alpha1-adrenoceptor antagonists are first-line agents for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia, while their adverse effects on sexual function are reported frequently in recent years, especially the induction of ejaculatory dysfunction. This review presents the distribution of alpha 1-adrenoceptors in the male genital system and the relationship of alpha1-adrenoceptors with ejaculatory function. It also highlights the interesting phenomenon of ejaculatory dysfunction related to these drugs and its possible mechanism, with the intention to provide some essential clues for further research on this problem as well as some references to safer use of these drugs in clinical settings.
Adrenergic alpha-1 Receptor Antagonists ; Adrenergic alpha-Antagonists ; adverse effects ; pharmacology ; Ejaculation ; physiology ; Erectile Dysfunction ; chemically induced ; physiopathology ; Humans ; Male ; Receptors, Adrenergic, alpha-1 ; physiology

OBJECTIVETo study the biological activities of several alpha1-adrenoceptor antagonists in vitro.

METHODSThe anococcygeal muscle from male Sprague-Dawley rats (300-350 g) was isolated, removed and suspended in a 20-ml organ chamber containing Krebs solution at 37 degrees C, pH 7.4. The muscle preparations were set at a resting tension of 1.0 g and allowed to equilibrate for 1 h in the Krebs solution. After thorough washing, the anococcygeal muscle preparations were examined for the effects of the tested compounds with increased concentrations on its contractile/relaxant responses and the pA2 of antagonistic activity was assessed.

RESULTSSome of the target compounds displayed blocking activity to alpha1-adrenoceptor.

CONCLUSIONCompounds WB IV-1 and WB IV-3 showed good inhibiting activity, and were worth further studying.

Adrenergic alpha-1 Receptor Antagonists ; Adrenergic alpha-Antagonists ; pharmacology ; Anal Canal ; drug effects ; Animals ; In Vitro Techniques ; Male ; Muscle Contraction ; drug effects ; Rats ; Rats, Sprague-Dawley

Alpha1a-adrenergic receptor (AR) primarily mediates the contraction of the prostatic and cavernous smooth muscles. Among clinically available alpha1-AR antagonists for the medical management of benign prostatic hyperplasia (BPH), tamsulosin has a modest selectivity for alpha1A- and alpha1D- over alpha1B-ARs. To compare the effects of various alpha1-AR antagonists on relaxation responses of cavernous and trigonal smooth muscles, isometric tension studies with relatively selective (tamsulosin) and non-selective (prazosin, doxazosin, and terazosin) alpha1A-AR antagonists, were conducted in the cavernous and trigonal muscle strips of rabbits (n=10 each). Tamsulosin had the strongest inhibitory effect on contraction of trigonal smooth muscle among the various alpha1-AR antagonists, and the inhibitory activities of prazosin, doxazosin, and terazosin were not statistically different. All alpha1-AR antagonists caused concentration-dependent relaxation of the cavernous muscle strips. Tamsulosin was shown to have greater potency than prazosin (more than 100-fold), doxazosin (more than 1000-fold), and terazosin (more than 1000-fold), in relaxation of cavernous smooth muscle. In conclusion, tamsulosin might be the most effective drug among the four commonly used alpha1-AR antagonists for the medical management of BPH. Tamsulosin might be a potential substitute for phentolamine in combination with vasoactive agents as an intracavernous injection therapy for patients with erectile dysfunction.
Adrenergic alpha-Antagonists/pharmacology* ; Animal ; Comparative Study ; Doxazosin/pharmacology* ; In Vitro ; Muscle Contraction/drug effects ; Muscle Relaxation/drug effects* ; Muscle, Smooth/physiology ; Muscle, Smooth/drug effects* ; Prazosin/pharmacology* ; Rabbits ; Receptors, Adrenergic, alpha-1/antagonists & inhibitors* ; Sulfonamides/pharmacology*

OBJECTIVETo study the interactions between Ligusticum chuanxiong Hort extract and cardiac muscle membrane receptors.

METHODThe cell membrane of rabbit cardiac muscle was fixed on silicon to make cell membrane stationary phase (CMSP), and then the interactions were studied by comparing the retention characteristics of the extracts from different solvents with those of the antagonists or activators corresponding to known receptors in cardiac muscle membrane, and by competition effect on the retention characteristics of extracts when adding the antagonists or activators into the mobile phase.

RESULTWater extract and ethanol extract both had retentions on CMSP; the retention characteristics of water extract could be affected when water extract was in competition with the antagonists for alpha receptor, and could not be affected when with the activator beta1 receptor.

CONCLUSIONIt is possible that some components in water extract may combine with alpha receptor and no component with beta1 receptor, and that some components in ethanol extract may combine with cardiac muscle cell membrane. The process between active components and receptors in vivo can be imitated through the interactions between drugs and CMSP. The method provides references for the resolution of two applications: to screen the active components from Chinese medicine, and to figure out the type of receptors involved.

Adrenergic alpha-Agonists ; metabolism ; Adrenergic alpha-Antagonists ; metabolism ; Adrenergic beta-Agonists ; metabolism ; Adrenergic beta-Antagonists ; metabolism ; Animals ; Cell Membrane ; metabolism ; Chromatography, High Pressure Liquid ; methods ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Female ; Ligusticum ; chemistry ; Male ; Myocytes, Cardiac ; cytology ; metabolism ; Plants, Medicinal ; chemistry ; Protein Binding ; Rabbits ; Receptors, Adrenergic, alpha ; metabolism ; Receptors, Adrenergic, beta ; metabolism

PURPOSE: Fentanyl was reported to inhibit the alpha1-adrenoceptor agonist-induced contraction. The goal of this in vitro study was to identify the alpha1-adrenoceptor subtype primarily involved in the fentanyl-induced attenuation of phenylephrine-induced contraction in isolated endothelium-denuded rat aorta. MATERIALS AND METHODS: Aortic rings were suspended in order to record isometric tension. Concentration-response curves for phenylephrine (10-9 to 10-5 M) were generated in the presence or absence of one of the following drugs: fentanyl (3x10-7, 10-6, 3x10-6 M), 5-methylurapidil (3x10-8, 10-7, 3x10-7 M), chloroethylclonidine (10-5 M) and BMY 7378 (3x10-9, 10-8, 3x10-8 M). Phenylephrine concentration-response curves were generated in the presence or absence of fentanyl in rings pretreated with either 3x10-9 M prazosin, 10-9 M 5-methylurapidil or 3x10-9 M BMY 7378. RESULTS: Fentanyl (10-6, 3x10-6 M) attenuated phenylephrine-induced contraction in the rat aorta. 5-Methylurapidil and BMY 7378 produced a parallel rightward shift in the phenylephrine concentration-response curve. The pA2 values for 5-methylurapidil and BMY 7378 were estimated to be 7.71 +/- 0.15 and 8.99 +/- 0.24, respectively. Fentanyl (10-6 M) attenuated phenylephrine-induced contraction in rings pretreated with 10-9 M 5-methylurapidil, but did not alter the rings when pretreated with 3x10-9 M BMY 7378. Pretreatment of the rings with chloroethylclonidine showed a 72.9 +/- 2.3% reduction in phenylephrine-induced maximal contraction. CONCLUSION: The results suggest that fentanyl attenuates phenylephrine-induced contraction by inhibiting the pathway involved in the alpha1D-adrenoceptor-mediated contraction of the rat aorta.
Adrenergic alpha-Agonists/*pharmacology ; Adrenergic alpha-Antagonists/*pharmacology ; Animals ; Aorta/*drug effects ; Clonidine/analogs & derivatives/pharmacology ; Fentanyl/*pharmacology ; Male ; Phenylephrine/*pharmacology ; Piperazines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Vasoconstriction/*drug effects

AIMTo study the synthesis and anti alpha-adrenoceptor activity of 1,2-dihydro-quinoline-2-one compounds.

METHODSAcylation, bromination and cyclization, and substitute reactions were used in the synthesis of the title compounds IV. A proposed mechanism was showed to explain the unusual compounds 5 and 6 in the route C. The inhibition activity of the six target compounds were tested.

RESULTSTwelve new compounds were synthesized (II1-6 and IV1-6). Among them, six new compounds (IV1-6) are the title compounds. Structure of the title compounds were determined by IR, 1HNMR, MS and HRMS.

CONCLUSIONCompounds IV3, IV4 and IV6 showed inhibitiion activity, and were worth further studying.

Adrenergic alpha-Antagonists ; chemical synthesis ; pharmacology ; Animals ; Aorta ; drug effects ; In Vitro Techniques ; Molecular Structure ; Phenethylamines ; chemical synthesis ; pharmacology ; Quinolones ; chemical synthesis ; pharmacology ; Rabbits ; Receptors, Adrenergic, alpha ; drug effects ; metabolism ; Technology, Pharmaceutical

This study is to explore the possible mechanisms of the antidepressant-like effect of agmatine. By using two traditional "behavior despair" model, tail suspension test and forced swimming test, we examined the effects of some monoamine receptor antagonists (including beta-adrenergic receptor antagonist propranolol, beta-adrenergic receptor antagonist/5-HT1A/1B receptor antagonist pindolol, alpha2-adrenergic receptor antagonists yohimbine and idazoxan and 5-HT3 receptor antagonist tropisetron) on the antidepressant-like action of agmatine in mice. Activity of adenylate cyclase (AC) in the synapse membrane from rat frontal cortex was determined by radioimmunoassay. Single dose of agmatine (5-40 mg x kg(-1), ig) dose-dependently decrease the immobility time in tail suspension test in mice, indicating an antidepressant-like effect. The effect of agmatine (40 mg x kg(-1), ig) was antagonized by co-administration of beta-adrenergic receptor antagonist/5-HT1A/1B receptor antagonist pindolol (20 mg x kg(-1), ip), alpha2-adrenergic receptor antagonists yohimbine (5-10 mg x kg(-1), ip) or idazoxan (4 mg x kg(-1), ip), but not beta-adrenergic receptor antagonist propranolol (5-20 mg x kg(-1), ip) and 5-HT3 receptor antagonist tropisetron (5-40 mg x kg(-1), ip). Agmatine (5-40 mg x kg(-1), ig) also dose-dependently decrease the immobility time in forced swimming test in mice. The effect of agmatine (40 mg x kg(-1), ig) was also antagonized by pindolol (20 mg x kg(-1), ip), yohimbine (5-10 mg x kg(-1), ip), or idazoxan (4 mg x kg(-1), ip). Incubation of agmatine (0.1-6.4 micromol x L(-1)) with the synaptic membrane extracted from rat frontal cortex activated the AC in a dose-dependent manner in vitro. While the effect of agmatine (6.4 micromol x L(-1)) was dose-dependently antagonized by pindolol (1 micromol x L(-1)) or yohimbine (0.25-1 micromol x L(-1)). Chronic treatment with agmatine (10 mg x kg(-1), ig, bid, 2 w) or fluoxetine (10 mg x kg(-1), ig, bid, 2 w) increased the basic activity, as well as the Gpp (NH)p (1-100 micromol x L(-1)) stimulated AC activity in rat prefrontal cortex. These results indicate that regulation on 5-HT1A/1B and alpha2 receptors, and activation AC in the frontal cortex is one of the important mechanisms involving in agmatine's antidepressant-like action.
Adenylyl Cyclases ; metabolism ; Adrenergic alpha-Antagonists ; pharmacology ; Adrenergic beta-Antagonists ; pharmacology ; Agmatine ; administration & dosage ; pharmacology ; Animals ; Antidepressive Agents ; administration & dosage ; pharmacology ; Behavior, Animal ; drug effects ; Depression ; metabolism ; physiopathology ; Dose-Response Relationship, Drug ; Fenclonine ; pharmacology ; Idazoxan ; pharmacology ; Male ; Mice ; Pindolol ; pharmacology ; Random Allocation ; Rats ; Rats, Wistar ; Receptors, Biogenic Amine ; antagonists & inhibitors ; Serotonin 5-HT1 Receptor Antagonists ; Swimming ; Synapses ; enzymology ; Yohimbine ; pharmacology

Doxazosin, a high selective alpha1-adrenoceptor antagonist, is considered as the first-line therapy for the patients with benign prostatic hyperplasia (BPH) and also produce several side effects in cardiovascular system. In this study, we observed the isometric vasoconstrictive responses of the rabbit isolated arterial rings to electric field stimulation and noradrenaline ( NA ) to study the effects of R-doxazosin ( R-DOX ) and S-doxazosin ( S-DOX ) on the alpha1-adrenoceptor-regulated vasoconstrictive responses in the rabbit isolated ear artery, mesenteric artery and pulmonary artery, and the effects of higher concentration of S-DOX and R-DOX on presynaptic alpha2-adrenoceptor-regulated purinergic vasoconstriction in the rabbit isolated saphenous artery. We found that R-DOX and S-DOX competitively inhibited the vasoconstriction induced by NA in the rabbit isolated ear artery, mesenteric artery and pulmonary artery. The pA2 values of R-DOX and S-DOX against NA in the rabbit isolated ear artery, mesenteric artery and pulmonary artery were 7. 91 +/- 0. 03 and 7. 53 +/- 0. 05, 7. 80 +/- 0. 05 and 7. 29 +/-0. 07, 8. 32 +/- 0. 06 and 7. 97 +/- 0. 07, respectively. The pA2 values of R-DOX in the three arterial preparations were significantly higher than those of S-DOX (P < 0. 01). R-DOX and S-DOX at the concentrations of 0. 1 - 10 micromol x L (-1) did not affect the vasoconstriction induced by electric stimulation in the rabbit isolated saphenous artery. R-DOX and S-DOX at 100 micromol x L(-1) in the rabbit isolated saphenous artery completely inhibited the vascular responses to exogenous NA, but did not affect the vascular responses to exogenous adenosine triphosphate (1 mmol x L(-1) ). It is reasonable to suggest that R-DOX and S-DOX competitively inhibit the vasoconstriction induced by NA in the rabbit ear artery, mesenteric artery and pulmonary artery, and the pA2 values of S-DOX are significantly lower than those of R-DOX. The higher concentration (10 micromol x L(-1)) of R-DOX and S-DOX does not affect the presynaptic alpha2-adrenoceptors at sympathetic nerve terminals of the rabbit saphenous artery.
Adrenergic alpha-2 Receptor Antagonists ; Adrenergic alpha-Antagonists ; chemistry ; pharmacology ; Animals ; Blood Vessels ; drug effects ; physiology ; Dose-Response Relationship, Drug ; Doxazosin ; chemistry ; pharmacology ; Electric Stimulation ; In Vitro Techniques ; Male ; Mesenteric Arteries ; drug effects ; physiology ; Norepinephrine ; pharmacology ; Pulmonary Artery ; drug effects ; physiology ; Rabbits ; Receptors, Adrenergic, alpha-2 ; physiology ; Stereoisomerism ; Vasoconstriction ; drug effects

OBJECTIVETo investigate the antithrombotic effects and its molecular mechanisms of prazosin combined with anisodamine (Ani).

METHODSIsolated rat tail artery rings model was employed to evaluate the vasodilative effects of drugs, mice tail thrombosis model induced by carrageenan was used to study the antithrombotic effects and its molecular mechanisms of the drug composition.

RESULTSAmong alpha1-adrenoreceptor antagonists, prazosin(Pra) had the greatest relaxation rate, which was (82.6 +/- 8.9)%, and the EC50 value was 0.44 micromol/L. The drug composition of anisodamine and prazosin of different doses could decrease the length of the tail thrombosis from (24.6 +/- 4.6)mm to (6.9 +/- 2.7)mm, and the rate of thrombosis was decreased from 86.6% to 50.0%. The drug composition could prolong the prothrombin time (PT) distinctively, but it had no effect on the activated partial thromboplastin time (APTT). It also could restrain the decrease of serum levels of tissue plasminogen activator (t-PA) and 6- Keto -PGF1alpha as well as the increase of type-1 plasminogen activator inhibitor (PAI-1) and thromboxane B2 (TXB2) in the mice.

CONCLUSIONThe drug composition formed by anisodamine and prazosin has good effects of relaxing extremities tiny blood vessels and it can fight against thrombosis, its antithrombotic mechanisms may be related to the influence of the extrinsic coagulation pathway, inhibition of platelet activation functions and the promotion of fibrinolysis function.

Adrenergic alpha-1 Receptor Antagonists ; pharmacology ; Animals ; Disease Models, Animal ; In Vitro Techniques ; Male ; Prazosin ; pharmacology ; Rats ; Rats, Wistar ; Solanaceous Alkaloids ; pharmacology ; Thrombosis ; drug therapy

OBJECTIVETo study the effects of an alpha(1)-adrenoceptor antagonist, terazosin on the androgen-independent prostate cancer cell lines PC-3 and DU145.

METHODSTwo androgen independent cell lines, PC-3 and DU145, were used to determine cell viability, colony-forming ability, as well as cell cycle distribution, after exposure to terazosin. Western blot analysis was used to determine the expression of p21WAF1 and p27KIP1.

RESULTSThis study shows that terazosin inhibits not only prostate cancer cell growth but also its colony forming ability, both of which are main targets of clinical treatment. In addition, terazosin is shown to inhibit cell growth through G1 phase cell cycle arrest and the up-regulation of p27(KIP1).

CONCLUSIONThis study provides evidence that the alpha(1)-adrenoceptor antagonist terazosin may have therapeutic potential in the treatment of advanced hormone refractory prostate cancer.

Adrenergic alpha-Antagonists ; pharmacology ; Antineoplastic Agents ; pharmacology ; Cell Division ; drug effects ; Cell Line ; Humans ; Male ; Prazosin ; analogs & derivatives ; pharmacology ; Prostatic Neoplasms ; pathology ; Tumor Cells, Cultured