Androgen dependent mammary gland virilism in rats given the selective estrogen receptor modulator LY2066948 hydrochloride

A selective estrogen receptor modulator (SERM) is a nonsteroidal compound with tissue specific estrogen receptor (ER) agonist or antagonist activities. In animals, SERMs may produce morphologic changes in hormonally-sensitive tissues like the mammary gland. Mammary glands from female rats given the SERM LY2066948 hydrochloride (LY2066948) for 1 month at >or= 175 mg/kg had intralobular ducts and alveoli lined by multiple layers of vacuolated, hypertrophied epithelial cells, resembling in part the morphology of the normal male rat mammary gland. We hypothesized that these SERM-mediated changes represented an androgen-dependent virilism of the female rat mammary gland. To test this hypothesis, the androgen receptor antagonist flutamide was co-administered with LY2066948 (175 mg/kg) to female rats for 1 month. Female rats given SERM alone had hyperandrogenemia and the duct and alveolar changes described here. Flutamide cotreatment did not affect serum androgen levels but completely blocked the SERM-mediated mammary gland change. In the mouse, a species that does not have the sex-specific differences in the mammary gland observed in the rat, SERM treatment resulted in hyperandrogenemia but did not alter mammary gland morphology. These studies demonstrate that LY2066948 produces species-specific, androgen-dependent mammary gland virilism in the female rat.     

Spatial memory performance in androgen insensitive male rats

Masculinization of the developing rodent brain critically depends on the process of aromatization of circulating testosterone (T) to its estrogenic metabolite 17beta-estradiol, which subsequently interacts with estrogen receptors to permanently masculinize the brain. However, it remains unclear what role other androgenic mechanisms may play in the process of masculinization. A novel way of examining this is through the study of male rats that express the tfm mutation of the androgen receptor (AR) gene; such males are fully androgen insensitive and manifest a female phenotype due to a failure of AR-mediated masculinization of peripheral structures. Because tfm-affected males develop secretory testes and have near-normal T titers during development, aromatization would be expected to proceed normally, and brain mechanisms may be developmentally masculinized despite the feminized periphery. We compared tfm-affected males (X(tfm)Y) with normal males and females in the Morris Water Maze, a task in which males typically perform better than females. Performance of tfm-affected males was intermediate between that of normal males and females. While an overall male superiority was found in the task, the X(tfm)Y group reached male-typical escape latencies faster than females. Furthermore, in the X(tfm)Y group, the granule cell layer of the dentate gyrus was significantly larger than in females. These results support the suggestion that that AR mediated mechanisms contribute to the masculinization of spatial behaviours and hippocampal morphology, and this may be independent of estrogenic processes.     

MaxiK channel roles in blood vessel relaxations induced by endothelium-derived relaxing factors and their molecular mechanisms.

The endothelium of blood vessels plays a crucial role in the regulation of blood flow by controlling mechanical functions of underlying vascular smooth muscle. The regulation by the endothelium of vascular smooth muscle relaxation and contraction is mainly achieved via the release of vasoactive substances upon stimulation with neurohumoural substances and physical stimuli. Nitric oxide (NO) and prostaglandin I2 (prostacyclin, PGI2) are representative endothelium-derived chemicals that exhibit powerful blood vessel relaxation. NO action involves activation of soluble guanylyl cyclase and PGI2 action is initiated by the stimulation of a cell-surface receptor (IP receptor, IPR) that is coupled with Gs-protein-adenylyl cyclase cascade. Many studies on the mechanisms by which NO and PGI2 elicit blood vessel relaxation have highlighted a role of the large conductance, Ca2+-activated K+ (MaxiK, BKCa) channel in smooth muscle as their common downstream effector. Furthermore, their molecular mechanisms have been unravelled to include new routes different from the conventionally approved intracellular pathways. MaxiK channel might also serve as a target for endothelium-derived hyperpolarizing factor (EDHF), the non-NO, non-PGI2 endothelium-derived relaxing factor in some blood vessels. In this brief article, we review how MaxiK channel serves as an endothelium-vascular smooth muscle transducer to communicate the chemical signals generated in the endothelium to control blood vessel mechanical functions and discuss their molecular mechanisms.     

Nitric oxide (NO) primarily accounts for endothelium-dependent component of beta-adrenoceptor-activated smooth muscle relaxation of mouse aorta in response to isoprenaline.

Isoprenaline is known to produce vascular relaxation through activation of beta-adrenoceptors. In recent years, beta-adrenoceptor-activated vascular relaxation has been the focus of pharmacological study in terms of both the receptor subtypes and the intracellular signaling mechanisms which trigger smooth muscle mechanical functions. In addition, the possible contribution of the endothelium to beta-adrenoceptor-activated relaxation of vascular beds has provoked considerable discussion, with consensus still to be established. In the present study, we examined the effects of isoprenaline on isolated mouse aortic smooth muscles to determine whether the presence of the endothelium plays a substantial role in the relaxation it produces. A possible role for nitric oxide (NO) as a primary endothelium-derived factor released in response to isoprenaline was also elucidated pharmaco-mechanically. In isolated thoracic and abdominal aortae pre-contracted with phenylephrine (3 x 10(-7)-10(-6) M), isoprenaline elicited relaxation in a concentration-dependent fashion (10(-9)-10(-5) M). In endothelium-denuded preparations, isoprenaline-elicited relaxation was reduced to 40-50% of the response obtained in endothelium-intact preparations. In the preparations treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 3 x 10(-4) M; an NO synthase inhibitor) or 1H-[1,2,4]-oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ, 10(-5) M; a soluble guanylyl cyclase inhibitor), isoprenaline-elicited relaxation was attenuated almost to the same degree as the response in endothelium-denuded preparations. The degree of endothelium-dependency in isoprenaline-elicited relaxation was largely diminished when treated with propranolol (3 x 10(-6) M). The present findings indicate that isoprenaline substantially relaxes the mouse aorta with both endothelium-dependent and -independent mechanisms. The endothelium-dependent component seems to correspond to about 50% of the isoprenaline-elicited relaxation, and is almost entirely due to endothelium-derived NO. Activation of propranolol (3 x 10(-6) M)-inhibitable beta-adrenoceptors seems to be primarily responsible for the NO-mediated endothelium-dependent pathway in isoprenaline-elicited relaxant response of mouse aorta.     

Effects of the testicular feminization mutation (tfm) of the androgen receptor gene on BSTMPM volume and morphology in rats

The posteromedial bed nucleus of the stria terminalis (BSTMPM) is an important component of the extended amygdala that is sexually dimorphic in rats. We examined the effect of the testicular feminization mutation (tfm), which renders the androgen receptor (AR) dysfunctional, on BSTMPM volume and average somal area. As expected, we found a significant sex difference in the volume of the BSTMPM, with females having a smaller BSTMPM than wild type males. Size of the BSTMPM in tfm males was also significantly smaller than that of wildtype males, although this difference was significant only on the left side. We found no sex difference in BSTMPM somal areas. These findings support the role of androgen receptors in the sexual differentiation of this nucleus.     

Altered striatal vulnerability to 3-nitropropionic acid in rats due to sex hormone levels during late phase of brain development

Systemic administration of 3-nitropropionic acid (3-NPA) leads to a shortage of cellular ATP and induces striatum-specific lesions that resemble Huntington's disease. Gender differences, in terms of vulnerability of striatum to 3-NPA, have been shown in male rats. The goal of the present study was to determine whether changes in sex hormone levels during the critical period of sexual differentiation (E17-P4) influence striatal vulnerability to 3-NPA. An androgen receptor antagonist, flutamide, or an aromatase-inhibitor, fadrozole hydrochloride, which block conversion of testosterone to estradiol, were administered to embryonic rats during E17-E20 or E18-E20, respectively, with subsequent 3-NPA (20mg/(kg day) for 2 days) treatment during adulthood (8-9 weeks old). Motor behavior and histological changes (IgG exudation due to blood-brain barrier dysfunction and glial fibrillary acidic protein immunoreactivity) were assessed. Treatment with flutamide significantly decreased the 3-NPA-induced motor behavior in male rats, while administration of fadrozole hydrochloride increased atypical motor behavior in female rats. IgG exudation, as well as decreased glial fibrillary acidic protein reactivity, was observed in animals with motor defects. Flutamide decreased testosterone levels in male rats, while fadrozole hydrochloride increased testosterone levels in female rats. These results suggest that prenatal modulation of sexual hormonal levels greatly influences vulnerability to 3-NPA during adulthood and directly correlates to serum testosterone levels.     

Testosterone relaxes abdominal aorta in male Sprague-Dawley rats by opening potassium (K) channel and blockade of calcium (Ca) channel

Aim: To investigate the direct effect of testosterone and its precursor/derivative dehydroepiandrosterone (DHEA) on isolated rat abdominal aortic rings. Materials and methods: 3 mm abdominal aortic rings that were obtained from 3 months old male Sprague-Dawley rats were suspended in organ baths containing Hepes buffered PSS bubbled with 100% oxygen. Relaxation response to testosterone and DHEA was studied in noradrenalin pre-contracted rings. The role of aromatase and androgen receptor was assessed by inhibition using aminogluthetemide and blockade using flutamide respectively. Relaxation responses of the rings to testosterone in the presence of l-NAME, indomethacin, barium chloride, apamin, charybdotoxin, iberiotoxin, and nifedipine were also determined. Results: Both aromatase inhibition and androgen receptor blockade did not block the relaxing effect of testosterone on rings from rat abdominal aorta. Also there was no significant difference between testosterone relaxation response in the presence or absence of l-NAME and indomethacin. However 3 μM, BaCl₂ almost completely abolished the aortic ring relaxation response to testosterone while 1 μM, nifedipine potentiated the vasorelaxing effect of testosterone. Conclusion: Testosterone relaxes abdominal aorta directly via a non-genomic pathway which is independent of endothelial derived vasoactive substances, but involves activation of inward rectifying potassium channel (K_IR) and blockade of l-type calcium channel.     

Effects of long-term flutamide treatment during development in zebra finches

The molecular mechanisms responsible for the sexual differentiation of the zebra finch song system remain mysterious. Androgen receptors are expressed in a sexually dimorphic fashion in the zebra finch song system: males have more cells expressing androgen receptors, and this sex difference appears very early in development (day 9 posthatch). Estrogen administration to hatchling females up-regulates androgen receptor expression in their song system and profoundly masculinizes their song system's morphology. Co-administering flutamide, an androgen receptor blocker, with estrogen impedes estrogen's masculinizing effects on the song system, suggesting that androgens are required for masculine development. Accordingly, to investigate further the role of androgens in the sexual differentiation of the zebra finch song system, we sought to block androgen activity in males by administering large, sustained doses of flutamide from just before androgen receptors are expressed in the song system (day 7) through to the day of sacrifice (days 61-63). Flutamide profoundly reduced the size of the testes, demonstrating that this drug and mode of administration could have a large impact on tissues. In contrast, flutamide had only a minor impact on the song system: the number of RA neurons was slightly reduced, and the corrected HVC volume showed a trend toward demasculinization. Other brain measures (uncorrected HVC, and corrected and uncorrected volumes of Area X, lMAN, RA, and Rotundus; neuron size in lMAN, HVC, and RA; and number of HVC and LMAN neurons) were not significantly affected. The present results do not support an important role for androgen in masculinizing the song circuit after posthatch day 7.     

Effect of prenatal androgen receptor antagonist or aromatase inhibitor on sexual behavior, partner preference and neuronal Fos responses to estrous female odors in the rat accessory olfactory system

Many socially relevant odors are detected in rodent species by the vomeronasal organ and subsequently processed by the accessory olfactory system (AOS). We previously found that gonadectomized male and female rats treated in adulthood with testosterone propionate (TP) showed equivalent Fos responses in the AOS to odors derived from estrous females. Likewise, in contrast with numerous other mammalian species, gonadectomized female rats show surprisingly high levels of male-typical mounting behavior in response to adult TP. We tested the hypothesis that prenatal testosterone (T) exposure, acting via androgen receptors (ARs) or via estrogen receptors, masculinizes the AOS in rats of both sexes. Pregnant dams were treated with either the AR blocker, Flutamide, the aromatase inhibitor, 1,4,6-androstatriene-3,17-dione (ATD), or nothing (control) to assess the role of prenatal androgen and estradiol receptor activation, respectively, in this masculinization. Beginning at birth, male and female offspring were injected subcutaneously (sc) every other day with either ATD (pre- and neonatal ATD group) or oil vehicle (Flutamide and control groups) until postnatal Day 12. Subjects were gonadectomized as adults, hormonally treated and tested for different behaviors before having their AOS Fos responses to estrous female odors assessed. Prenatal treatment with Flutamide (but not ATD) significantly decreased anogenital distance and severely impaired intromissive and ejaculatory behaviors in males tested after TP replacement without disrupting mounting capacity in either sex. Pre- and neonatal treatment with ATD (but not Flutamide) enhanced lordosis responsiveness in males tested after sc injections of estradiol and progesterone, whereas these perinatal treatments had no effect on any aspect of masculine coital performance in either sex. After TP treatment, male and female control subjects preferred to approach a tethered stimulus female as opposed to a male, and prenatal Flutamide or perinatal ATD treatments did not modify this pattern of partner preference. Neuronal Fos responses to estrous odors were (as in previous studies) identical in the AOS of gonadectomized TP-treated control males and females. Prenatal Flutamide or perinatal ATD treatments failed to disrupt consistently this profile of Fos responses to estrous odors in the AOS of rats of either sex. These behavioral and neuroanatomical findings raise the possibility that the similar level of male-typical responsiveness to social odors that occurs in male and female rats after adult TP treatment results from nonsteroid-hormone-dependent, species-specific factors that act perinatally in the brains of rats of both sexes.     

Mechanism of the salutary effects of flutamide on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of estrogen receptor-{beta}-dependent HO-1

Hemeoxygenase (HO)-1 induction following adverse circulatory conditions is known to be protective, and precastrated males have less intestinal damage than sham-operated males following trauma-hemorrhage (T-H). Previous studies have also shown that administration of flutamide up-regulated estrogen receptor (ER) expression in males following T-H. We hypothesized that flutamide administration in males following T-H up-regulates HO-1 via an ER-dependent pathway and protects against intestinal injury. Male Sprague-Dawley rats underwent T-H [mean blood pressure (MBP) 40 mmHg for 90 min and then resuscitation]. A single dose of flutamide (25 mg/kg body weight), with or without an ER antagonist (ICI 182,780), a HO enzyme inhibitor [chromium-mesoporphyrin (CrMP)], or vehicle, was administered subcutaneously during resuscitation. At 2 h after T-H or sham operation, intestinal myeloperoxidase (MPO) activity, intercellular adhesion molecule (ICAM)-1, cytokine-induced neutrophil chemoattractant (CINC)-1, and CINC-3 levels were measured. Intestinal ER-alpha, ER-beta, androgen receptor, and HO-1 mRNA/protein levels were also determined. Results showed that T-H increased intestinal MPO activity, ICAM-1, CINC-1, and CINC-3 levels. These parameters were improved significantly in the flutamide-treated rats subjected to T-H. Flutamide treatment increased intestinal HO-1 and ER-beta mRNA/protein levels as compared with vehicle-treated T-H rats. Administration of the ER antagonist ICI 182,780 or the HO inhibitor CrMP prevented the flutamide-induced attenuation of shock-induced intestinal damage. Thus, the salutary effects of flutamide administration on attenuation of intestinal injury following T-H are mediated via up-regulation of ER-beta-dependent HO-1 expression.     

How do androgens affect episodic gonadotrophin secretion in postmenopausal women?

In the absence of any significant ovarian oestrogen secretion, as in post-menopausal women, the hypothalamic-pituitary axis may still be influenced by the androgens which continue to be produced. The episodic secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by post-menopausal women was accordingly assessed following short-term androgen antagonism induced by flutamide, a specific androgen receptor blocker. Blood samples were collected at 10-min intervals for 10 h in nine women before and during flutamide administration (750 mg/day for 6 days) for the determination of gonadotrophin and sex hormone concentrations by radibimmunoassay. On both occasions, 25 μg of gonadotrophin-releasing-hormone (GnRH) was injected intravenously 8 h after initiation of the blood collections. Flutamide administration decreased (P < 0.01 or less) androgen concentrations (testosterone, androstenedione and dehydroepiandrosterone sulphate) in relation to baseline values, but did not alter oestrogen (oestrone and oestradiol) or sex-hormone-binding globulin levels. The LH and FSH pulse characteristics (frequency, amplitude, interpulse interval and transverse mean levels) determined by a cluster algorithm in the gonadotrophin secretory profiles did not differ before and during androgen blockade. By contrast, androgen antagonism increased LH (P < 0.01) and tended to enhance FSH (P = 0.10) FSH release in response to GnRH stimulation. Hence, short-term androgen receptor blockade with flutamide did not greatly affect episodic gonadotrophin secretion. However, the combined evidence of the enhanced gonadotrophin release observed in response to GnRH stimulation and the unchanged gonadotrophin secretion during androgen antagonism suggests that alterations in the magnitude, but not the frequency, of hypothalamic GnRH release had occurred. Even in the presence of substantial serum androgen concentrations, the gonadotrophin pulse rhythm in hypogonadal women consitutes the maximal-rate GnRH-LH release pattern.     

Dietary salt-loading attenuates endothelium-dependent relaxation in response to histamine but not to acetylcholine in rat aortic rings

Endothelium-dependent relaxation in response to histamine and ACh has been studied on precontracted aortic rings from control and salt-loaded Sprague-Dawley rats. Both ACh and histamine caused relaxation of the noradrenaline-induced precontraction only in the presence of the endothelium. The relaxation response to ACh in rings from control and salt-loaded rats did not differ significantly whereas histamine-induced relaxation was significantly attenuated in aortae from salt-loaded rats. The results suggest that salt-induced hypertension is associated with impairment of endothelium-dependent relaxation to histamine but not to ACh.     

Endocrinology: The effect of flutamide on pulsatile gonadotrophin secretion in hyperandrogenaemic women

The pulsatile gonadotrophin secretion in hyperandrogenaemicwomen was examined, following short-term androgen antagonisminduced by flutamide, a specific androgen receptor blocker.Flutamide was administered to seven hyperandrogenaemic womenand five normal cycling women, at a dose of 250 mg on the eveningof day 1, followed by daily doses of 750 mg for 6 days. Bloodsamples were collected at 10 min intervals for 8 h before (day1) and during treatment (days 2 and 6). Gonadotrophin and prolactinconcentrations were measured in all samples while sex hormoneconcentrations were analysed in selected samples. Flutamideadministration to hyperandrogenaemic women was followed by adecrease in luteinizing hormone (LH) pulse amplitude (P <0.05), associated with an apparent decline in mean LH concentrations.Follicle stimulating hormone (FSH) showed a significant fallafter 6 days of treatment (P < 0.05). Total testosterone,free testosterone, androstenedione and dihydroepiandrosteronesulphate were significantly decreased during flutamide administration,while sex-hormone-binding globulin and oestradiol were not affected.Normal women showed no significant changes in the above mentionedparameters. These results demonstrate that short-term androgenreceptor blockade with flutamide reduces gonadotrophin secretionand androgen concentration in hyperandrogenaemic women. Sinceflutamide is devoid of intrinsic hormonal activity, it is suggestedthat the observed hormonal changes are secondary to the androgenblockade.     

Effects of neonatal flutamide treatment on hippocampal neurogenesis and synaptogenesis correlate with depression-like behaviors in preadolescent male rats

The prevalence of major depressive disorder (MDD) in adult men is roughly half that of women. Clinical evidence supports a protective effect of androgens against depressive disorders in men. The developing brain is subject to androgen exposure but a potential role for this in depression during adulthood has not been considered. In order to explore this question we treated newborn male rat pups with the androgen receptor antagonist flutamide to block endogenous androgen action and then conducted behavioral tests prior to puberty. Depression-like behaviors were assessed with the Forced Swim Test (FST) and the Sucrose Preference Test (SPT), and anxiety-like behaviors were assessed with the Open Field Test (OFT) and the Novelty-Suppressed Feeding Test (NSFT). Compared to the vehicle-treated controls, neonatal-flutamide treatment caused a significant increase in depression-like behaviors in preadolescent male rats but did not cause any significant difference in anxiety-like behaviors. In separate experiments, male pups with and without flutamide treatment were injected with 5-bromo-2′-deoxyuridine-5′-monophosphate (BrdU) from postnatal day (PND) 1 to 4 to label newly produced cells or the hippocampi were Golgi-Cox imbedded and pyramidal neurons visualized. Three lines of evidence indicate neonatal flutamide treatment inhibits hippocampal neurogenesis and neuronal dendritic spine formation in preadolescent male rats. Compared to vehicle controls, flutamide treatment significantly decreased (1) the number of microtubal associated protein-2+ (MAP-2) neurons in the CA1 region, (2) the number of MAP-2+ neurons in the dentate gyrus (DG) region of the hippocampus, and (3) the density of dendritic spines of pyramidal neurons in the CA1 region. However, there was no effect of flutamide treatment on the number of glial fibrillary acidic protein (GFAP)+ or GFAP+/BrdU+ cells in the hippocampus. This study suggests that the organizational effect of androgen-induced hippocampal neurogenesis is antidepressant.     

Play fighting in androgen-insensitive tfm rats: evidence that androgen receptors are necessary for the development of adult playful attack and defense

The frequency of playful attack and the style of playful defense, are modifiable by gonadal steroids and change after puberty in male and female rats. The present study examined the play behavior exhibited by testicular feminized mutation (tfm)-affected males, who are insensitive to androgens but can bind estrogens aromatized from androgens, to determine the relative contributions of androgens and estrogens to the age-related changes in play behavior. tfm males did not exhibit a decrease in playful attack with age and were more likely to maintain the use of complete rotations, a juvenile form of playful defense, into adulthood. tfm males did however, show age related changes in the use of partial rotations and upright postures, two other forms of playful defense, that were similar to normal males. These data suggest that the development of play fighting and defense in males is dependent on both androgen- and estrogen-receptor-mediated effects.     

Sex differences in juvenile rhesus macaque (Macaca mulatta) agonistic screams: life history differences and effects of prenatal androgens

This study investigated sex differences in juvenile rhesus macaque (Macaca mulatta) vocal behavior during agonistic contexts, and the effects of prenatal androgens on these differences. A total of 59 subjects (5-8 per treatment group) received exogenous androgen (testosterone enanthate), an anti-androgen (flutamide) or vehicle injections (DMSO) for 30 or 35 days during the second (early) or third (late) trimester of pregnancy. An additional 19 unmanipulated controls were included in the analysis. Screams by juvenile males and females between the ages of 1 and 3 years were compared to the screams of adult female exemplars using a discriminant function analysis. Juvenile females produced more adult-female like screams than did juvenile males. Females exposed to androgen treatment late in gestation produced a more masculine pattern of screams. Flutamide treatment in males either early or late in gestation did not significantly affect scream production. Flutamide treatments in females late in gestation, however, masculinized scream production. Androgen treatments administered late in gestation hyper-masculinized male scream production. No sex differences in the contextual usage of screams emerged. These findings suggest that both life history differences and the early hormone environment contribute to sex differences in juvenile rhesus macaque vocal production.     

Influence of endothelium in the in vitro vasorelaxant effect of magnesium on aortic basal tension in DOCA-salt hypertensive rat.

The objective of this study was to examine the influence of the endothelium on the extracellular magnesium induced relaxation of basal tension in isolated aortas from both mineralocorticoid-salt (DOCA-salt) hypertensive and control normotensive Sprague Dawley male rats. After incubation in magnesium-free physiological salt solution (PSS) (O mM magnesium), the increase of extracellular magnesium (1.2; 4.8 mM magnesium) caused a decrease in aortic tone which was significantly greater when endothelium was disrupted. Magnesium-induced relaxation was also more pronounced when endothelial NO production was blocked by 10(-4) M N omega-nitro-L arginine methyl ester (L-NAME). It is suggested that the vasorelaxation induced by extracellular magnesium is linked to the level of aortic basal tension developed in magnesium-free PSS. The endothelium does not seem to be directly implicated in magnesium-induced vasorelaxation in aortas from normotensive rats. However, in DOCA-salt hypertensive rats, the magnesium-induced relaxation of basal tension was less in the intact aorta (though not when the endothelium was disrupted) when the cyclo-oxygenase pathway was blocked by 10(-6) M indomethacin. These data therefore suggest that extracellular magnesium can promote relaxation by endothelium-dependent and cyclo-oxygenase-dependent mechanisms such as the production of relaxing prostacyclin in isolated aorta from DOCA-salt hypertensive rats.     

Play,copulation, anatomy,and testosterone in gonadally intact male rats prenatally exposed to flutamide

The role of prenatal androgen on the differentiation of sexually dimorphic juvenile play and adult copulatory patterns was evaluated in male offspring of rats injected with 5 mg of the androgen receptor blocker flutamide (4'-nitro-3'-trifluoromethylisobutyranilide) from Days 11-21 of pregnancy. Rough-and-tumble play was incompletely masculinized in flutamide-exposed males at 31 days of age. The copulatory potential tested at 70 days of age was severely attenuated by prenatal flutamide. There was no ejaculatory behavior, low levels of intromissions, and depressed levels of nonintromittive mounting when the animals were tested while gonadally intact. Adult plasma levels of testosterone (T) were not different in flutamide-exposed males and controls, but testicular and epididymal weight, anogenital (AG) distance, and penile length were reduced. While reductions in intromittive mounting and ejaculatory behavior may be due to the abnormalities in the external genitalia, the incomplete masculinization of play and the reduction in nonintromittive mounting probably resulted from effects the androgen antagonist exerted on sexual differentiation of the central nervous system. These data suggest that androgen released prior to birth is needed for the full masculinization of juvenile play behaviors in the rat, just as it is for the adult copulatory pattern.     

Modulation of serotonin-induced vasospasm by endothelium and monoamine oxidase

Endothelial modulation of flow induced by intraluminal serotonin (5-HT) in isolated and perfused bovine coronary artery segments was studied. A constant-pressure continuous perfusion apparatus was utilized. Control coronary arteries were perfused with a fixed volume of serotonin-containing solution followed by a serotonin-free solution, and flow-rate changes during onset and relaxation of vasospasm were measured. Both monoamine oxidase inhibition by iproniazide and endothelium disruption by collagenase increased the rate of onset and magnitude of vasospasm. When the endothelium was intact the vasospasm continued to increase, reaching maximum well after the end of the serotonin perfusion, followed by slow relaxation toward baseline. This contrasted with de-endothelialized vessels in which the increase in contractile response terminated abruptly at the end of the serotonin perfusion and returned rapidly to baseline. Coronary arteries stimulated with prostaglandin F2 alpha responded similarly to de-endothelialized vessels stimulated by 5-HT, although further de-endothelialization of F2 alpha-stimulated vessels showed increased rates of onset and relaxation of vasospasm, suggesting a physical barrier role for the endothelium towards unmetabolized agents. These observations are consistent with the hypothesis that endothelial cells are capable of taking up, storing and subsequently releasing serotonin. The results suggest a protective role of the endothelium as a metabolic and physical barrier. This may represent an anatomical substrate favouring the development of localized vasospasm at sites where the endothelium is injured.     

长期去窦弓神经大鼠胸主动脉收缩和舒张功能的改变

目的:观察长期去窦弓神经(SAD)对大鼠胸主动脉收缩和舒张功能的影响。方法:10周龄SD大鼠行SAD术或假手术(Sham),用离体动脉环实验测定SAD术后4、8、16、32周和相应Sham组大鼠胸主动脉对去甲肾上腺素(NE)和氯化乙酰胆碱(ACh)的收缩和舒张反应。结果:SAD大鼠离体胸主动脉环对NE的收缩反应进行性强于Sham组,对ACh的舒张反应进行性弱于Sham组。结论:大鼠去窦弓神经后单纯血压不稳定可引起类似于实验性高血压动物模型的血管功能的改变。