离子通道与阴茎勃起的关系

阴茎海绵体平滑肌的舒张是阴茎勃起的必要条件。近年来的研究显示：位于阴茎海绵体平滑肌细胞上的离子通道，是凋节阴茎海绵体舒缩的重要结构。因此，研究阴茎海绵体平滑肌细胞上的离子通道同阴茎勃起的关系，是当前的热点之一。本文就近年来关于离子通道与阴茎勃起关系的研究进展进行综述。     

K+通道在阴茎勃起中作用的研究进展

细胞间连接以及非连接性的离子通道是海绵体平滑肌张力调节的重要物质基础。后者中各种K 通道在细胞产生静息电位以及细胞活化后的跨膜电位中起重要作用。本文综述了各种K 通道在阴茎勃起生理过程中所起调节作用的机理 ,并探索作为海绵体平滑肌张力调节重要因素之一的K 通道在治疗阴茎勃起功能障碍中的应用前景     

离子通道在阴茎海绵体平滑肌紧张性调节中的作用

阴茎海绵体平滑肌舒张或收缩的调节 ,即海绵体平滑肌紧张性的生理学分别决定阴茎的勃起或疲软状态。众多的证据提示与其他血管组织一样 ,钾通道、钙通道是阴茎海绵体平滑肌紧张性的主要调节物质。在培养的海绵体平滑肌细胞和游离海绵体组织平滑肌条研究显示 :参与阴茎勃起的神经递质大多通过对平滑肌细胞离子通道及离子跨膜流动的作用而调节海绵体平滑肌紧张性。     

连接蛋白connexin43与阴茎勃起调控

连接蛋白43(Cx43)是构成阴茎海绵体平滑肌细胞缝隙连接的主要成分,Cx43的表达和缝隙连接的变化影响细胞间通讯,并调节阴茎海绵体平滑肌同步舒缩,参与阴茎勃起调控,现就这方面研究情况作一综述。     

K^＋能道在阴茎勃起中作用的研究进展

细胞间连接以及非连接 性的离子通道是海绵体平滑肌张力调节的重要物质基础。手者中各种K^ 通道在细胞产生静息电位以及细胞活化后的跨膜电位中起重要作用。本文综述了各种K^ 通道在阴茎勃起生理过程中所起调节作用的机理，并探索作为海绵体平滑肌张力调节重要因素之一的K^ 通道在治疗阴茎勃起功能障碍中的应用前景。     

勃起功能障碍患者及不同年龄与正常人阴茎海绵体平滑肌组织学观察

目的：了解正常及勃起功能障碍（ED）患者阴茎海绵体的差异和改变对阴茎勃起的影响。方法：取10例不同年龄正常及ED病人阴茎海绵体组织，镜下观察阴茎海绵体结构变化。结果：3例ED病人阴茎海绵体平滑肌细胞及弹力纤维减少。老年性阴茎海绵体平滑肌及弹力纤维明显减少。青壮年阴茎海绵体平滑肌细胞及弹力纤维极为丰富。结论：阴茎海绵体结构改变对阴茎勃起功能有较大的影响。     

高血压大鼠海绵体平滑肌细胞间连接的变化

目的:比较自发性高血压大鼠(SHR)和正常血压大鼠阴茎海绵体平滑肌细胞间连接改变及与阴茎勃起功能的关系。方法:注射阿朴吗啡(APO)观察14周龄SHR(SHR组,n=5)、W istar-Kyoto大鼠(WKY组,n=5)阴茎勃起情况,用透射电镜观察其阴茎海绵体平滑肌细胞间连接超微结构,RT-PCR测定海绵体平滑肌细胞Connexin 43的mRNA表达,免疫组化观察Connexin 43蛋白表达。结果:SHR组大鼠阴茎勃起次数明显低于WKY组(P<0.05),电镜发现SHR组大鼠阴茎海绵体平滑肌细胞间大量胶原纤维增生,Connexin 43蛋白及其mRNA表达较WKY组显著降低(P<0.05)。结论:高血压影响阴茎勃起功能,阴茎海绵体平滑肌细胞间连接的病理改变可能是高血压性勃起功能障碍的发病机制之一。     

PKB/Akt信号通路与阴茎勃起功能的关系

阴茎勃起是由神经内分泌调节下阴茎动脉和阴茎海绵体一系列血液动力学变化的过程.阴茎的勃起机制比较复杂,目前尚未完全明确.研究普遍认为,由一氧化氮合酶(NOS)催化合成的一氧化氮(NO)作为海绵体平滑肌舒张的重要调节因子,在阴茎勃起过程中发挥关键作用.NOS有三种亚型,分别命名为神经元型(nNOS)、内皮型(eNOS)和诱导型(iNOS).其中eNOS在阴茎中活性较高,在海绵体平滑肌松弛和阴茎勃起过程中起重要作用.蛋白激酶B (PKB/Akt)即作用于eNOS,使其磷酸化后激活,激活的eNOS进而催化合成NO,最后促进阴茎勃起.     

兔阴茎海绵体平滑肌细胞的快速分离及鉴定

目的探讨兔阴茎海绵体平滑肌细胞快速分离方法,为应用膜片钳技术研究阴茎勃起机制提供实验材料.方法采用木瓜蛋白酶和胶原酶两步酶解消化法,快速分离出新西兰大白兔阴茎海绵体平滑肌细胞并应用免疫组化鉴定.结果分离的细胞成活率较高,贴壁呈长梭形,胞膜光滑完整,胞浆均匀,可用于膜片钳记录.免疫组化鉴定为兔阴茎海绵体平滑肌细胞.结论酶解消化快速分离兔阴茎海綿体平滑肌细胞为全细胞膜片钳技术研究阴茎勃起功能障碍的电生理机制提供了较好的实验材料.     

阴茎海绵体平滑肌细胞表型转化及其影响因子的研究进展

阴茎海绵体平滑肌细胞是组成阴茎海绵体的主要功能成分,其表型转化是平滑肌细胞增殖和迁移的关键性起始步骤。因此,探讨平滑肌细胞表型转化的机制及其影响因子在阴茎勃起功能障碍的防治过程中具有重要意义。目前通常将平滑肌细胞分为收缩型(分化型)和合成型(未分化型、增殖型或去分化型)两种类型,并发现L转化生长因子(TGF-β)、转录因子E2F1、基本转录元件结合蛋白2(BTEB2)、胰岛素等因素可能影响平滑肌细胞表型转化。本文就近年来阴茎海绵体平滑肌细胞表型转化及其影响因子的研究进展作一简要综述。     

阴茎海绵体平滑肌细胞内信号转导研究进展

阴茎海绵体平滑肌细胞信号转导通路是海绵体平滑肌张力调节的细胞内分子机制。各种神经递质通过活化细胞膜受体蛋白或细胞内酶途径产生细胞外化学信号 ,细胞内第二信使分子和离子传递并放大这些信号 ,使平滑肌细胞舒张 ,最终诱发勃起。因此 ,海绵体平滑肌细胞信号转导的研究对于理解勃起生理学、勃起功能障碍的病理生理学以及开发治疗勃起功能障碍的新的选择性药物具有重要意义     

Pathophysiology of Erectile Dysfunction

Physiology of erection and pathophysiology erectile dysfunction is reviewed. Analysis is obtained from basic and clinical research including animals studies, anatomical studies, and molecular and cellular research on corporal tissue obtained during penile prosthesis implantation. Supraspinal influences and spinal influence on penile erection has been learned from spinal cord injury patient. Corporal smooth muscle relaxation of penile arteries and corpus cavernosum leads to penile erection, results from parasympathetic/nonadrenergic noncholinergic neural pathway activation and simultaneous inhibition of sympathetic outflow. Anatomical studies taught understanding of the mechanism for restriction of blood outflow from the corpora cavernosa. The change of smooth muscle tone has emerged as a key factor in erection and detumescence. Many independent factors converge on the modulation of corporal smooth muscle tone. Neuronal and local neurotransmitter effects via gap junction, potassium channels, and calcium channel. A nitric oxide/cyclic guanosine monophosphate mechanism as well as cyclic aminomonophosphate has an important role in mediating the corporal smooth muscle relaxation necessary for erectile function. Erectile dysfunction can be due to vasculogenic, neurogenic, hormonal, veno-occlusive, psychogenic and/or pharmacogenic factors as well as alterations in the nitric oxide/cyclic guanosine monophosphate (cGMP) or cyclic aminophosphate (cAMP) pathway or other regulatory mechanisms including gap junction or ionic channel resulting in an imbalance in corporal smooth muscle contraction and relaxation. Our present knowledge of the hemodynamics, functional anatomy, neurophysiology, and neuropharmacology of penile erection and dysfunction at the cellular and molecular level has led to better understanding of physiology and pathophysiology of erectile dysfunction.     

Recombinant PAI‐1 therapy restores myoendothelial junctions and erectile function in PAI‐1‐deficient mice

Myoendothelial junctions are specialised projections of cell : cell contact through the internal elastic lamina between endothelial cells and vascular smooth muscle cells. These junctions allow for endothelial cells and vascular smooth muscle cells to make direct membrane apposition and are involved in cell : cell communication. In this study, we evaluated for the presence of myoendothelial junctions in murine corporal tissue and used plasminogen activator inhibitor (PAI)‐1‐deficient mice, which lack myoendothelial junctions, to determine whether myoendothelial junctions affect erectile function. Transmission electron microscopy demonstrated the presence of myoendothelial junctions in the corporal tissue of wild‐type mice and confirmed the decreased junction numbers in the tissue of PAI‐1^?/? mice. A potential role for myoendothelial junctions in tumescence was established; in that, PAI‐1^?/? mice demonstrated a significantly longer time to achieve maximal intracavernous pressure. Treatment of PAI‐1^?/? mice with recombinant PAI‐1 restored the number of myoendothelial junctions in the corporal tissue and also induced a significant decrease in time to maximal corporal pressures. Myoendothelial junctions were similarly identified in the human corporal tissue. These results suggest a critical role for myoendothelial junctions in erectile pathophysiology and therapies aimed at restoring myoendothelial junction numbers in the corporal tissue may provide a novel therapy for erectile dysfunction.     

The “syncytial tissue triad”: a model for understanding how gap junctions participate in the local control of penile erection

Summary Recent findings from both clinical and experimental studies document the importance of syncytial relaxation and contraction of corporal smooth muscle to penile erection and detumescence, respectively. However, the mechanism(s) permitting coordinated response generation among the vast array of largely inexcitable corporal smooth muscle cells is unclear. In this report the compelling evidence for a major role of intercellular communication through gap junctions to erectile function is reviewed. Moreover, a novel concept is advanced to explain more fully the putative mechanistic basis for integrative erectile tissue biology. Specifically, the presence of gap junctions; in concert with the autonomic nervous system and myogenic intracellular signal transduction mechanisms, is postulated to form a syncytial tissue triad that is largely responsible for the local modulation of corporal smooth muscle tone. It is reasonable to assume that the existence of this syncytial tissue triad confers a plasticity, adaptability, and flexibility to erectile function that may well account for the observed diversity of mechanisms known to regulate penile erection as well as the multifaceted etiology of erectile dysfunction.     

Gap junctions and ion channels: relevance to erectile dysfunction

The corporal myocyte is a critical determinant of erectile capacity whose functional integrity, in the vast majority of impotent patients, is sufficient to guarantee its relevance as a therapeutic target. As with numerous other smooth muscle cell types, ion channels are important modulators of corporal smooth muscle tone/contractility. As such, the transmembrane flow of ions (ie Ca(2+), K(+) and Cl(-)) plays an important role in modulating membrane potential and contractile status in individual human corporal smooth muscle cells, while intercellular ion flow ensures the functionality of myocyte cellular networks. The integral membrane proteins that selectively regulate many aspects of these critical transmembrane (eg K(+) and Ca(2+) channels) and intercellular (eg gap junctions) ionic movements have been identified. To date, the large conductance calcium-sensitive K(+) channel (ie K(Ca)), the metabolically regulated K+ channel (ie K(ATP)), and the L-type voltage-dependent Ca(2+) channel appear to be the most physiologically relevant nonjunctional ion channels. With respect to intercellular ionic/solute/second messenger movement, connexin43-derived gap junction channels are widely recognized as an obligatory component to normal integrative erectile biology. The presence of an intercellular pathway ensures that individual cellular alterations are carefully orchestrated in the rapid and syncytial fashion required for normal erectile function. This report reviews the known details concerning junctional and nonjunctional ion channels in human corporal tissue, and illustrates how one particular application of this knowledge, that is, preclinical studies utilizing low efficacy gene therapy (ie low transfection efficiency) with the K(Ca) channel has further confirmed the physiological relevance and therapeutic potential of gap junctions and ion channels to erectile physiology/dysfunction. International Journal of Impotence Research (2000) 12, Suppl 4, S15-S25.     

Integrative erectile biology. The effects of age and disease on gap junctions and ion channels and their potential value to the treatment of erectile dysfunction

Initiation, maintenance, and modulation of corporal smooth muscle tone are critically dependent upon agonist-induced changes in intracellular calcium levels and mobilization as well as transmembrane calcium flux. The transient control of myocyte excitability and contractility at the cellular level is inextricably linked to membrane potential, which, in turn, is modulated by potassium ion efflux through one of the four known corporeal smooth muscle potassium ion channels. Corporal tissue responses are subsequently coordinated by means of the movement of intracellular second messenger molecules (i.e., IP3, cAMP, cGMP) and ions (i.e., K+ and Ca2+) among the corporal myocytes by means of intercellular communication through gap junction channels. Knowledge of the critical contribution of these interlinking cellular (nonjunctional ion channels [e.g., maxi-K]) and tissue (gap junction channels [e.g., connexin 43]) systems to the modulation of erectile capacity has provided the scientific rationale for the promulgation of the successful preclinical testing of hSlo ion channel gene therapy for the normalization of erectile status in both aged and diabetic rats.     

Prostaglandin E1 activates the large-conductance KCa channel in human corporal smooth muscle cells.

The large conductance calcium-sensitive potassium channel (KCa or maxi-K) is an important modulator of human corporal smooth muscle tone, and therefore, erectile capacity. The goal of this investigation was to evaluate the actions of prostaglandin E1 (PGE1), the most widely used and effective drug for the treatment of impotence, on the activity of the KCa channel, a prominent K+ current present in human corporal smooth muscle. Whole-cell patch clamp studies conducted on short-term cultured and enzymatically dissociated human corporal smooth muscle cells, revealed mean resting potentials of -50.8 +/- 2.1 mV (n = 8) and -34 +/- 4 mV (n = 8), respectively. In the attached-patch configuration, the corresponding single-channel slope conductance values for the KCa channel subtype were 173 +/- 4 pS (n = 8) in cultured cells, and 190 +/- 13 pS (n = 3) in freshly isolated myocytes. Furthermore, voltage clamp experiments revealed that relative to control values, the application of PGE1 to cultured cells (3.3 or 33 microM) elicited an apparent increase in both the open probability (Po; ranging from 1.2-23 fold), and the mean open time (5-6 fold) of the KCa channel at membrane potentials of +90 mV and +110 mV. PGE1-induced alterations in KCa channel activity were also observed in freshly isolated corporal myocytes. In the whole cell-recording mode, statistically significant, Charybdotoxin-sensitive (100 nM) 2-3 fold increases in the outward K+ currents were observed in both cultured and freshly isolated corporal myocytes. The presence of a PKA inhibitor (fragment 6-22 amide; 10 microM) in the pipette tip was also associated with a nearly complete ablation of the observed PGE1-induced whole cell K+ currents. Taken together, these data confirm and extend our previous observations, and indicate that PGE1-induced relaxation of human corporal smooth muscle is related, at least in part, to activation of the KCa channel subtype resulting in cellular hyperpolarization.     

Ion Channels and Gap Junctions: Their Role in Erectile Physiology, Dysfunction, and Future Therapy

A flurry of research and clinical activity during this past decade has documented that the tonicity and synchronicity of the corporal smooth muscle cells of the penis are major determinants of erectile capacity and function. Specifically, the effects of diverse and bifurcating intracellular signal transduction pathways on the activity of nonjunctional ion channels such as potassium (K(+)), calcium (Ca(2+)), and chloride (C(1-)) govern the former, whereas intercellular communication through gap junctions provides the anatomic substrate for the latter. Recent studies at the tissue, cellular, subcellular, and molecular levels have verified this supposition and provided important insight into how subtle alterations in the balance between contraction and relaxation of the corporal smooth muscle cells can predispose a man to erectile failure. This report reviews the available information concerning the participation of gap junctions and K(+), Ca(2+), and C(1-) channels in the erectile process and describes their importance as potential molecular targets for the future therapy of erectile dysfunction (ED). It is argued that a major goal should now be to proceed on at least two fronts simultaneously: (1) to capitalize on these new mechanistic insights by developing novel treatments for ED centered on the modulation of ion channel activity; and (2) simultaneously to take advantage of the unique therapeutic opportunities afforded by the presence and ubiquitous distribution of gap junction channels in the human corpora. One strategy that fulfils both criteria will be briefly reviewed, that is, gene therapy with the maxi-K(+) channel subtype.