Effects of indoramin in rat vas deferens and aorta: concomitant alpha(1)-adrenoceptor and neuronal uptake blockade

1 the actions of the alpha(1)-adrenoceptor antagonist indoramin have been examined against the contractions induced by noradrenaline in the rat vas deferens and aorta taking into account a putative neuronal uptake blocking activity of this antagonist which could. result in self-cancelling actions.2 Indoramin behaved as a simple competitive antagonist of the contractions induced by noradrenaline in the vas deferens and aorta yielding pA(2) values of 7.38 +/- 0.05 (slope = 0.98 +/- 0.03) and 6.78 +/- 0.14 (slope = 1.08 +/- 0.06), respectively.3 When the experiments were repeated in the presence of cocaine (6 mu M) the potency (pA(2)) of indoramin in antagonizing the contractions of the vas deferens to noradrenaline was increased to 8.72 +/- 0.07 (slope = 1.10 +/- 0.05) while its potency remained unchanged in the aorta (pA(2) = 6.69 +/- 0.12; slope = 1.04 +/- 0.05).4 In denervated vas deferens, indoramin antagonized the contractions to noradrenaline with a potency similar to that found in the presence of cocaine (8.79 +/- 0.07; slope = 1.09 +/- 0.06).5 It is suggested that indoramin blocks alpha(1)-adrenoceptors and neuronal uptake in rat vas deferens resulting in Schild plots with slopes not different from unity even in the absence of selective inhibition of neuronal uptake. As a major consequence of this double mechanism of action, the pA(2) values for this antagonist are underestimated when calculated in situations where the neuronal uptake is active, yielding spurious pK(B) values.

Investigation of the Effects of a1-Adrenoceptor Antagonism and L-Type Calcium Channel Blockade on Ejaculation and Vas Deferens and Seminal Vesicle Contractility In Vitro

Introduction. Premature ejaculation is one of the most common male sexual dysfunctions. Current pharmacological treatments involve reduction in penile sensitivity by local anesthetics or increase of ejaculatory threshold by selective serotonin reuptake inhibitors. a1-Adrenoceptors (a1-ARs) and L-type calcium channels are expressed in the smooth muscles of the male reproductive tract, and their activations play an important role in the physiological events involved in the seminal emission phase of ejaculation.Aim. To evaluate if the inhibition of the contractility of the vas deferens and seminal vesicle by alpha(1)-AR antagonism or the L-type calcium channel blockade can delay ejaculation.Methods. The effects of the alpha(1)-AR antagonist tamsulosin and of the L-type calcium channel blockers, nifedipine and (S)-(+)-niguldipine, on contractions induced by norepinephrine in the rat vas deferens and seminal vesicles in vitro and on the ejaculation latency of male rats in behavioral mating tests were evaluated.Main Outcome Measure. Tension development of vas deferens and seminal vesicles in response to norepinephrine in vitro and behavioral mating parameters were quantified.Results. Tension development of vas deferens and seminal vesicle to alpha(1)-AR activation was significantly inhibited by tamsulosin, nifedipine, and (S)-(+)-niguldipine. Tamsulosin displayed insurmountable antagonism of contractions induced by norepinephrine in the rat vas deferens and seminal vesicle. Ejaculation latency of male rats was not modified by tamsulosin, nifedipine, or (S)-(+)-niguldipine; however, both the number and weight of the seminal plugs recovered from female rats mated with male rats treated with tamsulosin were significantly reduced.Conclusion. Seminal emission impairment by inhibition of vas deferens or seminal vesicle contractility by L-type calcium channel blockade or alpha(1)-AR antagonism is not able to delay the ejaculation. de Almeida Kiguti LR and Pupo AS. Investigation of the effects of alpha(1)-adrenoceptor antagonism and L-type calcium channel blockade on ejaculation and vas deferens and seminal vesicle contractility in vitro. J Sex Med 2012; 9: 159-168.

Multiple effects of sibutramine on ejaculation and on vas deferens and seminal vesicle contractility

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effects of swimming and nandrolone decanoate treatment on vas deferens response to norepinephrine

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Tissue alterations in the Guinea pig lateral prostate following antiandrogen flutamide therapy

The flutamide antiandrogenic effects oil the Guinea pig male prostate morphology in puberal, post-puberal and adult ages were evaluated in the present study. Daily-treated group animals received flutamide Subcutaneous injection at a dose of 10 mg/Kg body weight for 10 days. The control group animals received a pharmacological vehicle under the same conditions. The lateral prostate was removed, fixed and processed for light and transmission electron microscopy. The results revealed all increase of the acinus diameter in the treated puberal animals and straitness in the stromal compartment around the acini. The epithelial cells exhibited cubic phenotype. In the post-puberal and adult animals, a decrease of the acinus diameter was observed, as well as an increase of the smooth muscle layer and presence of the folds at epithelium. The ultrastructural evaluation of the secretory cells in the treated group demonstrated endomembrane enlargement, mainly in the rough endoplasmic reticulum and Golgi apparatus. In addition, a decrease of the microvilli and alterations in the distribution patterns and density of the stromal fibrillar components were observed. In Conclusion, the flutamide treatment exerts tissue effects oil the lateral prostate, promoting stroma/epithelium alterations.

The effect of L-arginine on guinea-pig and rabbit airway smooth muscle function in vitro

We have investigated the effects of L-arginine, D-arginine and L-lysine on airway smooth muscle responsiveness to spasmogens in vitro. Both L-arginine and D-arginine (100 mM) significantly reduced the contractile potency and maximal contractile response to histamine but not to methacholine or potassium chloride in guinea-pig epithelium-denuded isolated trachea. Similarly, the contractile response to histamine was significantly reduced by L-arginine (100 mM) in rabbit epithelium-denuded isolated bronchus. The amino acid L-lysine (100 mM) failed to significantly alter the contractile potency of histamine in guinea-pig isolated trachea (P>0.05). In guinea-pig isolated trachea precontracted with histamine, both L-arginine and D-arginine produced a concentration-dependent relaxation which was not significantly altered by epithelium removal or by the presence of the nitric oxide synthase inhibitor, NG-nitro L-arginine methyl ester (L-NAME; 50 µM). Thus, at very high concentrations, arginine exhibit a non-competitive antagonism of histamine-induced contraction of isolated airway preparations that was independent of the generation of nitric oxide and was not dependent on charge. These observations confirm previous studies of cutaneous permeability responses and of contractile responses of guinea-pig isolated ileal smooth muscle. Taken together, the data suggest that high concentrations of arginine can exert an anti-histamine effect.

Effect of cyproterone acetate on alpha1-adrenoceptor subtypes in rat vas deferens

Gonadal hormones regulate the expression of alpha1-adrenoceptor subtypes in several tissues. The present study was carried out to determine whether or not cyproterone acetate, an anti-androgenic agent, regulates the alpha1-adrenoceptor subtypes that mediate contractions of the rat vas deferens in response to noradrenaline. The actions of subtype selective alpha1-antagonists were investigated in vas deferens from control and cyproterone acetate-treated rats (10 mg/day, sc, for 7 days). Prazosin (pA2 ~9.5), phentolamine (pA2 ~8.3) and yohimbine (pA2 ~6.7) presented competitive antagonism consistent with activation of alpha1-adrenoceptors in vas deferens from both control and treated rats. The pA2 values estimated for WB 4101 (~9.5), benoxathian (~9.7), 5-methylurapidil (~8.5), indoramin (~8.7) and BMY 7378 (~6.8) indicate that alpha1A-adrenoceptors are involved in the contractions of the vas deferens from control and cyproterone acetate-treated rats. Treatment of the vas deferens from control rats with the alpha1B/alpha1D-adrenoceptor alkylating agent chloroethylclonidine had no effect on noradrenaline contractions, supporting the involvement of the alpha1A-subtype. However, this agent partially inhibited the contractions of vas deferens from cyproterone acetate-treated rats, suggesting involvement of multiple receptor subtypes. To further investigate this, the actions of WB 4101 and chloroethylclonidine were reevaluated in the vas deferens from rats treated with cyproterone acetate for 14 days. In these organs WB 4101 presented complex antagonism characterized by a Schild plot with a slope different from unity (0.65 ± 0.05). After treatment with chloroethylclonidine, the complex antagonism presented by WB 4101 was converted into classical competitive antagonism, consistent with participation of alpha1A-adrenoceptors as well as alpha1B-adrenoceptors. These results suggest that cyproterone acetate induces plasticity in the alpha1-adrenoceptor subtypes involved in the contractions of the vas deferens.

INVOLVEMENT OF SWIMMING-INDUCED ACUTE STRESS IN THE SENSITIVITY OF RAT VAS-DEFERENS TO NOREPINEPHRINE

1. The effects of swimming-induced stress on rat sensitivity to norepinephrine were studied.2. Through microscopic analysis of the stomach from swimming stressed rats significant ulceration was observed, confirming that the stress situation was really present.3. Sensitivity to norepinephrine either in the presence or in the absence of cocaine and propranolol in acutely swimming stressed rats was not altered significantly.4. Bilateral adrenalectomy was performed in rats 2 days before swimming and acute stress resulted in a supersensitivity to norepinephrine, indicating that adrenal glands may, at least, partially mediate the sensitivity to this drug in vasa deferentia isolated from these animals.

PHARMACOLOGICAL EVALUATION OF THE INHIBITORY EFFECT OF EXTRACTS FROM ANCHIETIA-SALUTARIS ON THE HISTAMINE-RELEASE INDUCED IN THE RAT AND THE GUINEA-PIG

The tea made with leaves and stems of plant Anchietia salutaris is traditionally used in Brazil to treat allergies. We examined the effects of a crude aqueous extract and of purified fractions of this plant on the histamine release induced in rat and guinea pig tissues. The crude extract (3-10 mu g/ml) inhibits the histamine release induced by compound 48/80 (0.5 mu g/ml) and antigen in rat peritoneal mast cells. The inhibition is significant after 10 s of preincubation and is completed after 3 min. The crude extract dissolved in the perfusion fluid (1-30 mu g/ml) also inhibits the histamine release induced in guinea pig heart by cardiac anaphylaxis and in hearts from pretreated animals (10-100 mg/kg i.p.). In pretreated animals, the effect manifests after 3 h, is maximum after 12 h and disappears after 48 h. The histamine release induced in isolated guinea pig heart by ionophore A23187 is inhibited by similar doses as in antigen-induced histamine release. Extraction with solvents concentrated the active principle (s) in the hexane fractions, as demonstrated by the inhibition of the histamine release induced by antigen in isolated cells from guinea pig heart dispersed with collagenase. In subfractions produced by the fractionation of the hexane fraction, the active principle(s) concentrated in the subfractions obtained by extraction with hexane and ethyl acetate, which shows the low polarity of the compound(s). The same subfractions that inhibit the histamine release induced by antigen in cells from guinea pig heart also inhibit pulmonary cells. Our result show that A. salutaris contains low-polarity compound(s) that inhibit the histamine release induced by three different mechanisms in mast cells from two animal species. These facts suggest that the active principle(s) of A, salutaris could be useful in the treatment of allergies and/or as a tool for the study of mast cell secretions.

The potentiation of the histamine release induced by adenosine in mast cells from guinea pig lung and heart: Sharp dependence on the time of preincubation

We studied here the effect of a wide range of adenosine concentration and time of preincubation, on the histamine release induced in the guinea pig mast cells by different stimulus. Adenosine (10(-5)-10(-3) M) potentiated the histamine release induced by antigen in the guinea pig heart (isolated and dispersed tissue) and lung mast cells but not induced by ionophore A23197. The potentiation caused by adenosine (10(-4) M) was maximum after 1-3 min of preincubation and is probably an extracellular effect since it was not avoided by dipyridamol (3 x 10(-7)-10(-6) M) that inhibit the uptake of adenosine. Similar potentiation was also produced by the adenosine mimetic 2-chloroadenosine (10(-5) M) and both effects were inhibited by 8-phenyltheophylline indicating an effect on the type A receptors. It is suggested that the adenosine potentiation may not be related to changes on the cyclic AMP levels. (C) 2000 Academic Press.

PHARMACOLOGICAL REACTIVITY OF RAT VAS-DEFERENS IN CHRONIC AND SUBACUTE LEAD-INTOXICATION

The influence of subacute and chronic lead intoxication on the responsiveness of the rat vas deferens was investigated by determining pD2 and relative responsiveness ratio (p) values for noradrenaline and for acetylcholine. Thus, the pD2 values of noradrenaline and acetylcholine from vas deferens of lead-treated rats were greater than those from normal rats, indicating that lead, in the dose and periods of treatment utilized, provoked a rise in vas deferens sensibility to noradrenaline and acetylcholine. Since it is known that the cirurgical or chemical denervation of the sexual ducts also provokes hypersensitivity, it may be suggested that this would be a possible mechanism for the observed alterations. A local lead toxic effect on the smooth muscle or at the level of androgen receptors should also be considered.