The Efficacy and Safety of Tamsulosin 0.2mg/day on Sexual Function in BPH: A Multicenter Open-label, Non-comparative, 3 Months Observational, Phase IV Prospective Study / 대한남성과학회지

PURPOSE: The aim of this study was to assess the efficacy and safety of tamsulosin, 0.2mg/day on sexual function in Korean BPH patients. Patients and Methods: 116 patients (mean age: 60 yrs) with BPH were enrolled in this study and 0.2mg of tamsulosin was administrated every night for 3 months. Primary efficacy was evaluated with changes of IIEF and GEQ. Secondary efficacy parameters were changes of IPSS and QoL, uroflowmetry, changes of total IIEF and IIEF domain score according to the severity of IPSS, and retrograde ejaculation. RESULTS: Before treatment, patients of moderate IPSS (8-19) and severe IPSS (20-35) were 56% and 44% and QoL3 were 33.6% and 66.4%. In primary efficacy evaluation, total IIEF score was significantly increased from 37.0+/- 18.2 to 40.5+/- 18.9 (p<0.01). All domains of IIEF except orgasmic function were significantly improved. GEQ showed improvement of erection in 34.4% and intercourse ability in 30.1%. In secondary efficacy evaluation, IPSS was significantly decreased from 18.4+/- 6.9 to 12.9+/- 6.7 (p<0.01) and QoL was significantly improved from 3.8+/- 1.1 to 2.7+/- 1.4 (p<0.01). Qmax significantly increased from 14.2+/- 8.3 to 16.5+/- 11.3 ml/sec (p<0.01). Total IIEF score and EF domain score were significantly improved from 36.8+/- 18.5 to 41.8+/- 19.1 (p<0.01) and from 13.0+/- 7.1 to 14.7+/- 7.9 (p<0.01) in patients of moderate IPSS but no improvement in severe patients. Retrograde ejaculation occurred in 2 patients (2%). No serious adverse reactions were observed. CONCLUSIONS: Tamsulosin, 0.2mg/day was effective and safe dose for the improvement of LUTS and sexual function for Korean BPH/LUTS patients.

Effects of Alpha 1 Adrenoceptor Antagonist Tamsulosin on Sexual Function in Patients with Benign Prostatic Hyperplasia / 대한남성과학회지

PURPOSE: We evaluated the effectiveness of alpha 1 adrenoceptor antagonist tamsulosin on erectile function in the treatment of the patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We recruited 268 patients who had BPH with lower urinary tract symptoms in the period of June 2003 to September 2003. The study utilized an open-label approach. Patients were evaluated by physical examination, transrectal ultrasonography (TRUS), serum prostate specific antigen (PSA), uroflowmetry, international prostatic symptom score (IPSS), quality of life (QOL) assessment, voiding diary for 3 days, brief international index of erectile function (IIEF)-7 score, and the global efficacy assessment questionnaire (GEAQ)-2. All evaluations were performed before medication, and again at 4 and 12 weeks of treatment. The patients suspected to have prostatic carcinoma based on the digital rectal examination and/or PSA level above 4 ng/ml underwent transrectal ultrasonography guided biopsy of the prostate. The patients found to have prostate cancer were not included in the study. RESULTS: A total of 165 patients completed the study. Total IIEF scores did not change significantly. Question 10 of IIEF was significantly different between 4 and 12 weeks. There was a statistically significant difference in GEAQ-2 between 4 and 12 weeks of medication. Ejaculation volume decreased 14% and 22% at 4 and 12 weeks, respectively. However, orgasmic function significantly improved between 4 and 12 weeks. CONCLUSIONS: In patients with BPH, tamsulosin therapy improved sexual and orgasmic function, although it decreased ejaculation volume. We need a longer follow-up period and more patients to establish the effects of tamsulosin on erectile function in the patients with BPH.

Diagnosis and treatment of bladder outlet obstruction caused by bladder neck fibrosis (report of 30 cases) / 中华泌尿外科杂志

Objective To present experience on the diagnosis and treatment of bladder outlet obstruction (BOO) caused by bladder neck fibrosis. Methods 30 cases of BOO caused by bladder neck fibrosis were studied. All the patients were treated by transurethral partial resection or incision of the cervix vesicae combined with alpha 1 adrenoceptor antagonists such as tamsulosin and terazosin or parazosin. Results Urination has been improved in all.The patients have been followed up for 3 to 30 months.On repeated uroflowmetry,the 30 patients showed the urine flow rates have been more than 15ml/s. IPSS scores was 5.3?1.7(25.4?4.2 preoperative) and quality of life scores was 1.4?0.6(4.1?0.8 preoperative).Fibroblast proliferation was noted in all the 30 and obvious chronic inflammation in 18. Conclusions Clinical symptoms, pressure rate measurement and cystoscopy are the reliable diagnostic methods.Transurethral partial resection or incision of cervix vesicae combined with alpha 1 adrenoceptor antagonists is effective.

Adrenergic sensitivity of uninjured C-fiber nociceptors in neuropathic rats

We investigated the adrenergic sensitivity of afferent fibers in the L4 dorsal roots of rats with a unilateral ligation of the L5-L6 spinal nerves. About 12% of nociceptive fibers on the affected side were excited by sympathetic stimulation or by intra-arterial injection of norepinephrine which did not affect A beta-fiber activity. Sympathetic excitation of nociceptive fibers was suppressed by alpha 1-antagonist prazosin, while it was unaffected by alpha 2-antagonist yohimbine. Most of these fibers were excited by intra-arterial injection of alpha 1-agonist phenylephrine, without being affected by an injection of alpha 2-agonist clonidine. Sympathetic excitation was blocked by lidocaine applied near the receptive fields of recorded fibers. The results suggested that some nociceptors remaining intact after partial nerve injury become sensitive to sympathetic activity by the mediation of alpha 1-adrenoceptors in the peripheral endings.

The Role of Spinal and Peripheral alpha1 Adrenoceptors in Micturition Reflex in Rats / 대한비뇨기과학회지

PURPOSE: The role of spinal alpha1 adrenoceptors in normal micturition reflex of rat has not been known clearly yet. The purpose of this study is to elucidate the role of alpha1 adrenoceptor both at the spinal and peripheral level in mediating the micturition reflex which is induced by bladder distension in normal anesthetized rat and to compare the effects of different alpha1 adrenoceptor antagonists against the micturition reflex. MATERIALS AND METHODS: Wtih eighty female Sprague-Dawley rats(200-250gm) anesthetized with urethane, continuous cystometry was done by infusion of saline at a rate of 0.5ml/min. The following drugs were injected into femoral artery(intraarterial, i.a.) and subarachnoid space(intrathecal, i.t.) at the level of L6-S1 spinal cord segment; phentolamine, prazosin, doxazosin and tamsulosin. Cystometric parameters were analyzed before and after the drug injections; basal pressure(BP), micturition pressure(MP), bladder capacity(BC), micturition volume(MV), frequency and residual volume(RV). RESULTS: After i.a. injections of prazosin, doxazosin and tamsulosin, MP was significantly decreased. Doxazosin(i.a.), markedly increased MV, BC and RV. MP was more inhibited by doxazosin than prazosin or tamsulosin injection intraarterially. After i.a. injection of phentolamine, decrease in MP and frequency but increase in MV and BC were noted. Phentolamine(i.t.) raised BP and abolished MR followed by overflow incontinence. Prazosin(i.t.) induced marked increases in MV. Tamsulosin(i.t.) caused significant decreases in frequency but increases in BC. CONCLUSIONS: At spinal level, antagonism of micturition reflex evoked by bladder distension was more prominent by phentolamine. Inhibition of micturition reflex with alpha1 adrenoceptor blockers were greater peripherally. With these results, it could be suggested that micturition reflex evoked by volume-induced bladder distension could be modulated through alpha1 adrenoceptors at both the spinal and peripheral level. In some selected cases, alpha1 adrenoceptor agonist or antagonist can be useful for the management of lower urinary tract dysfunction

Pharmacological characterization of synthetic tetrahydroisoquinoline alkaloids, YS 51 and YS 55, on the cardiovascular system

Tetrahydroisoquinoline (THI) alkaloids can be considered as cyclized derivatives of simple phenylethylamines, and many of them, especially with 6,7-disubstitution, demonstrate relatively high affinity for catecholamines. Two -OH groups at 6 and 7 positions are supposed to be essential to exert beta-receptor activities. However, it is not clear whether -OH at 6,7 substitution of THIs also shows alpha-adrenoceptor activities. In the present study, we investigated whether -OH or -OCH3 substitutions of 6,7 position of THIs differently affect the alpha1-adrenoceptor affinity. We synthesized two 1-naphthylmethyl THI alkaloids, 1-beta-naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline HBr (YS 51) and 1-beta-naphthylmethyl-6, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline HCl (YS 55), and their pharmacological actions on alpha1-adrenoceptor were compared. YS 51 and YS 55, concentration-dependently relaxed endothelium-denuded rat thoracic aorta precontracted with phenylephrine (PE, 0.1 micrometer) in which pEC50 were 5.89+0.21 and 5.93+ 0.19, respectively. Propranolol (30 nM) did not affect the relaxation-response curves to YS 51 and YS 55. Concentration-response curves to PE were shifted to right by the pretreatment with YS 51 or YS 55. The pA2 values of YS 51 and YS 55 showed 6.05 + 0.24 and 5.88 + 0.16, respectively. Both probes relaxed KCl (65.4 mM)-contacted aorta and inhibited CaCl2-induced contraction of PE-stimulated endothelium-denuded rat thoracic aorta in Ca2+-free solutions. In isolated guinea pig papillary muscle, 1 and 10 micrometer YS 51 increased contractile force about 4- and 8- fold over the control, respectively, along with the concentration-dependent increment of cytosolic Ca2+ ions. While, 10 micrometer YS 55 reduced the contractile force about 50 % over the control and lowered the cytosolic Ca2+ level, in rat brain homogenates, YS 51 and YS 55 displaced (3H)prazosin binding competitively with Ki 0.15 and 0.12 micrometer, respectively. However, both probes were ineffective on (3H)nitrendipine binding. Therefore, it is concluded that two synthetic naphthylmethyl-THI alkaloids have considerable affinity to alpha1-adrenenoceptors in rat aorta and brain.

A new member of alpha 1-adrenoceptor-coupled G alpha h (transglutaminase II) family in pig heart: purification and characterization

We previously reported an identification of a 77-kDa GTP-binding protein that co-purified with the alpha 1-adrenoceptor following ternary complex formation. In the present paper, we report on the purification and characterization of this GTP-binding protein (termed G alpha h5) isolated from pig heart membranes. After solubilization of pig heart membranes with NaCl, G alpha h5 was purified by sequential chromatographies using DEAE-Cellulose, Q-Sepharose, and GTP-agarose columns. The protein displayed high-affinity GTP gamma S binding which is Mg(2+)-dependent and saturable. The relative order of affinity of nucleotide binding by G alpha h5 was GTP > GDP > ITP >> ATP > or = adenyl-5'-yl imidodiphosphate, which was similar to that observed for other heterotrimeric G-proteins involved in receptor signaling. Moreover, the G alpha h5 demonstrated transglutaminase (TGase) activity that was blocked either by EGTA or GTP gamma S. In support of these observations, the G alpha h5 was recognized by a specific antibody to G alpha h7 or TGase II, indicating a homology with G alpha h (TGase II) family. These results demonstrate that 77-kDa G alpha h5 from pig heart is an alpha 1-adrenoceptor-coupled G alpha h (TGase II) family which has species-specificity in molecular mass.

Regulation of Mg2+ release in guinea pig heart and isolated ventricular myocytes by alpha1-adrenergic stimulation

Mg2+ is the fourth most abundant cation in cellular organisms. Although the biological chemistry and the physiological roles of the magnesium ion were well known, the regulation of intracellular Mg2+ in mammalian cells is not fully understood. More recently, however, the mechanism of Mg2+ mobilization by hormonal stimulation has been investigated in hearts and in myocytes. In this work we have investigated the regulation mechanism responsible for the Mg2+ mobilization induced by alpha1-adrenoceptor stimulation in perfused guinea pig hearts or isolated myocytes. The Mg2+ content of the perfusate or the supernatant was measured by atomic absorbance spectrophotometry. The elimination of Mg2+ in the medium increased the force of contraction of right ventricular papillary muscles. Phenylephrine also enhanced the force of contraction in the presence of Mg2+/-free medium. alpha1-Agonists such as phenylephrine were found to induce Mg2+ efflux in both perfused hearts or myocytes. This was blocked by prazosin, a alpha1-adrenoceptor antagonist. Mg2+ efflux by phenylephrine was amplified by Na+ channel blockers, an increase in extracellular Ca2+ or a decrease in extracellular Na+. By contrast, the Mg2+ influx was induced by verapamil, nifedipine, ryanodine, lidocaine or tetrodotoxin in perfused hearts, but not in myocytes. W7, a Ca2+/calmodulin antagonist, completely blocked the phenylephrine-, A23187-, veratridine-, Ca2+/-induced Mg2+ efflux in perfused hearts or isolated myocytes. In addition, Mg2+ efflux was induced by W7 in myocytes but not in perfused heart. In conclusion, An increase in Mg2+ efflux by alpha1-adrenoceptor stimulation in hearts can be through IP3 and Ca2+/-calmodulin dependent mechanism.

Relationship between Pressure Response to Repeated Elevation of Intracranial Pressure and Central alpha-Adrenoceptor in Rabbit

It is well documented that elevation of intracranial pressure is accompanied by arterial blood pressure(cushing response) in laboratory animals as well as in human. When the elevation of intracranial pressure(ICP) was repeated in a rabbit at an interval of 30-60 min, the blood pressure increased more promtly than in the first elevation of ICP, suggesting that mechanism involved in the pressure might be different. Therefore, this study was undertaken to clarify the pharmacological characteristics of the response to the first and repeated(second) elevation of ICP in urethane anesthetized rabbits. Increasing ICP, induced by infusion of saline into a ballooned in the epidural space, produced arise of the arterial blood pressure. When the blood pressure reached a peak, the balloon was suddenly deflated to reduced the ICP and blood pressure declined (the first ICP elevation experiment). After 30-60 min the same procedure was repeated (the second ICP-elevation experiment) Results are summarized as follows; 1) In the first ICP elevation experiment, the arise of ICP was relatively slow at the beginning of the infusion but became sharp as the infusion proceeded. When ICP increased sharply BP also increased abruptly and heart rate decreased. 2) In the second ICP elevation experiment, the slight decrease in BP which appeard at the beginning of the first ICP elevation experiment rat observed, so that only an abrupt arise of BP was seen. 3) Intravenous chlorisondamine inhibited the pressure responses in the second ICP elevation experiment. 4) Intraventricular corynanthine had little effect on the pressure response to the first ICP elevation but inhibited the pressure response to the second ICP elevation. 5) Intraventricular clonidine, yohimbine and prazosin little effect on the pressure response to the second ICP elevation. From this results that functional integrity of central alpha 2-adrenoceptor which took part in the pressure response to the first ICP elevation might have deranged in the second ICP elevation and that central alpha 1-adrenoceptors play a dominant role in the pressure response to the second ICP elevation.