Randomized, controlled trial of topical phenylephrine for fecal incontinence in patients after ileoanal pouch construction

INTRODUCTION: Fecal incontinence is experienced by some patients with an ileoanal reservoir pouch. The ₁-adrenergic agonist phenylephrine raises resting anal sphincter pressure in healthy volunteers and may be of value in these patients. METHODS: Twelve patients (7 female), median age 44 (range, 29–67) years were studied. All had fecal incontinence despite a noninflamed pouch of normal size and ultrasonographically structurally normal anal sphincter muscles. Patients were treated with topical 10 percent phenylephrine and placebo gels, allocated in random order in a double-blind, crossover study for two four-week periods. Before and during treatment, maximum resting anal sphincter pressure and anodermal blood flow were measured, a symptom questionnaire was completed, and incontinence score was determined using a validated scale. RESULTS: Six of 12 (50 percent) patients improved subjectively after phenylephrine compared with one on placebo (P=0.07). Four patients had complete cessation of incontinence with active treatment. Phenylephrine significantly reduced the incontinence score (P=0.015). It also resulted in a significant rise in mean maximum resting anal sphincter pressure when compared with placebo (P=0.012). For all 12 patients, mean percent subjective improvement was higher after phenylephrine compared with placebo (P=0.04). There were no side effects. CONCLUSIONS: Topical phenylephrine significantly improves fecal continence in patients with an ileoanal pouch. In some patients it totally eliminates nocturnal episodes. The mechanism of benefit is likely to be one of altered neural sphincter control. This is the first study of the use of a topical pharmacologic agent to treat fecal incontinence and may have a wider application.E. Carapeti is supported by the Robert Luff Foundation. Abstract presented at the meeting of the Association of Coloproctology of Great Britain and Ireland, Jersey Channel Island, June 28 to July 1, 1998.     

Lack of correlation between the positive inotropic effect evoked by alpha-adrenoceptor stimulation and the levels of cyclic AMP and/or cyclic GMP in the isolated ventricle strip of the rabbit.

In electrically driven isolated right ventricle strips of the rabbit, phentolamine (10^?6m) shifted the dose-response curve for the positive inotropic effect of phenylephrine by about 1.0 log unit to the right, whereas pindolol (3 × 10^?8m) shifted only its upper part to the right. Under the blockade of β-adrenoceptors by 3 × 10^?8m pindolol, phenylephrine (3 × 10^?5m) increased the contractile force of the ventricular strips without changing the levels of cAMP and cGMP; inhibition of the phosphodiesterase by papaverine (10^?5m) did not influence these effects of phenylephrine. Isoprenaline (3 × 10^?7m) produced a rise of the cAMP-content preceding the increase of the contractile force; the cGMP-level, however, remained unchanged. 10^?6m phenylephrine, a concentration, which stimulates predominantly α-adrenoceptors, did not influence the effects evoked by isoprenaline. From the present results it is concluded, that in the ventricular myocardium of the rabbit there exist α-adrenoceptors mediating the positive inotropic effect and that the stimulation of α-adrenoceptors does not influence the cAMP- and cGMP-generating system, neither its basal nor its stimulated activity.     

pcDNA3-HERG转染抑制苯肾上腺素诱导的心肌细胞肥大的动物实验

目的 探讨HERG基因真核表达质粒pcDNA3-HERG（编码人快激活延迟整流钾通道α亚单位）转染抑制α1肾上腺素能受体激动剂苯肾上腺素（phenylephrine，PE）诱导的乳兔心室肌细胞肥大的电生理机制。方法 培养乳兔心室肌细胞，观察10μmol／LPE作用6h和48h心肌肥大指标（细胞体积、总蛋白含量及膜电容）、动作电位时限（APD）及钙调神经磷酸酶（CaN）活性的变化；以真核表达质粒pcDNA3-HERG转染心室肌细胞，观察转染细胞经PE诱导48h后上述指标的变化。结果 PE作用6h，心室肌细胞动作电位复极达90％时限（APD90）延长14．3％（P〈0．05），而此时并无心肌肥大和CaN活性增加。PE作用48h，心室肌细胞APD90延长18．8％（P〈0．05），细胞体积、总蛋白含量、膜电容以及CaN活性分别增加40．0％、41．8％、36．4％、124．1％（P〈0．01）；pcDNA3-HERG转染可过度表达ⅠHERG，其尾电流密度约为未转染HERG组快激活延迟整流钾电流（ⅠKr）尾电流密度的4倍（P〈0．05），可促进复极，明显缩短PE引起的APD90延长（P〈0．05），显著抑制PE诱导心肌肥大和CaN活性增加。结论 PE诱导乳兔心室肌细胞肥大过程中，APD延长并非继发于而是早于心肌肥大。APD延长，继而导致Ca^2＋内流和胞内Ca^2＋增加，激活CaN信号通路可能在PE诱导心肌肥大中起重要作用。     

盐酸苯福林滴眼液的含量测定及NaHSO_3对其pH的影响

目的考察盐酸苯福林滴眼液pH值的变化,在此基础上选择最佳pH稳定剂,建立双波长分光光度法测定盐酸苯福林滴眼液的含量。方法配制加抗氧剂,不加抗氧剂,以及加抗氧剂与pH值稳定剂的盐酸苯福林滴眼液,以溶液的pH值为指标,考察亚硫酸氢钠对其pH值的影响并筛选出最佳pH值稳定剂;同时采用双波长紫外分光光度法,以273 nm为测定波长,240.4 nm为参比波长测定盐酸苯福林滴眼液的含量。结果在酸性条件下亚硫酸氢钠可致盐酸苯福林滴眼液的pH值下降,且药液的pH值越高,pH下降幅度越大;加入pH值稳定剂枸橼酸钠的药液pH下降的幅度最小。盐酸苯福林在10¹20μg/ml的范围浓度内线性关系良好(r=0.999 9),平均回收率为98.7%,RSD为0.21%。结论盐酸苯福林滴眼液pH值下降是因亚硫酸氢钠被氧化所致,加入枸橼酸钠可使pH下降幅度最小。双波长紫外分光光度法测定盐酸苯福林滴眼液的含量简便,快速,准确,符合医院制剂快速检验的要求。     

不同剂量去氧肾上腺素静脉注射对腰麻下剖宫产产妇及新生儿的影响

目的观察不同剂量去氧肾上腺素静脉注射对腰麻下剖宫产产妇及新生儿的影响。方法择期腰麻剖宫产单胎产妇60例,随机均分为三组,在蛛网膜下腔注入0.5%重比重布比卡因2.5ml,鞘内注药后立即静脉泵注去氧肾上腺素150μg(P1组)、300μg(P2组)或等量生理盐水(C组)各3ml,速率1ml/min。若发生低血压时追加去氧肾上腺素100μg。监测并记录产妇SBP、DBP、HR、每搏输出量(SV)和心输出量(CO),以及低血压、高血压、恶心呕吐及心动过缓的发生次数。记录新生儿Apgar评分,并取脐带动静脉血行血气分析。结果与入室后比较,腰麻后1、5minC组SBP、DBP明显降低(P<0.05),P1、P2组无显著变化;腰麻后1、5min和分娩前1minP1、P2组HR明显减慢,C组仅在分娩前1min显著减慢(P<0.05);腰麻后1、5minP2组SV显著升高,腰麻后5minC组显著降低(P<0.05),且腰麻后5minP1、P2组明显高于C组(P<0.05);腰麻后5min和分娩前1minP1、P2组CO显著降低(P<0.05),分娩前1minC组也显著降低(P<0.05)。P1组和P2组低血压的发生率显著低于C组(P<0.05)。P1组和P2组分别有1例和3例高血压。结论小剂量去氧肾上腺素静脉输注能减少分娩前产妇低血压的发生率,对母体和胎儿影响较小。     

Metformin exaggerates phenylephrine-induced AMPK phosphorylation independent of CaMKKβ and attenuates contractile response in endothelium-denuded rat aorta

Metformin, a widely prescribed antidiabetic drug, has been shown to reduce the risk of cardiovascular disease, including hypertension. Its beneficial effect toward improved vasodilation results from its ability to activate AMPK and enhance nitric oxide formation in the endothelium. To date, metformin regulation of AMPK has not been fully studied in intact arterial smooth muscle, especially during contraction evoked by G protein-coupled receptor (GPCR) agonists. In the present study, ex vivo incubation of endothelium-denuded rat aortic rings with 3 mM metformin for 2 h resulted in significant accumulation of metformin (∼600 pmoles/mg tissue), as revealed by LC–MS/MS MRM analysis. However, metformin did not show significant increase in AMPK phosphorylation under these conditions. Exposure of aortic rings to a GPCR agonist (e.g., phenylephrine) resulted in enhanced AMPK phosphorylation by ∼2.5-fold. Importantly, in metformin-treated aortic rings, phenylephrine challenge showed an exaggerated increase in AMPK phosphorylation by ∼9.7-fold, which was associated with an increase in AMP/ATP ratio. Pretreatment with compound C (AMPK inhibitor) prevented AMPK phosphorylation induced by phenylephrine alone and also that induced by phenylephrine after metformin treatment. However, pretreatment with STO-609 (CaMKKβ inhibitor) diminished AMPK phosphorylation induced by phenylephrine alone but not that induced by phenylephrine after metformin treatment. Furthermore, attenuation of phenylephrine-induced contraction (observed after metformin treatment) was prevented by AMPK inhibition but not by CaMKKβ inhibition. Together, these findings suggest that, upon endothelial damage in the vessel wall, metformin uptake by the underlying vascular smooth muscle would accentuate AMPK phosphorylation by GPCR agonists independent of CaMKKβ to promote vasorelaxation.     

Extracellular catechol and indole turnover in the nucleus of the solitary tract of spontaneously hypertensive and Wistar-Kyoto normotensive rats in response to drug-induced changes in arterial blood pressure

Drug-induced alterations in arterial blood pressure are reflected in the extracellular fluid neurotransmitter levels of the nucleus of the solitary tract (NTS). Urethane-anesthetized spontaneously hypertensive rats (SHRs) and Wistar-Kyoto normotensive (WKY) rats were used in this study. The extracellular neurochemical profile of the NTS was quantified using the in vivo microdialysis technique. In SHR, phenylephrine-induced hypertension produced no significant changes in the extracellular norepinephrine (NE) and dihydroxyphenylacetic acid concentrations, whereas a significant increase in the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) concentration was observed. Wistar normotensive rats, in response to phenylephrine-induced hypertension, showed a significant increase in extracellular NE and 5-HIAA concentrations. Hypotension produced by the intravenous infusion of nitroprusside failed to show significant changes in the extracellular neurotransmitters in both SHR and WKY rats. However, there was a significant increase in 5-HIAA concentration in SHRs during the rebound hypertension, which followed the nitroprusside-infused hypotension. No such change was observed in the case of the WKY rats. These results suggest the possible involvement of the serotonergic mechanisms of NTS in the regulation of normal arterial blood pressure in these two rat strains.     

Influence of thyroid hormone on the positive inotropic effects mediated by α- and β-adrenoceptors in isolated guinea pig atria and rabbit papillary muscles

Effects of thyroxine treatment for 7–11 days on the positive inotropic effects mediated by α- and β-adrenoceptors were studied in isolated guinea pig atria and rabbit papillary muscles. In guinea pig atria, the thyroxine treatment inhibited the positive inotropic effect of lower concentrations of phenylephrine (PHE), and attenuated the inhibitory effect of phentolamine on the PHE response. The effect of isoproterenol (ISO) was potentiated by the thyroxine treatment. In rabbit papillary muscles, the thyroxine treatment shifted the dose—response curve for PHE to the right and attenuated the inhibitory effect of phentolamine on the PHE response. Propranolol, in both guinea pig atria and rabbit papillary muscles, inhibited the PHE response more effectively in preparations from thyroxine-treated animals than in controls. In guinea pig atria, the attenuation of the PHE response mediated by α-adrenoceptors was observed after the thyroxine treatment for only 2 days, whereas the potentiation of the ISO response required the thyroxine treatment for a longer period. It was concluded that the thyroxine treatment attenuated the positive inotropic effect mediated by α-adrenoceptors and potentiated that mediated by β-adrenoceptors in guinea pig atria and rabbit papillary muscles, and that the changes in the α- and β-adrenoceptor-mediated positive inotropic effects due to the thyroxine treatment may be independent of each other.     

去氧肾上腺素、麻黄素对腰硬联合麻醉下剖宫产母婴的影响

目的探讨和麻黄素相比,去氧肾上腺素用于腰硬联合麻醉下剖宫产,对母体和新生儿的影响。方法选择择期剖宫产术病人60例,ASAⅠ～Ⅱ级,随机分为两组。分别给予静脉泵注去氧肾上腺素100μg/ml(P组)和麻黄素3mg/ml(E组)维持术中收缩压在基础水平。记录术中HR、BP、SpO2、ECG,采集新生儿脐静脉、脐动脉血监测pH、PO2、PCO2,记录产妇术中恶心、呕吐发生率。结果E组术中HR、RPP高于P组(p<0.05);P组新生儿脐静脉血pH、PO2高于E组(p<0.05);P组术中恶心、呕吐发生率低于E组(p<0.05)。结论和麻黄素相比,去氧肾上腺素用于维持腰硬联合麻醉下剖宫产患者的术中血压,能降低新生儿酸中毒的发生率和降低产妇术中恶心、呕吐的发生率。     

EFFECTS OF GENDER AND AGE ON THE CARDIAC BARORECEPTOR REFLEX IN HYPERTENSION

The present study examined whether alterations in the cardiac baroreceptor reflex in hypertension may be a function of constitutional differences associated with gender and age. These hypotheses were tested using a cross-sectional design that compared 20 normotensive and 21 hypertensive men and women of varying age for differences in baroreceptor reflex sensitivity and response latency for heart rate, obtained using a modified bolus phenylephrine (Oxford) method.

Relative to their respective normotensive controls, baroreceptor reflex sensitivity was reduced in hypertensive men, but not in hypertensive women. Among normotensive subjects, men had greater baroreceptor reflex sensitivity than women. Independent from the effects associated with differences in blood pressure, age was not a significant predictor of reduction in baroreceptor reflex sensitivity. However, a combination of high blood pressure and older age was associated with a significant increase in baroreceptor reflex response time. In summary, gender and aging interacted with hypertension to alter two different aspects of the baroreceptor reflex. These results provide a preliminary indication that a decline in arterial baroreflex sensitivity may be more specific to hypertension in men than in women. Prolongation in baroreflex response latency in older hypertensive subjects also suggested that aging and hypertension may have a synergistic effect on cardiac parasympathetic function.