Infection of owl monkeys (Aotus trivirgatus) and cynomolgus monkeys (Macaca fascicularis) with hepatitis E virus from Mexico.

Owl and cynomolgus monkeys were inoculated with hepatitis E virus (HEV) to compare disease models and produce antibody and virus. By immune electron microscopy (IEM), all six owl monkeys were shown to have serologic responses manifested by unusually high levels of anti-HEV at 6 months, but only three developed hepatitis. Virus-related antigen in liver (HEV Ag) was detected by immunofluorescence microscopy of biopsies from two of four owl monkeys; one with HEV Ag also had HEV in acute-phase bile (detected by IEM) and feces (detected by infecting another owl monkey). In contrast, cynomolgus monkeys propagated HEV to higher levels and all five had hepatitis. Moderate-to-high levels of HEV Ag correlated with detectable HEV in bile for both species. Thus, the value of using HEV-infected cynomolgus was confirmed. Owl monkeys were shown to be HEV-susceptible and sources of high-level anti-HEV; Sustained anti-HEV in these monkeys may also be useful for understanding immune responses.     

Development of antigen-specific cell-mediated immune responses after infection of cynomolgus monkeys (Macaca fascicularis) with Rickettsia tsutsugamushi

Cynomolgus monkeys were evaluated for cellular immune responses after infection with the Karp strain of Rickettsia tsutsugamushi. Antibody and clinical signs of localized and systemic infection were also evaluated. Animals challenged with homologous or heterologous strains at various times after a primary infection were also followed up. Naive monkeys developed eschars, lymphadenopathy, rickettsemia, and elevated body temperatures. Antibody in these animals was IgM followed by IgG. Lymphocyte proliferation and production of gamma-interferon by peripheral blood mononuclear leukocytes also were demonstrated. If challenged six years after the initial infection, clinical signs and cellular responses were indistinguishable from naive animals but an anamnestic IgG antibody response was noted. If challenged eight months after the initial infection, complete resistance was noted, but if challenged at one year, a localized cutaneous lesion developed. The majority of animals infected previously had preexisting lymphocyte activity, a characteristic suggesting long-term immunologic memory that was not protective against rechallenge.     

Transient testicular warming enhances the suppressive effect of testosterone on spermatogenesis in adult cynomolgus monkeys (Macaca fascicularis)

CONTEXT: The context of the study was to examine whether combined testosterone (T) and heat (H) treatment have additive or synergistic effects on suppression of spermatogenesis. OBJECTIVE: The objective of the study was to determine whether T+H induces a greater suppression of spermatogenesis than either treatment alone in monkeys. DESIGN: The study was a randomized, placebo-controlled study. SETTING: The study was conducted at a primate center in China. PARTICIPANTS: The study population was comprised of 32 adult cynomolgus monkeys. INTERVENTIONS: Groups of eight adult monkeys were treated for 12 wk with: 1) two empty implants (C); 2) two T implants (T); 3) daily testicular heat exposure (43 C for 30 min) for 2 consecutive days (H); or 4) two T implants plus testicular heat exposure (T+H). Treatment was followed by an 8-wk recovery period. MAIN OUTCOME MEASURES: Measures included sperm counts and germ cell apoptosis. RESULTS: Serum T levels were elevated in both the T and T+H groups during treatment but not in the C or H group. Sperm counts were transiently suppressed after heat to 16.4% of baseline at 4 wk and then returned to pretreatment levels. Sperm counts were suppressed slowly after T treatment to nadir of 6.4% of pretreatment levels at 12 wk. T+H rapidly suppressed sperm output as early as 4 wk to 3.9% of pretreatment levels that was maintained throughout treatment. The decreased sperm counts were due to increased germ cell apoptosis in all treatment groups. Sperm counts recovered to the pretreatment levels in all groups by 8 wk after treatment. CONCLUSION: This proof-of-concept study demonstrates that transient testicular warming enhances and hastens the effect of T implant on the suppression of spermatogenesis in monkeys.     

Blood value changes in flavivirus-inoculated Macaca fascicularis monkeys

Blood values were analysed in eighteen cynomolgus monkeys on pre-and post-neurovirulence testing of dengue-2 and yellow fever vaccine viruses, dengue-2 parental and Japanese encephalitis viruses. Certain changes between blood chemistry, hematology and serology were observed and briefly discussed.     

The neurovirulence of flaviviruses in crab-eating monkeys (Macaca fascicularis)

The neurovirulent properties of attenuated dengue-2 and yellow fever (YF) vaccines, dengue-2 (DEN-2) and Japanese encephalitis (JE) viruses were studied in crab-eating monkeys (Macaca fascicularis). Number of central nervous system sites (as proportion affected) with neurovirulence (NV) lesions were compared. The results indicate that these monkeys reliably developed NV-lesion when inoculated with either JE or YF vaccine viruses (87%). NV-lesions occurred in a minority when inoculated with DEN-2 vaccine virus, were of minimal severity (9%), were probably biologically insignificant, and were of equal or less severity than lesions produced by its parental virus (10%).     

Oxytocin in the corpus luteum of the cynomolgus monkey (Macaca fascicularis)

To determine if oxytocin (OT) is present in cynomolgus monkey corpus luteum, OT was measured by a specific and sensitive RIA in 13 corpora lutea, ovarian venous plasma on the ipsilateral side and peripheral venous plasma at different stages of the luteal phase. Serial dilution of acetic acid extract of the corpus luteum showed parallelism with standard OT in the RIA. Total content of OT in corpus luteum was 1.9 +/- 0.5 ng (mean +/- SEM) with a content of 0.4-0.8 ng in early luteal phase, 1.0-6.2 ng in midluteal phase, and 0.4-0.7 ng in late luteal phase. OT concentrations in corpus luteum were 21.0-75.2 ng/g wet wt in early luteal phase, increasing to 34.4-602.5 ng/g in midluteal phase; and declining to 3.4-117.4 ng/g in late luteal phase. OT concentrations per mg protein in the corpus luteum were 0.05-19.6 ng with peak concentrations of 14.7-19.6 ng/mg protein on day 22. Sephadex G-25 column chromatography of the corpus luteum extract revealed a single peak for binding activity similar to that of synthetic OT on the RIA. Ovarian vein blood from the same side as the corpus luteum had a significantly higher OT concentrations of 161.2 +/- 29.7 pg/ml on days 15-24 than 16.8 +/- 3.6 pg/ml on days 25-28 (P less than 0.01) and peripheral plasma OT levels of 23.2 +/- 3.4 pg/ml (P less than 0.025). Our findings indicate that OT is present and probably produced by monkey corpus luteum with peak OT concentrations found in midluteal phase. Thus OT may play a role in primate corpus luteum function.     

Ovarian oxytocin and neurophysin concentrations in the cynomolgus monkey (Macaca fascicularis)

The neurohypophysial hormone oxytocin has previously been found in the ovaries of several animal species. In ruminants ovarian oxytocin is postulated to have a luteolytic function, because of its high concentrations in the corpus luteum. In primates the role of ovarian oxytocin is not known. In the present study we measured the immunoreactive oxytocin and oxytocin-neurophysin content in paired ovaries removed from cynomolgus monkeys (Macaca fascicularis) during the late luteal phase of the cycle (Days 12-14 of the luteal phase or Days 26-28 of a menstrual cycle). Each animal was pulsed with synthetic gonadotropin-releasing hormone to maintain normal menstrual cyclicity. The concentration of oxytocin and its neurophysin during the late luteal phase was greater in the non-corpus luteum than corpus luteum-bearing ovary. By high pressure liquid chromatography and bioassay the oxytocin in both the corpus luteal and non-corpus luteal ovaries was similar to synthetic and posterior pituitary oxytocin. The finding of high concentrations of immunoreactive oxytocin in the non-corpus luteum-bearing ovary suggests that the function of ovarian oxytocin in primates may not be confined specifically to the corpus luteum.     

Induction and maintenance of ethanol self-administration in cynomolgus monkeys (Macaca fascicularis): long-term characterization of sex and individual differences

BACKGROUND: Investigations of oral ethanol self-administration in nonhuman primates have revealed important parallels with human alcohol use and abuse, yet many fundamental questions concerning the individual risk to, and the biological basis of, excessive ethanol consumption remain unanswered. Moreover, many conditions of access to ethanol in nonhuman primate research are largely unexplored. This set of experiments extends within- and across-session exposure to ethanol to more fully characterize individual differences in oral ethanol self-administration. METHODS: Eight male and eight female adult cynomolgus monkeys (Macaca fascicularis) were exposed to daily oral ethanol self-administration sessions for approximately 9 months. During the first 3 months, a fixed-time (FT) schedule of food delivery was used to induce the consumption of an allotted dose of ethanol in 16-hr sessions. Subsequently, the FT schedule was suspended, and ethanol was available ad libitum for 6 months in 16- or 22-hr sessions. RESULTS: Cynomolgus monkeys varied greatly in their propensity to self-administer ethanol, with sex and individual differences apparent within 10 days of ethanol exposure. Over the last 3 months of ethanol access, individual average ethanol intakes ranged from 0.6 to 4.0 g/kg/day, resulting in blood ethanol concentrations from 5 to 235 mg/dl. Males drank approximately 1.5-fold more than females. In addition, heavy-, moderate-, and light-drinking phenotypes were identified by using daily ethanol intake and the percentage of daily calories obtained from ethanol as criteria. CONCLUSIONS: Cynomolgus monkeys displayed a wide intersubject range of oral ethanol self-administration with a procedure that used a uniform and prolonged induction that restricted early exposure to ethanol and subsequently allowed unlimited access to ethanol. There were sex and stable individual differences in the propensity of monkeys to consume ethanol, indicating that this species will be important in characterizing risk factors associated with heavy-drinking phenotypes.     

Comparison of ethanol metabolism in male and female cynomolgus macaques (Macaca fascicularis)

The physiological consequences of drinking ethanol differ among men and women; however, the biological basis of this gender difference is unknown. Our study characterized sex-related blood ethanol concentration (BEC) 60 min postethanol administration and ethanol elimination rates in male and female monkeys and across the phases of the menstrual cycle. Subjects were male (n = 4) and female (n = 4) cynomolgus monkeys (Macaca fascicularis) with a history of ethanol exposure and maintained at a lean body weight by food restriction. On three separate occasions, each monkey was administered 1.0 g/kg ethanol intragastrically and blood samples (20 microl) were collected every 60 min over a 5-hr period. For females, three phases of the menstrual cycle were determined by the presence of menses and plasma progesterone levels. There was no effect of menstrual cycle on mean 60 min BECs or mean rates of elimination. Mean BECs 60 min after 1.0 g/kg ethanol were: males = 86 mg/dl (+/- 2; n = 4) and females = 82 mg/dl (+/- 5; n = 4). There was no effect of sex on the highest BEC measured, which occurred at the 60 min time point in all subjects. Female monkeys did have faster average rates of ethanol elimination [34 +/- 2 (mg/dl)/hr] compared with males [23 +/- 1 (mg/dl)/hr]. The sex differences in metabolism of ethanol found with the macaque monkey model correlates well with human subject studies and suggests this is an appropriate model to further explore gender differences in response to ethanol.     

Recombinant BCG Tokyo (Ag85A) protects cynomolgus monkeys (Macaca fascicularis) infected with H37Rv Mycobacterium tuberculosis

One tuberculosis vaccine candidate that has shown a promising degree of protective efficacy in guinea pigs is recombinant BCG Tokyo (Ag85A)(rBCG-Ag85A[Tokyo]). As a next step, cynomolgus monkeys were utilized because they are susceptible to Mycobacterium tuberculosis and develop a continuous course of infection that resembles that in humans both clinically and pathologically. The recombinant BCG vaccine was administered once intradermally in the back skin to three groups of cynomolgus monkeys, and its protective efficacy was compared for 4 months with that of its parental BCG Tokyo strain. Vaccination of the monkeys with the rBCG-Ag85A[Tokyo] resulted in a reduction of tubercle bacilli CFU (p<0.01) and lung pathology in animals challenged intratracheally with 3000 CFU H37Rv M. tuberculosis. Vaccination prevented an increase in the old tuberculin test after challenge with M. tuberculosis and reaction of M. tuberculosis-derived antigen. Thus, it was shown in monkeys that rBCG-Ag85A[Tokyo] induced higher protective efficacy than BCG Tokyo. This warrants further clinical evaluation.     

Serum immunoreactive inhibin levels before and after luteectomy in the cynomolgus monkey (Macaca fascicularis)

Whereas studies in women have demonstrated that serum immunoreactive inhibin concentrations peak during the luteal phase of the menstrual cycle and that the corpus luteum (CL) encodes mRNA for the inhibin subunits, a clear link between the presence of the CL and circulating inhibin has not been established in primates. Therefore, we measured serum immunoreactive inhibin levels in monkeys before and after luteectomy as well as immunoreactive inhibin concentrations and mRNA encoding the alpha-inhibin subunit in luteal tissue. Monkeys were assigned to one of four groups depending on which day of the luteal phase luteectomy was performed: group A, days 4-5; group B, days 7-8; group C, days 9-10; and group D, days 11-12 (the day after the estrogen surge = day 1 of the luteal phase). Daily blood samples were obtained for 3 days before luteectomy, immediately before surgery, and for 2 days after luteectomy. Immunoreactive inhibin concentrations were measured with a double antibody RIA using an antiserum to bovine 31-kDa inhibin, bovine 31-kDa inhibin for iodination, and a human follicular fluid inhibin preparation as standard. Total RNA was isolated from luteal tissue and transferred by Northern blot onto a Zeta-probe membrane. The probe used for hybridization was the PstI/NcoI restriction enzyme fragment (381 basepairs) of alpha-inhibin DNA generated from a human ovarian cDNA library. Serum inhibin concentrations decreased (P less than 0.05) 24 h after removal of the corpus luteum in each of the four groups studied.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exogenous gonadotrophin-releasing hormone (GnRH) stimulates LH secretion in male monkeys (Macaca fascicularis) treated chronically with high doses of a GnRH antagonist.

We reported previously that after a single injection of a gonadotrophin-releasing hormone (GnRH) antagonist to male monkeys, exogenous GnRH stimulated LH secretion in a time- and dose-dependent manner, indicating that GnRH antagonist-induced blockade of LH secretion resulted from pituitary GnRH receptor occupancy. The present study was performed to investigate whether GnRH can also restore a blockade of LH and testosterone secretion during chronic GnRH antagonist administration. Four adult male cynomolgus monkeys (Macaca fascicularis) received daily s.c. injections of the GnRH antagonist [N-Ac-D-pCl-Phe1,2,D-TRP3,D-Arg6-D-Ala10]-GnRH (ORG 30276) at a dose of 1400-1600 micrograms/kg for 8 weeks. Before the GnRH antagonist was given and during weeks 3 and 8 of treatment, pituitary stimulation tests were performed with 0.5, 5, 50 and 500 micrograms synthetic GnRH, administered in increasing order at intervals of 24 h. At 8 weeks, a dose of 1000 micrograms GnRH was also given. All doses of GnRH significantly (P less than 0.05) stimulated serum concentrations of bioactive LH (3- to 8-fold) and testosterone (2.6- to 3.8-fold) before the initiation of GnRH antagonist treatment. After 3 weeks of GnRH antagonist treatment, only 50 and 500 micrograms GnRH doses were able to increase LH and testosterone secretion. Release of LH was significantly (P less than 0.05) more elevated with 500 micrograms compared with 50 micrograms GnRH. After 8 weeks, only the highest dose of 1000 micrograms elicited a significant (P less than 0.05) rise in LH secretion. Basal hormone levels just before the bolus injection of GnRH were similar (P greater than 0.10-0.80).(ABSTRACT TRUNCATED AT 250 WORDS)     

Thrombin activity induced by balloon angioplasty of the coronary artery in Macaca fascicularis (cynomolgus monkey)

In this paper we address the question of whether balloon angioplasty induces thrombin action. In the studies reported here we measured fibrinopeptide A levels in a group of atherosclerotic monkeys undergoing coronary angioplasty. A blood collection catheter was introduced into the inferior vena cava through a femoral vein, and the angioplasty catheter introduced via the femoral artery. Heparin was administered immediately after insertion of the arterial catheter. Serial blood samples were collected for 20 min before angioplasty and for 10 min after angioplasty. Baseline levels of FpA were high, presumably in response to the trauma of introducing the catheters. After heparin administration the FpA concentration declined with a half-time of 1.1 min. In response to balloon inflation there was a clear increase in the concentration of FpA, despite the presence of a therapeutic concentration of heparin. The magnitude of the FpA rise was markedly different between animals, but was evident in the aggregate data after subtraction of background levels of FpA. By integration of the plasma FpA concentration curve, the amount of fibrinogen converted to fibrin in response to angioplasty was calculated to be approximately 0.4 mg/animal. We conclude that angioplasty induces significant activation of the coagulation system.     

Ethanol self-administration and alterations in the livers of the cynomolgus monkey, Macaca fascicularis

Background: Most of the studies of alcoholic liver disease use models in which animals undergo involuntary administration of high amounts of ethanol and consume diets that are often high in polyunsaturated fatty acids. The objectives of this study were (1) to evaluate whether cynomolgus monkeys (Macaca fascicularis) drinking ethanol voluntarily and consuming a diet with moderate amounts of lipid would demonstrate any indices of alcoholic liver disease past the fatty liver stage and (2) to determine whether these alterations were accompanied by oxidative stress. Methods: Six adult male and 6 adult female cynomolgus monkeys were allowed to consume ethanol voluntarily for 18 to 19 months. Additional monkeys were maintained on the same consumption protocol, but were not provided with ethanol. During the course of the study, liver biopsy samples were monitored for lipid deposition and inflammation, serum for levels of liver enzymes, and urine for concentrations of the isoprostane (IsoP) metabolite, 2,3‐dinor‐5,6‐dihydro‐15‐F_2t‐IsoP, a biomarker for oxidative stress. Liver mitochondria were monitored for respiratory control and liver for concentrations of neutral lipids, adenine nucleotides, esterified F₂ isoprostanes, oxidized proteins, 4‐hydroxynonenal (HNE)‐protein adducts, and protein levels of cytochrome P‐450 2E1 and 3A4. Results: Ethanol consumption ranged from 0.9 to 4.05 g/kg/d over the period of the study. Serum levels of aspartate amino transferase were elevated in heavy‐consuming animals compared with those in ethanol‐naïve or moderate drinkers. Many of the ethanol consumers developed fatty liver and most showed loci of inflammation. Both hepatic energy charge and phosphorylation potential were decreased and NADH‐linked respiration was slightly, but significantly depressed in coupled mitochondria as a result of heavy ethanol consumption. The urinary concentrations of 2,3‐dinor‐5,6‐dihydro‐15‐F_2t‐IsoP increased as high as 33‐fold over that observed in ethanol‐abstinent animals. Liver cytochrome P‐450 2E1 concentrations increased in ethanol consumers, but there were no ethanol‐elicited increases in hepatic concentrations of the esterified F₂ isoprostanes, oxidized proteins, or HNE‐protein adducts. Conclusion: Our studies show that cynomolgus monkeys undergoing voluntary ethanol consumption for 1.5 years exhibit many of the features observed in the early stages of human alcoholic liver disease. Ethanol‐elicited fatty liver, inflammation, and elevated serum aspartate amino transferase were evident with a diet that contained modest amounts of polyunsaturated lipids. The dramatic increases in urinary IsoP demonstrated that the animals were being subjected to significant oxidative stress that correlated with their level of ethanol consumption.     

Norethisterone enanthate has neither a direct effect on the testis nor on the epididymis: a study in adult male cynomolgus monkeys (Macaca fascicularis)

OBJECTIVE: Norethisterone enanthate (NETE) is evaluated in trials of hormonal male contraception. It has been speculated that progestins may exert their contraceptive effects not only by suppressing gonadotropins but also by direct effects on male organs. NETE was given to monkeys in which endogenous gonadotropin secretion was suppressed by a gonadotropin releasing hormone (GnRH) antagonist, and replaced by human follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG). If NETE has a direct effect on spermatogenesis and/or epididymal function, some changes in testicular histology, sperm motility and/or morphology should occur soon after exposure to NETE. METHODS: Fifteen adult intact male monkeys were grouped and treated for a 38-day period. Group I received GnRH antagonist, FSH, hCG and NETE while group II received a regime identical to group I without NETE and group III received only NETE and vehicle. Ejaculates, body weight, testicular biopsies and volume, and hormones were evaluated. RESULTS: There was a similar pattern of serum FSH and testosterone in groups I and II. Testicular volume and the proportion of tubuli exhibiting spermatids was significantly decreased in group III. There were no significant differences between group I and group II in any parameters measured. The forward progression of sperm was not affected by NETE treatment. The consistently low percentages of grade c sperm indicated no sign of hyperactivation. No changes in the gross morphology of the acrosome were detected. CONCLUSIONS: Short-term NETE treatment has neither a direct effect on the testis nor on the epididymis in this nonhuman primate model and its contraceptive effects appear to be exerted exclusively through gonadotropin suppression.     

Caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): metabolic, physiologic, and atherosclerotic measures from a 4-year intervention trial

Caloric restriction (CR) retards aging processes, extends maximal life span, and consistently improves insulin resistance in lower species. Insulin resistance is associated with cardiovascular disease, but data is lacking demonstrating that increased insulin sensitivity reduces atherosclerosis progression. We initiated a study in 32 adult cynomolgus monkeys to evaluate increased insulin sensitivity secondary to CR on atherosclerosis extent. Following pretrial determinations, animals were randomized to a moderately atherogenic (0.25 mg cholesterol/Cal containing 30% of calories from fat)-fed control group or CR group (30% reduction) with equivalent dietary cholesterol intake. CR significantly improved insulin sensitivity and reduced intraabdominal fat over the 4-year intervention, while no significant differences were seen for the lipid profile between groups. Despite improved insulin sensitivity with CR, atherosclerosis extent did not differ between the ad libitum-fed or CR groups. These studies demonstrate that CR significantly improves insulin sensitivity, but when elevated plasma cholesterol concentrations were held similar, there was no effect on atherosclerosis extent. However, the composition of these lesions and changes in endothelial function may have been improved but were not evaluated in this study. Thus, further studies are needed to determine if improved insulin sensitivity might decrease arterial inflammation and improve endothelial function, despite no changes in atherosclerosis extent.     

Lack of effects of recombinant human GH on spermatogenesis in the adult cynomolgus monkey (Macaca fascicularis)

OBJECTIVE: The effects on male reproductive parameters after 1 year of treatment with recombinant human GH to the cynomolgus monkey were investigated. DESIGN: Twenty-four male cynomolgus monkeys were given daily subcutaneous doses of 0 (vehicle) (n=7), 0.4 (n=5), 2.0 (n=5) and 10.0 (n=7) IU/kg bodyweight for 52 weeks. At completion of the treatment period two control and two high-dose animals were left for a 12-week treatment-free period. METHODS: Before and during the treatment period and during the recovery period, sperm analyses, testicular volume measurements and hormone analyses of prolactin (PRL), LH, FSH, testosterone and IGF-I in serum, and analysis of serum antibodies against human GH were performed. Testicular morphology was monitored by biopsies, predose and on day 15 of the study, and with light microscopy on organ samples collected at time of death, at the end of the treatment, and during recovery periods respectively. RESULTS: Of all studied parameters, alterations were observed only in serum levels of IGF-I and PRL. IGF-I showed a dose-dependent increase throughout the treatment, with a normalisation during the treatment-free period. PRL decreased significantly in animals given 10.0IU/kg per day from week 14 of treatment and throughout the study but with a normalisation upon cessation of treatment. Spermatogenesis, as judged from semen analysis, testicular volume measurements and testicular morphology was not affected. CONCLUSION: This controlled preclinical study demonstrates that high doses of human GH do not alter male reproductive parameters in a non-human primate model.     

Perinephritis hypertension in Macaca fascicularis (cynomolgus monkey): studies of the renin-angiotensin-aldosterone axis and renal hemodynamic function

The purpose of the present study was to characterize the etiology of bilateral perinephritis hypertension in the non-human primate. Hypertension was induced in female cynomolgus (Macaca fascicularis) monkeys by wrapping both kidneys under sterile surgical procedures. Mean arterial pressure (MAP), plasma renin activity (PRA), plasma aldosterone concentration (ALDO), para-aminohippurate (PAH) clearance, glomerular filtration rate (GFR), urine volume, and sodium and potassium excretion were measured before and weekly after induction of the hypertension. MAP increased progressively from 108 +/- 1 to 135 +/- 4 mmHg during the first 6 weeks; thereafter, MAP remained at this elevated level, PRA was elevated two- to fivefold for up to 10 weeks after the hypertension and ALDO was elevated during 1 (139%), 4 (60%), 6 (196%), 8 (249%) and 10 (148%) weeks of the hypertension. PAH clearance and GFR were significantly reduced during week 1 of the hypertension, but returned to control values by week 2. Urine volume was increased significantly during the first week of the hypertension, while sodium and potassium excretion were not changed. Captopril (15 mumol/kg, intravenously) normalized the blood pressure regardless of the severity or duration of the disease. Additionally, captopril lowered ALDO and increased PRA. It is concluded that bilateral perinephritis hypertension in the monkey is dependent on increased activity of the renin-angiotensin-aldosterone axis.     

Impairment of spermatogonial development and spermiation after testosterone-induced gonadotropin suppression in adult monkeys (Macaca fascicularis)

Human male hormonal contraceptive regimens do not consistently induce azoospermia, and the basis of this variable response is unclear. This study used nine adult macaque monkeys (Macaca fascicularis) given testosterone (T) implants for 20 weeks to study changes in germ cell populations in relation to sperm output. Germ cell numbers were determined using the optical disector stereological method. Four animals achieved consistent azoospermia (azoo group), whereas five animals did not (nonazoo group). T-induced gonadotropin suppression in all animals decreased A pale (Ap) spermatogonia to 45% of baseline within 2 weeks, leading to decreased B spermatogonia (32--38%) and later germ cells (20--30%) after 14 and 20 weeks. Though the reduction in later germ cell types could be primarily attributed to the loss of spermatogonia, the data suggested that some cells were lost during the spermatocyte and spermatid phase of development. B spermatogonial number was more markedly suppressed in azoospermic animals, compared with the nonazoo group, as was the conversion ratio between Ap and B spermatogonia. Abnormal retention of elongated spermatids (failed spermiation) was also prominent in some animals after long-term T administration. We conclude that: 1) the variable suppression of sperm output is attributed to the degree of inhibition of germ cell development from type B spermatogonia onwards, and this is related to the degree of FSH suppression; and 2) inhibition of Ap and B spermatogonial development and of spermiation are the major defects caused by long-term T administration to monkeys.