes were assessed by three-color flow cytometry. The presence of E. bieneusi DNA in feces was assessed by nested PCR. In addition, selected samples of feces were examined by competitive quantitative PCR to assess the level of E. bieneusi infection. Low (n = 5) to undetectable (n = 7) quantities of E. bieneusi were present in feces of the twelve animals in prior to inoculation with SIV. After SIV inoculation the number of animals shedding E. bieneusi increased (n = 10) as did the quantity of E. bieneusi shedding in the feces. Of the twelve juvenile animals, five animals died within 8 months post-SIV inoculation with symptoms of AIDS. Four of the five deceased animals showed shedding of E. bieneusi DNA in feces (> or =100 spores/g) for at least three consecutive months. Increased number of E. bieneusi in feces was accompanied by decreased counts of circulating CD4+ T lymphocytes and increased SIV plasma viral load.     

Growth of the masseter muscle in rhesus monkeys (Macaca mulatta)

The growth of the masseter muscle in eight infant, juvenile, and adolescent female rhesus monkeys (M. mulatta) was examined over a 2.5 year period using serial radiographic cephalometric techniques with the aid of radiopaque muscle markers. The radiopaque markers, which are composed of small pieces of root canal broach inserted into the muscle belly, make it possible to determine longitudinal masseter muscle growth as well as migration of the masseter muscle relative to the mandible. It was found that the masseter muscle increased in length by 64% during the total growth period, most of which occurred between 6 and 18 months of age. Relative to the cranium, the masseter muscle grew markedly inferiorly and only slightly posteriorly. Relative to the mandible, the masseter migrated in a posterior and slightly superior direction, keeping pace with the ramus and condyle as they grew posteriorly and posterosuperiorly throughout the study period. It was concluded that: 1) radiopaque muscle markers are a valuable tool for analysis of muscle growth and alteration of muscle location; 2) the masseter muscle in the rhesus monkey undergoes elongation, probably due to addition of sarcomeres at the fiber-tendon junctions; and 3) posterior migration of the masseter muscle relative to the corpus of the mandible, probably due to the nature of its periosteal attachment, results in a stability of the anteroposterior position of the masseter muscle despite the anterior displacement of the mandible.     

Segregation distortion and differential fitness at the albumin locus in rhesus monkeys (Macaca mulatta)

The observed patterns of segregation of two co-dominant alleles at the macaque albumin locus in 400 rhesus monkey offspring were compared with those expected for five segregating mating phenotypes. Rates of reproductive loss and conception were also compared among females of each albumin phenotype. The common albumin allele in macaques, Al^A_mac, segregated more frequently than expected when the mother was heterozygous but less frequently than expected when she was homozygous for Al^B_mac. In both cases, the phenotype identical to that of the mother appeared to be favored. Mothers who were either homozygous for Al^A_mac or heterozygous were also found to experience higher conception rates than mothers homozygous for Al^B_mac. It is hypothesized that phenotypic differences in bilirubin binding, and in competitive binding by dietary constituents, by albumin influences both these results and the nonrandom distribution of Al^B_mac in Asian macaques.