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A M Traish

Publications and source records attributed to A M Traish.

81 records · Page 5Linked to original sources
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Interaction of cyproterone acetate with rat prostatic androgen receptors.

We have investigated the binding of cyproterone acetate (CA) to cytosolic androgen receptors (RC) and translocation of the RCCA complex into the nucleus. In a cell-free system (3H)CA binds to cytosolic androgen receptors with high affinity (KD = 11.6 nM) and limited capacity (180-200 femtomoles/mg protein). (3H)CA, however, dissociates very rapidly from the cytosolic and nuclear androgen receptors (Rn) at 0 degree C. Incubation of RC (3H)CA at 20 degrees C increased its ability to bind to nuclei. Translocation of RC (3H)CA to nuclei of intact cells was demonstrated after incubation of prostatic tissue with (3H)CA in tissue culture medium at 37 degrees C. In vivo administration of CA to castrated rats promoted RCCA translocation but did not induce androgen receptor replenishment. These data demonstrate that CA binds to and translocates androgen receptors to nuclei without concomitant receptor replenishment.

Androgen Antagonists↗
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Binding of (3H)7 alpha,17 alpha-dimethyl-19-nortestosterone (mibolerone) to progesterone receptors: comparison with binding of (3H)R5020 and (3H)ORG2058.

The binding characteristics of (3H)7 alpha,17 alpha-dimethyl-19-nortestosterone [3H)DMNT) to progesterone receptors (PgR) of calf uterine tissue cytosol were determined and compared to those of the synthetic progestins (3H)ORG2058 and (3H)R5020. Scatchard plot analysis of the equilibrium binding data showed that (3H)DMNT binds to calf uterine PgR with a KD of 2.35 +/- 1.1 nM. This value is slightly higher than that of (3H)R5020 (KD = 1.16 +/- 0.4 nM) and (3H)ORG2058 (KD = 1.04 +/- 0.65 nM). Analysis of dissociation kinetics showed that (3H)DMNT dissociates much more rapidly from the receptor than the other two ligands. Competition experiments showed that ORG2058 has a lower inhibition constant (Ki) than DMNT. Sucrose density gradient (SDG) analysis of PgR showed that (3H)ORG2058-PgR complexes sediment as 8S, (3H)R5020-PgR complexes sediment as 8S and 4S, and (3H)DMNT-PgR complexes sediment as 8S entities along with dissociated (3H)steroid. These data suggest that (3H)DMNT binds to PgR with lower affinity than (3H)ORG2058 and (3H)R5020. The number of binding sites detected with (3H)DMNT are significantly lower than those measured with (3H)ORG2058.

Animals↗
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Modulation of steroid affinity for the androgen receptor by sucrose.

The effects of sucrose on androgen binding to its receptor were investigated. Sucrose decreased the rate of thermal inactivation of unoccupied and occupied androgen receptor (AR) and the rates of [3H]5 alpha-dihydrotestosterone [( 3H]DHT) dissociation from both activated and nonactivated AR complexes. Binding of [3H]DHT to AR in vivo, or in intact cells at 37 degrees C, caused reduction of [3H]DHT dissociation from cytosolic and nuclear complexes, as compared to in vitro labeled receptor complexes. Further, exposure of these complexes to sucrose at 0 degrees C caused an additional reduction of dissociation rates. Thus, the decrease of [3H]DHT dissociation induced by sucrose is independent of the reaction that reduces DHT dissociation from activated and transformed AR. Sucrose also reduced the ability of mersalyl acid to inactivate AR complexes. This effect of sucrose was markedly diminished in the presence of 2M urea. Sucrose did not significantly affect the association rate, sedimentation properties, or nuclear binding ability of AR complexes, but it did decrease the equilibrium dissociation constant. Other monosaccharides and disaccharides also stabilized AR. These data suggest that sucrose induces conformational changes in the steroid binding domain of androgen receptor, thereby reducing the rates of inactivation, steroid dissociation, and the accessibility of sulfhydryl groups to mersalyl.

Animals↗
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Weapons of penile smooth muscle destruction: androgen deficiency promotes accumulation of adipocytes in the corpus cavernosum.

In men with erectile dysfunction, venous leakage is a common condition among non-responders to medical management and is attributed to penile smooth muscle atrophy. Androgens play a role in regulating trabecular smooth muscle growth and function. Further, androgens stimulate differentiation of progenitor cells into smooth muscle cells and inhibit their differentiation into adipocytes. We postulate that androgens exert a direct effect on penile tissue to maintain erectile function, and that androgen deficiency produces metabolic and structural imbalances in the corpus cavernosum, resulting in venous leakage and erectile dysfunction. To date, research efforts on the mechanisms by which androgens regulate penile erectile physiology have mainly focused on investigating the role of the NO/cGMP pathway. However, androgen-dependent mechanisms that regulate tissue remodeling have been poorly defined. Characterization of the molecular and cellular mechanisms by which androgens regulate corpus cavernosum structural and functional integrity would provide significant gains in knowledge and understanding of an important pathogenic process. In this review, we discuss the potential role of androgen in maintaining differentiation of progenitor cells into smooth muscle lineage and inhibition of differentiation into adipocytes. Androgen deficiency promotes differentiation into adipogenic lineage, and accumulation of adipocytes in the corpus cavernosum may contribute to erectile dysfunction.

Adipocytes↗
PubMedDate not supplied

Hemodynamic evaluation of the female sexual arousal response in an animal model.

The goal of this study was to assess the utility of existing and new techniques for characterizing and measuring hemodynamic changes in the vagina and clitoris in response to pelvic nerve stimulation (PNS) in an animal model. Using female New Zealand White rabbits, we measured the following parameters before, during, and after PNS at 4, 16, and 32 hertz (Hz): clitoral hemoglobin (Hb) content by laser oximetry, clitoral blood flow by laser Doppler flowmetry, vaginal luminal pressure of upper and lower segments, and clitoral intracavernosal pressure. Clitoral tissue concentrations of total and oxygenated hemoglobin (oxy-Hb) increased in a frequency-dependent manner while deoxygenated hemoglobin (deoxy-Hb) concentration decreased. The duration of the responses at 16 and 32 Hz were significantly greater than at 4 Hz. Clitoral blood flow increased significantly only at 32 Hz with a prolonged response duration, relative to 4 Hz. PNS caused vaginal luminal pressure changes that were highly variable, but qualitatively different, between the upper and lower regions. Clitoral intracavernosal pressure did not change significantly in response to PNS. Measurement of changes in tissue Hb content by the novel technique of laser oximetry provides a direct assessment of blood flow in a noninvasive manner and may prove to be a powerful tool in evaluating hemodynamic aspects of the female genital sexual response.

Animals↗
PubMedDate not supplied

Intracavernosal sildenafil facilitates penile erection independent of the nitric oxide pathway.

Sildenafil, in nanomolar serum levels, is an effective phosphodiesterase type 5 inhibitor, and facilitates penile erection only during sexual stimulation. However, there is limited information on the pharmacological activity of this agent when tissue levels approach millimolar concentrations following intracavernosal injection. The aim of this study was to investigate whether sildenafil causes penile erection in the absence of active neurogenic input. Organ bath preparations of rabbit penile cavernosal tissue strips were contracted with 1 microM phenylephrine and exposed to increasing concentrations of sildenafil in the absence or presence of the nitric oxide (NO) synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME; 0.6 mM). Sildenafil caused dose-dependent relaxation of rabbit cavernosal smooth muscle at high concentrations (>0.1 microM) with little or no effect at concentrations below 0.1 microM. The addition of L-NAME did not affect this response. In a separate protocol, sildenafil dose response determinations were performed in the presence of the guanylyl cyclase inhibitor, 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ; 3 microM) or vehicle (50% dimethyl sulfoxide [DMSO]). Relaxation to sildenafil in the presence of DMSO was significantly enhanced relative to sildenafil alone. ODQ treatment partially attenuated relaxation to sildenafil, but failed to completely inhibit the response. In cavernosal tissue strips, sildenafil elevated basal cyclic guanosine monophosphate (cGMP) levels twofold (0.54 vs. 1.10 pmol/mg prot). To further investigate these observations, anesthetized rabbits were injected intracavernosally with sildenafil (0.3-1.3 mg). In the absence of pelvic nerve stimulation, the magnitude and duration of the intracavernosal pressure increased in a dose-dependent fashion in response to sildenafil, approaching the systemic arterial pressure at higher doses. Intracavernosal administration of L-NAME, at doses that inhibited pelvic nerve stimulated penile erection, did not alter the response to intracavernosal sildenafil at 1.3 mg. Sildenafil, at the doses tested, did not significantly change the systemic arterial pressure. These data suggest that intracavernosal sildenafil, at tissue levels approaching millimolar concentrations, can cause relaxation of vascular smooth muscle and penile erection by a novel mechanism independent of the classical NO/cGMP pathway.

Animals↗