Regional differences in the density and subtype specificity of endothelin receptors in rabbit urinary tract

We investigated the binding characteristics of endothelin (ET) receptors in rabbit ureter, bladder dome, bladder base, and urethra and compared the observed receptor properties with those of cloned human ET_A and ET_B receptors expressed in Chinese hamster ovary K-1 (CHO) cells. Receptor binding experiments with [¹²⁵I]ET-1 revealed the presence of a single class of specific, saturable, high affinity [¹²⁵I]ET-1 binding sites in all of the regions of the studied urinary tract. The rank order of the densities (Borax values) of [¹²⁵I]ET-1 binding sites was: ureter bladder dome > bladder base = urethra. ET-1 and ET-2 inhibited [¹²⁵I]ET-1 binding to the membrane particulates from the various regions of the urinary tract with single high affinity constants. A selective ET_A receptor antagonist, BQ 123, and selective ET_B agonists, ET-3 and sarafotoxin S6c (STXc), inhibited [¹²⁵I] ET-1 binding to bladder dome, bladder base, and urethra with high and low affinity constants indicating the presence of both ET_A and ET_B receptor subtypes in these tissues. The subtype specificity of ET receptors in the rabbit tissues is confirmed with inhibition data obtained from similar binding studies in cloned human ET_A and ET_B receptors. The proportions of high affinity binding sites for ET-3, representing ET_B receptors, were approximately 25%, 27%, and 46% in bladder dome, bladder base, and urethra, respectively. Corresponding values for STXc were approximately 17%, 28%, and 43% in bladder dome, bladder base, and urethra, respectively. In contrast to the findings for ET-3 and STXc, the proportions of high affinity binding sites for BQ 123, representing ET_A receptors, in bladder dome, bladder base, and urethra were approximately 84%, 74%, and 60%, respectively. In ureter, these selective compounds inhibited [¹²⁵I]ET-1 binding with either a low (ET-3 and STXc) or a high binding affinity (BQ 123), suggesting the presence of only a single receptor subtype (ET_A) in this tissue. These data indicate that there are regional differences in the density and subtype specificity of ET receptors in the rabbit urinary tract.     

Synthesis, QSAR and calcium channel antagonist activity of new 1,4-dihydropyridine derivatives containing 1-methyl-4,5-dichloroimidazolyl substituents

A group of dialkyl and diarylester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 was replaced by a 1-methyl-4,5-dichloroimidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K(+)concentration of guinea-pig ileum longitudinal smooth muscle. The structure of all compounds was confirmed by IR,(1)H-NMR, and mass spectra. The calcium-channel antagonist activity of compounds 10a-f demonstrated that compound 10b was the most active and 10f the least active one. With unsymmetrical diesters 12a-k, the most active compound was the ethyl, phenethyl derivative. Structural parameters on the calcium-channel antagonist activity were evaluated by QSAR analysis and a linear correlation was found between the -log IC(50) values of these compounds and their constitutional and topological properties.     

Pharmacological effects of saw palmetto extract in the lower urinary tract

Saw palmetto extract （SPE）, an extract from the ripe berries of the American dwarf palm, has been widely used as a therapeutic remedy for urinary dysfunction due to benign prostatic hyperplasia （BPH） in Europe. Numerous mechanisms of action have been proposed for SPE, including the inhibition of 5a-reductase. Today, al-adrenoceptor antagonists and muscarinic cholinoceptor antagonists are commonly used in the treatment of men with voiding symptoms secondary to BPH. The improvement of voiding symptoms in patients taking SPE may arise from its binding to pharmacologically relevant receptors in the lower urinary tract, such as al-adrenoceptors, muscarinic cholinoceptors, 1,4-dihyropyridine receptors and vanilloid receptors. Furthermore, oral administration of SPE has been shown to attenuate the up-regulation of α1-adrenoceptors in the rat prostate induced by testosterone. Thus, SPE at clinically relevant doses may exert a direct effect on the pharmacological receptors in the lower urinary tract, thereby improving urinary dysfunction in patients with BPH and an overactive bladder. SPE does not have interactions with co-administered drugs or serious adverse events in blood biochemical parameters, suggestive of its relative safety, even with long-term intake. Clinical trials （placebo-controlled and active-controlled trials） of SPE conducted in men with BPH were also reviewed. This review should contribute to the understanding of the pharmacological effects of SPE in the treatment of patients with BPH and associated lower urinary tract symptoms （LUTS）.     

Phencyclidine increases the affinity of dihydropyridine calcium channel antagonist binding in rat brain

Summary Phencyclidine (PCP) significantly reduces the apparent dissociation constant (K _D) of the dihydropyridine (DHP) calcium channel antagonist, [³H]nitrendipine, in synaptosomal membranes of rat and mouse brain without significantly effecting the maximum binding capacity (B _max). At an optimum concentration of PCP (10 M) the apparentK _D of [³H]nitrendipine was reduced from 178±9 pM to 112±9 pM in rat forebrain, a 58% increase in affinity. The structural derivatives of PCP, P-Br-PCP {1-[1-(4-bromophenyl-cyclohexyl)piperidine]}, m-NH₂-PCP {1-[1-(3-anilo)-cyclohexyl]piperidine}, (±)-PCMP [1-(1-phenyl)-cyclohexyl-3-methylpiperidine] also increased the apparent affinity of [³H]nitrendipine in the following order, p-Br-PCP PCMp>PCP>m-NH₂-PCP. Local anesthetics either reduced the apparent affinity of [³H]nitrendipine or had no effect. Kinetic analysis revealed that PCP both increased the microassociation rate constant and decreased the microdissociation rate contant of [³H]nitrendipine. The magnitude of this enhanced binding varied with the brain region studied; the greatest increase in apparent affinity of [³H]nitrendipine was observed in striatum, while no significant increase in affinity was observed in brainstem. In some brain areas, PCP was more effective in reducing theK _D in crude homogenates than in washed tissue. PCP (10 M) did not alter theK _D of [³H]nitrendipine to rat cardiac tissue. Both Ca²⁺ and Mg²⁺ inhibited the effect of PCP, while monovalent ions were ineffective in this regard. These data are consistent with an allosteric modulation of DHP calcium channel antagonist binding sites by PCP and structural derivatives that is not mediated through the brain PCP binding site. This modulation of DHP binding sites may account for some of the psychopharmacologic actions PCP and related compounds in vivo.     

The behavioral effects of the calcium agonist BAY K 8644 in the mouse: Antagonism by the calcium antagonist nifedipine

Summary Mice injected with the calcium agonist BAY K 8644 (2–4 mg/kg, i. p.) displayed profound behavioral changes including ataxia, decreased motor activity, Straub tail, arched back, limb clonus and tonus, and an increased sensitivity to auditory stimulation. BAY K 8644 significantly impaired rotorod performance in mice with an ED₅₀ of 0.8 mg/kg. The behavioral effects of BAY K 8644 were antagonized by nifedipine, but not by the non-dihydropyridine calcium channel antagonist verapamil or the -adrenoceptor antagonist prazosin. Further, the actions of BAY K 8644 were not mimicked by the -adrenoceptor agonist methoxamine at doses up to 4.5 mg/kg. These observations, coupled with the findings that BAY K 8644 is a potent, competitive inhibitor of [³H]nitrendipine binding to the dihydropyridine binding site in mouse brain (K _i=7.0×10^–9M), suggests that BAY K 8644 may produce its behavioral actions via an interaction with the DHP binding site, which has been linked to the control of calcium flux across membranes in peripheral tissues.     

国产头孢呋辛治疗下呼吸道、泌尿道感染的随机对照、多中心临床试验

目的　评价国产头孢呋辛和进口头孢呋辛治疗感染性疾病的疗效和安全性。方法　随机、对照、多中心研究 ,每组 6 0例 ,其中下呼吸道、泌尿道感染各 30例 ,两药剂量均为每次 1.5 g,q8h,静滴 ,疗程 7～14 d。结果　国产和进口头孢呋辛治疗下呼吸道感染的临床痊愈率分别为 70 %和 6 0 % ,有效率均为 93.3% ;治疗泌尿是感染痊愈率分别为 93%和 83% ,有效率均为 10 0 % ,细菌清除率国产头孢呋辛组 96 .4 % ;进口头孢呋辛组 96 .3%。国产和进口头孢呋辛组不良反应发生率分别为 1.7%和 3.3%。两组疗效和不良反应无统计学差异 (P>0 .0 5 )。结论　国产头孢呋辛治疗下呼吸道感染、泌尿道感染性疾病安全、有效 ,与进口产品等效。     

Resistance of bacteria in urinary tract infections

Bacterial infection of the urinary tract is a common health problem in young women but also the most common nosocomial infection (>33%) contributing to the mortality of patients, and increasing the duration and cost of hospitalization. Escherichia coli is the most predominant organism and its prevalence varies in different studies. The high consumption of inappropriately prescribed antibiotics, combined with multiple pathology and frequent use of invasive devices, is a major factor contributing to high levels of resistance. There is a serious decrease in susceptibility of E. coli strains to amoxycillin, due to the presence of R-TEM enzymes, to cotrimoxazole and trimethoprim. Nitrofurantoin and fosfomycin-trometamol remain highly active against urinary Enterobacteriaceae, with over 90% of E. coli being susceptible. Knowledge of the most likely causative organisms and the prevalence of resistance pathogens to antimicrobial agents is essential to select antibiotics and to establish guidelines for the empirical treatment of urinary tract infections.     

加替沙星治疗急性泌尿系统感染疗效研究

目的评价加替沙星注射液治疗急性泌尿系统感染的临床疗效与安全性。方法采用随机单盲对照试验,以左氧氟沙星注射液为对照,两组药物的用量用法均为200mg、ivgtt、q12h、疗程7～14d。治疗前后均行尿液细菌学检查。结果加替沙星组和左氧氟沙星组的临床疗效和细菌清除率分别为84.62%、83.08%;91.8%、90.0%(P>0.05)。且两组药物的临床副反应率分别为9.2%与7.7%。结论加替沙星是治疗急性泌尿系统感染的安全、有效的抗生素。     

Effects of natural tachykinins on ovine lower urinary tract smooth muscle

1 Numerous studies have demonstrated that the urinary bladder is particularly sensitive to tachykinins; rat, rabbit and guinea pig bladders, besides human detrusor, have been the most extensively studied, whereas very little is known about most large animal detrusors. The aim of this work was to study natural tachykinin activity on the lower urinary tract of ovine to make a comparison with data obtained in laboratory animals. 2 As in other animal species, tachykinins are also able to contract ovine bladder smooth muscle. 3 The results reported in this study indicate that in ovine bladder, neurokinin 2 (NK2) receptors are expressed most. In fact, on lamb and sheep bladder neurokinin A (NKA), a NK2‐ almost selective peptide, was shown to be > 100% more active than the natural tachykinins kassinin (KASS) and eledoisin (ELED). Eledoisin was shown to be 50% less active than KASS, which is typical behaviour for an almost exclusively NK2 receptor population. Moreover, NK1‐ preferential peptides, namely substance P (SP) and physalaemin (PHYS), showed a lack of activity even when applied at high concentrations. 4 The results reported in this study show that lamb and sheep detrusor represent a good alternative model for the characterization of NK2‐selective tachykinins.     

舒氨新在治疗泌尿系统感染中的应用

自1995年8至10月份,单独使用舒氨新治疗泌尿系统感染患者40例,取得较好疗效。剂量:每日3～6克溶于5％的葡萄糖溶液中分两次静脉滴入,每次60～90分钟,连续用药7～14天。结果:痊愈22例(55％),显效15例(37.5％),进步1例(2.5％),无效2例(5％),总有效率为92.5％。     

Effects of natural tachykinins on porcine lower urinary tract smooth muscle

1. The aim of our study was to ascertain the possible differences and/or similarities in natural tachykinin activity in vitro on lower urinary tract of large-sized animals as compared with data obtained in laboratory animals. 2. Besides tachykinins normally present in mammals, namely substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), we tested non-mammalian tachykinins, such as eledoisin (ELED), physalaemin (PHYS), kassinin (KASS) and PG-kassinin II (PG-KASS II). 3. NKA, KASS and ELED were found to be the most potent peptides in contracting detrusor strips from porcine bladder. In particular, NKA showed a pD2 of 7.14, whereas KASS and ELED showed pD2 values of 7.20 and 7.22, respectively. The activity of NKB and PG-KASS II corresponded to 72.4 and 55.0% respectively of that of NKA. SP and PHYS activity corresponded to only 2% of that of NKA. 4. NKA (pD2 7.92) was the most active peptide in contracting bladder neck tissues as well. ELED and KASS were found to have lower, similar pD2 values (7.62 and 7.70, respectively), whereas NKB and PG-KASS II were much less active (pD2 7.12 and 6.74, respectively). Moreover, SP and PHYS showed an activity range lower than 2% of that of NKA. 5. The reported results confirm that, on pig vesical neck and detrusor, NK1 receptors represent a minority as compared with NK2 and NK3 receptors. By contrast, the presence of NK2 receptors is demonstrated by a greater potency of NKA. The presence of NK3 receptors both on detrusor and neck is evidenced by NKB activity and by results achieved with PG-KASS II.     

Clinical experience with indanyl carbenicillin in urinary tract infections

Summary

A trial was carried out in 30 patients to assess the effectiveness of indanyl carbenicillin in acute or chronic urinary tract infections, many of which were complicated by a pathological urological or medical condition. In all patients, infection was due to a single species of pathogen: E. coli (19), Proteus (6), and Pseudomonas (5). Oral doses of 1 g indanyl carbenicillin were given 6-hourlyfor an average of 10 days.

Results showed a clinical and bacteriological cure in 13 {43.8 %)patients. In 6 patients, although there was initial clinical improvement, the pathogen developed resistance during therapy. In 7 patients, there was super-infection with another organism. Four patients were withdrawn early in treatment because of side-effects, mainly gastrointestinal in origin. Indanyl carbenicillin proved very effective in eradicating all strains of Proteus and Pseudomonas and 12 (70.6%) of the 17 strains of E. coli in patients completing the full course of treatment.     

Proteinase-activated receptors in the lower urinary tract

Proteinase-activated receptors (PARs) are G-protein-coupled receptors that convert specific extracellular proteolytic activity into intracellular signals, and have been suggested to play diverse roles in the body. In this review, evidence for the roles of PARs in bladder contractility and inflammation are presented. The role of PARs in prostate cancer is also reviewed. The existing literature in this area can be difficult to interpret due to the many nonspecific actions of the pharmacological tools employed. Although there are reports that PAR activators can cause contraction of bladder smooth muscle, further pharmacological and molecular studies are required to define roles for these receptors in bladder contractility. While structural studies suggest that roles for PARs in bladder inflammation are likely, few functional investigations have been performed. The significance of the expression of PARs on sensory nerves innervating the bladder and changes in receptor expression in inflammatory disease models are fascinating areas for future research. Finally, it seems probable that PARs, particularly PAR₁, may play important roles in the growth and metastasis of prostate cancers.     

氨曲南联合头孢吡肟治疗泌尿系统感染疗效分析

目的 分析氨曲南联合头孢吡肟治疗泌尿系统感染的临床疗效.方法 123例泌尿系统感染患者,采用随机区组分组法分为观察组、对照1组和对照2组三组,每组41例.对照1组给予头孢吡肟治疗,对照2组给予氨曲南治疗,观察组则联合给予氨曲南和头孢吡肟,疗程均为7d.结果 观察组总有效率达95.1％,与对照1组(85.4％)和对照2组(82.9％)相比,差异均有统计学意义(x2=12.89、13.56,均P＜0.05).治疗结束后,观察组细菌清除率达94.3％,较对照1组和对照2组稍高.各组治疗过程中仅发生轻微不良反应,不影响继续用药,并且停药后症状消失.且各组不良反应发生率差异均无统计学意义(P＞0.05).结论 头孢吡肟联合氨曲南用于泌尿系统感染治疗,可提高治疗疗效,且不良反应没有增加.     

Responsiveness of smooth muscle in the lower urinary tract of rabbits to various agonists

• 1.1. We compared the responsiveness of smooth muscle in the lower urinary tract and prostate from rabbits to the agonists noradrenaline, phenylephrine, clonidine, acetylcholine, prostaglandin F_2α, and histamine.
• 2.2. These agonists contracted smooth muscle in the lower urinary tract and prostate. In terms of maximal developed tension, contractile responses to the agonists were produced in the following order of potency: acetylcholine>prostaglandin F_2α>histamine⩾phenylephrine⩾noradrenaline>clonidine in the urinary bladder body; acetylcholine=noradrenaline=phenylephrine>prostaglandin F_2α>histamine⩾clonidine in the urinary bladder base; noradrenaline⩾phenylephrine⩾clonidine>acetylcholine>prostaglandin F_2α⩾histamine in the urethra; and noradrenaline⩾phenylephrine>histamine= acetylcholine=clonidine=prostaglandin F_2α in the prostate.
• 3.3. These results suggest that considerable responsiveness variation occurs in the lower urinary tract and prostate and support the idea that the urinary bladder body is primarily governed by cholinergic mechanisms (parasympathetic nerves), whereas the urethra and prostate are regulated by α₁-adrenergic mechanisms (sympathetic nerves) and the bladder base by both.

     

Salidiuretic action of the calcium antagonist nitrendipine in dogs

Summary In an attempt to define the effects of a calcium antagonist, nitrendipine, on renal function, intrarenal hemodynamics, and renin release, we infused the drug into the renal artery of anesthetized dogs. Infusion of nitrendipine at a rate of 5 ltg/min in both hydropenic and hydrated dogs resulted in a significant increase in renal blood flow (RBF), glomerular filtration rate (GFR), urine flow and renin release, with no change in systemic blood pressure, indicating a significant renal vasodilation. The urinary excretion rate of sodium increased by the same proportion as that of calcium. The intrarenal blood flow as measured by hydrogen washout rate showed that the outer cortical flow increased by the same proportion as the inner cortical flow. During nitrendipine infusion, free water reabsorption rate ( ) in hydropenic dogs or free water clearance ( ) in hydrated dogs increased in proportion to the urine flow. Neither the ratio of nor that of to osmoral clearance changed throughout the experiment. These data suggest that nitrendipine may not inhibit sodium transport in the medullary portion of the ascending limb of Henle and may induce an enhancement of the delivery of sodium to the Henle loop. Thus, nitrendipine exerts its diuretic and natriuretic actions via the alteration of renal hemodynamic and the inhibitory effect on proximal sodium reabsorption. Send offprint requests to Y. Abe     

加替沙星与左氧氟沙星治疗尿路感染80例临床对比分析

目的：探讨加替沙星与左氧氟沙星治疗尿路感染的临床效果。方法：选择80例尿路感染患者,随机分为加替沙星组、左氧氟沙星组。两组分别用加替沙星0.2g/次,左氧氟沙星0.2g/次静脉滴注,均每日2次。疗程均为7～10天。结果：加替沙星组和左氧氟沙星组治疗尿路感染的有效率分别为97.5%,82.5%（P〈0.05）,细菌清除率分别为96.2%和84.3%（P〈0.01）;不良反应发生率分别为5%和7.5%。结论：加替沙星治疗尿路感染疗效确切、安全性高。     

常用国产和进口钙离子拮抗剂治疗高血压的成本-效果分析

目的在国产和进口的钙离子拮抗剂中寻求治疗高血压的最佳方案。方法利用已有的文献资料及临床调查研究,根据药物经济学的原理,采用成本-效果分析方法进行评价。结果国产非洛地平缓释（立方）片为治疗高血压的最佳治疗方案。结论在优化治疗方案、指导经济、合理用药等方面,成本-效果分析方法有着重要作用。     

左氧氟沙星序贯疗法治疗尿路感染可行性观察

目的探讨利用左氧氟沙星进行序贯疗法治疗尿路感染的临床疗效评价。方法选取笔者所在医院2010年6月~2011年6月收治的尿路感染患者共176例。观察组患者采用左氧氟沙星序贯疗法治疗;对照组采用常规的静脉注射左氧氟沙星注射液治疗。结果两组患者临床疗效差异无统计学意义(P>0.05),观察组患者的不良反应以及治疗费用均明显低于对照组(P<0.01)。结论利用左氧氟沙星序贯疗法治疗尿路感染能获得满意的临床效果,而且临床不良反应较少,费用较低,值得在临床上推广使用。     

女性泌尿系统病原学检测分析

目的 探讨女性泌尿系感染(UTI)病原菌的分布与特点,以提高临床诊治水平.方法 对129例以"尿道刺激症"为主诉的女性UTI患者的中段尿培养,阴道分泌物检测,并进行细菌学、支原体、衣原体、真菌、寄生虫鉴定.结果 129例女性UTI病原微生物为:革兰阴性菌(53.49%)、革兰阳性菌(19.38%),支原体(14.73%),真菌(9.30%)、衣原体(4.65%)、寄生虫(1.55%);其中分别又以大肠埃希菌、肺炎克雷伯菌、粪肠球菌、金黄色葡萄球菌感染多见;性传播疾病(27.91%)以非淋病性尿道炎多见;混合感染(17.38%)以解脲支原体合并其他感染为主,年龄多为青、中年.结论 女性UTI感染致病微生物以革兰阴性菌为主,性传播疾病、混合感染应引起临床医师重视,建议女性UTI患者常规进行病原学检测,以提高诊断治疗水平.