Sequence of events in relaxation of visceral smooth muscle:

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1 Note 19 Written by:

2 Relaxation of smooth muscle: Intracellular calcium concentrations are very important in regulating smooth muscle contraction. The concentration of intracellular calcium depends upon the balance between the calcium enters the cells, and the calcium that is released by intracellular storage sites (e.g., sarcoplasmic reticulum), and removal of calcium either back into storage sites or out of the cell. Calcium is re-sequestered by the sarcoplasmic reticulum by a ATP-dependent calcium pump. Calcium is removed from the cell to the external environment by either ATP-dependent calcium pump or by the sodium-calcium exchanger. Sequence of events in relaxation of visceral smooth muscle: 1. De-phosphor-lation of myosin by myosin light chain phosphatase: myosin is de-phosphor-ylated by myosin light chain phosphatase in the cell, which will cause relaxation. 2. De-phosphor-lation of myosin light chain kinase does not necessarily lead to relaxation of the smooth muscle. Various mechanisms are involved. One appears to be a (latch bridge) mechanism by which myosin crossbridges remain attached to actin for some time after the cytoplasmic Ca concentration falls. This produces sustained contraction with little expenditure of energy, which is especially important in vascular smooth muscle relaxation. Relaxation of the muscle presumably occurs when there is final dissociation of the Ca-calmodulin complex or when someother mechanism comes into play. تذك ر سر ع بآل ة االنمباض : 1 ((ز ادة ترك ز الكالس وم داخل الخل ة إما من خالل دخوله من السائل الخلوي الخارج أو خروجه من مخازنه ف داخل الخل ة 2 ((التماإه مع calmodulin ح ث ترتبط 4 ذرات كالس وم 3 ((المركب المكون من calmodulin والكالس وم ( calmodulin-calcium )complex عمل على تحف ز myosin light chain kinase الذي عمل بدوره على إزالة ذرة فوسفات من ATP و لصمها ب myosin light chain 4 ((بدء عمل ة االنمباض

3 ارتخاء العضلة ال حصل دون انخفاض مستوى الكالس وم هذا االنخفاض حصل عن أما من خالل: *خروجه من الخل ة عن طر ك calcium ATP-ase أو sodium-calcium exchanger *إعاداالرتخاء:ن تخز نه آل ة االرتخاء : انفصال الفوسفات عن myosin و تتم عمل ة االنفصال بوجود myosin phosphatase ولكن المشكلة بؤن عمل ة انفصال الفوسفات عمل ة بط ئة جدا تبتدأ فعل ا خطوة ونملة االرتخاء إذا ما انفصل الكالس وم عن calmoduline ح ث صبح الكالس وم حر مالحظة : وجد آل ة اسمها latch bridges وه أن تبمى خ وط الم وس ن مرتبطة مع خ وط االكت ن حتى بعد انخفاض ترك ز الكالس وم ف داخل الخل ة هذا األمر الذي ولد انمباض مستمر مع صرف لل ل للطالة وهو مهم جدا ف عمل ة ارتخاء vascular smooth muscle

4 Comparison of Smooth Muscle Contraction and Skeletal Muscle Contraction Although most skeletal muscles contract and relax rapidly, most smooth muscle contraction is prolonged tonic contraction, sometimes lasting hours or even days. Therefore, it is to be expected that both the physical and the chemical characteristics of smooth muscle versus skeletal muscle contraction would differ. Some of the differences are noted in the following sections. (1) Slow Cycling of the Myosin Cross-Bridges. The rapidity of cycling of the myosin cross-bridges in smooth muscle that is, their attachment to actin, then release from the actin, and reattachment for the next cycle is much slower than in skeletal muscle; in fact, the frequency is as little as 1/10 to 1/300 that in skeletal muscle. Yet, the fraction of time that the cross-bridges remain attached to the actin filaments, which is a major factor that determines the force of contraction, is believed to be greatly increased in smooth muscle. A possible reason for the slow cycling is that the cross-bridge heads have far less ATPase activity than in skeletal muscle, and thus degradation of the ATP that energizes the movements of the cross-bridge heads is greatly reduced, with corresponding slowing of the rate of cycling. اآلن السإال هو ما سبب التماء االكت ن مع الم وس ن لفترة زمن ة أطول ف العضالت الملساء بسبب للة وجود ATP-ase الذي موم بتحر ر الفوسفات وإنتاج ATP لتعاد الدورة من جد د (2) Low Energy Requirement to Sustain Smooth Muscle Contraction. Only 1/10 to 1/300 as much energy is required to sustain the same tension of contraction in smooth muscle as in skeletal muscle. This, too, is believed to result from the slow attachment and detachment cycling of the cross-bridges and because only one molecule of ATP is required for each cycle, regardless of its duration. This low energy utilization by smooth muscle is important to the overall energy economy of the body because organs such as the intestines, urinary bladder, gallbladder, and other viscera often maintain tonic muscle contraction almost indefinitely. Tonic muscles as continuously active muscles within the body that are usually filled with fluid. Phasic muscles are active for short periods but spend most of the time in a relaxed state

5 منطم ا عندما تعمل العضلة لفترة أطول تحتاج طالة أكثر ولكن الذي حصل ف العضالت غ ر ذلن بسبب: العضالت اله كل ة فترة التماء الم وس ن مع االكت ن لص رة وال بد من تجد دها بصورة مستمرة وسر عة حتى حدث االنمباض وهذا تطلب استهالن كم ات اكبر جز ئات الطالة أما ف العضالت الملساء تكون فترة االلتماء أطول واستهالن جز ئات الطالة ألل أهم ة التصاد ة العضالت الملساء بالطالة هو إن معظم هذه العضالت تعمل لمدة زمن ة طو لة مثل عضالت الملساء ف جدار الجهاز الهضم لد تعمل لمدة 6-3 ساعات حتى تهضم الطعام (3) Slowness of Onset of Contraction and Relaxation of the Total Smooth Muscle Tissue. A typical smooth muscle tissue begins to contract 50 to 100 milliseconds after it is excited, reaches full contraction about 0.5 second later, and then declines in contractile force in another 1 to 2 seconds, giving a total contraction time of 1 to 3 seconds. This is about 30 times as long as a single contraction of an average skeletal muscle fiber. However, because there are so many types of smooth muscle, contraction of some types can be as short as 0.2 second or as long as 30 seconds. The slow onset of contraction of smooth muscle, as well as its prolonged contraction, is caused by the slowness of attachment and detachment of the cross-bridges with the actin filaments. In addition, the initiation of contraction in response to calcium ions is much slower than in skeletal muscle.

6 ي ا سثك ػشف ا تأ ف انؼعالخ ان هساء فتشج انتماء ان س االكت أغ ل تانتان صي ج ذ انفؼم س ك أغ ل ح ج : 1 ((تثذأ انخه ح تاال مثاض تؼذ يهه حا ح ي تحف ض ا 2 ((فتشج اال مثاض تست ش 5.5 يهه حا ح 3(( فتشج االستخاء تستغشق 2-1 حا ح تانتان يج م فتشج اال مثاض االستخاء تك ي 3-1 حا ح ز انفتشج أغ ل ب 35 يشج ي انؼعالخ ان كه ح يالحظح : ال ت جذ ل اػذ حاتتح ف انؼعالخ ان هساء ح ج أ ا تختهف تحسة اختالف ت ص ؼ ا داخم انجسى فف تؼط األ اع لذ تستغشق فتشج 5.2 حا ح ف أ اع أخش 35 حا ح تسثة: 1 ((خ غ االكت ان س تشتثػ ت فصم تثػء شذ ذ 2 ((ػ ه ح تج ض انخه ح نال مثاض تحتاد فتشج صي ح أغ ل ح ج انؼعالخ ان كه ح تتطهة فمػ خش د ا اخ انكانس و ي يخاص ا أيا انؼعالخ ان هساء فتتطهة خش د ا اخ انكانس و ي يخاص ا تاإلظافح إن دخ ن ا ي انسائم انخه انخاسج (4) The Maximum Force of Contraction Is Often Greater in Smooth Muscle Than in Skeletal Muscle. Despite the relatively few myosin filaments in smooth muscle, and despite the slow cycling time of the cross-bridges, the maximum force of contraction of smooth muscle is often greater than that of skeletal muscle as great as 4 to 6 kg/ cm2 cross-sectional area for smooth muscle, in comparison with 3 to 4 kilograms for skeletal muscle. This great force of smooth muscle contraction results from the prolonged period of attachment of the myosin cross-bridges to the actin filaments ي طم ا ف انؼعالخ ان هساء ك ػذد خ غ ان س صف ػذد ا ف انؼعالخ ان كه ح تانتان ت لغ أ تك ل ج اال مثاض الم إال أ انؼكس حصم تسثة: فتشج االنتماء ت ان س االكت تك أغ ل ح ج انم ج ان تجح ف انؼعالخ ان هساء= 6-4 كغ/سى 2 ت ا انم ج ان تجح ف انؼعالخ ان كه ح= 4-3 كغ/سى 2 )ان صف تمش ثا( characteristic skeletal smooth مدة انمباض العضلة)التماء الم وس ن مع االكت ن( الصر أطول لوة االنمباض الل اكبر Energy requirement أكثر الل Action potential duration لص ر طو ل جدا العاللة ب ن مدة االنمباض والموة عاللة طرد ة

7 (5) The Latch Mechanism Facilitates Prolonged Holding of Contractions of Smooth Muscle. Latch: قفل أو ترباس أو اقفل أو تربس Once smooth muscle has developed full contraction, the amount of continuing excitation can usually be reduced to far less than the initial level even though the muscle maintains its full force of contraction. Further, the energy consumed to maintain contraction is often minuscule, sometimes as little as 1/300 the energy required for comparable sustained skeletal muscle contraction. This mechanism is called the latch mechanism. The importance of the latch mechanism is that it can maintain prolonged tonic contraction in smooth muscle for hours with little use of energy. Little continued excitatory signal is required from nerve fibers or hormonal sources. Among the many mechanisms that have been postulated, one of the simplest is the following: When the myosin kinase and myosin phosphatase enzymes are both strongly activated, the cycling frequency of the myosin heads and the velocity of contraction are great. Then, as the activation of the enzymes decreases, the cycling frequency decreases, but at the same time, the deactivation of these enzymes allows the myosin heads to remain attached to the actin filament for a longer and longer proportion of the cycling period. Therefore, the number of heads attached to the actin filament at any given time remains large. Because the number of heads attached to the actin determines the static force of contraction, tension is maintained, or latched, yet little energy is used by the muscle because ATP is not degraded to ADP except on the rare occasion when a head detaches. كلمة Latch تعن لفل ترباس أو مزالج : الحظنا انه ف العضالت اله كل ة كلما أعط نا تحف ز عضل اكبر كانت الموة العضل ة المنتجة اكبر أما ف العضالت الملساء فعند إعطاء التحف ز العضل تزداد الموة المنتجة حتى تصل الجد األلصى و تتنالص الموة الكهربائ ة بنفس الولت السبب ف ذلن أن الخال ا اله كل ة تحفز فمط عصب ا أما الملساء فتحفز عصب ا وهرمون ا فتعط لوة أكبر وطالة ألل ما سبك فسر من خالل عمل اإلنز م ن : )) 1 kinase myosin ارتباط أكت ن وم وس ن phosphatase)) myosin انفصال أكت ن وم وس ن 2 عندما كون ترك زهما كل هما عال كون االرتباط واالنفصال سر ع ب نما عندما كون ترك زهما كل هما منخفض فااللتماء كون بط ء واالنفصال كذلن تولد لوة اكبر وتحتاج طالة

8 (6) "Stress-relaxation" of smooth muscle "Stress-relaxation" or "delayed compliance" of visceral smooth muscle Another important characteristic of smooth muscle, especially the visceral unitary type of smooth muscle of many hollow organs, is its ability to return to nearly its original force of contraction seconds or minutes after it has been elongated or shortened. For example, a sudden increase in fluid volume in the urinary bladder, thus stretching the smooth muscle in the bladder wall, causes an immediate large increase in pressure in the bladder. However, during the next 15 seconds to a minute or so, despite continued stretch of the bladder wall, the pressure returns almost exactly back to the original level. Then, when the volume is increased by another step, the same effect occurs again. Conversely, when the volume is suddenly decreased, the pressure falls drastically at first but then rises in another few seconds or minutes to or near to the original level. These phenomena are called stress-relaxation and reverse stress-relaxation. Their importance is that, except for short periods, they allow a

9 hollow organ to maintain about the same amount of pressure inside its lumen despite sustained, large changes in volume. It is this property that is referred to as the (plasticity) of smooth muscles. The best example for this property is the gall bladder ف العضالت اله كل ة تماما مثل لطعة مطاط ة أو زنبرن كلما زادت لوة الشد زادت لوة رجوعها إلى وضعها األصل أما ف العضالت الملساء فالحظ العلماء انه عندما تشد العضلة رأسا لوة الشد تزداد ولكن بعد فترة زمن ة تبدأ بالتنالص وهذا الكالم نطبك على معظم hallow visceral organs األعضاء الت تمتلئ بالسوائل مثل المثانة البول ة ح ث عندما تمتلئ بالبول وتصل لحجم 151 مل شعر اإلنسان برغبة ف التبول ولكن الحظ زوالها بعد فترة لص رة ومن ثم ستمر البول بالتجمع حتى صل إلى حجم 411 مل وعندها تؤت رغبة التبول مرة أخرى ولكن تستمر إلى ح ن إفراغ المثانة البول ة اآلن السإال لماذا عند 151 مل اختفت الرغبة ف التبول العضلة عندما انشدت إلى حجم 151 مل ازدادت لوة الشد ولكن بعد 15 ثان ة إلى دل مة تنخفض هذه الموة و حصل ف ها ارتخاء ح ث تسمى هذه العمل ة بrelaxation Stress وتستمر هذه العمل ة حتى الوصول إلى حجم 411 مل عندها جب إفراغ المثانة اآلن الذي حصل كون العكس تماما ح ث مل الحجم وتزداد لوة الشد وهو ما سمى ب Reverse stress relaxation ما حصل سابما طلك عل هplasticity smooth muscle أي مرونة العضالت الملساء واستجابتها للتك فات المختلفة

10 Mechanisms of Capillary Exchange Capillaries are the only place for exchange between blood and surrounding tissue. ال capillary ه الشع رات الدمو ة الدل مة وهووي منتشورة فو الجسوم كامول و توتم ف هوا عمل وة تبادل المواد ب ن مكونات الدم و الخال ا و بالعكس وهذا ال حدث اال بال capillary النه المكوان الوح د ف الدورة ادمو ة الذي تكون من صف واحد من الخال ا تسمى endothelium وهوذا شومل بالعوادة الموواد الصوو رة و الذايبوة فو الودهون diffusion طرق تبادل المواد 1- عن طر ك ال النها تستط ع عبور جدار الخل ة 2- عن طر ك الفراغ الموجود ب ن الخال وا و تشومل الموواد المتوسوطة و الصوو رة و تكوون ذايبة ف الماء العضول الموبطن لالوع وة الثموب ب ن الخال ا ف النسو 3- عن طر ك ال fenestration تنتمل خاللها المواد المتوسطة بالحجم و الذائبة ف الماء exo& endocytosis و تنمول المووواد كب ورة 4- عون طر وك ال vesicular التوو تمثول ال الحجم Route across endothelial cells: 1. Diffusion: Across cell membrane by Simple diffusion for lipid soluble substances: Particularly important for gases (O2 and CO2) and lipid-soluble substances (e.g., anesthetics); fluid and electrolytes are also exchanged, in part, by diffusion forces (Fick's First Law of diffusion) Factors that affect diffusion: a. Lipid-Soluble Substances Diffuse Directly Through the Cell Membranes of the Capillary Endothelium

11 b. Effect of concentration difference on net rate of diffusion through the Capillary Membrane. The net rate of diffusion of a substance through any membrane is proportional to the concentration difference of the substance between the two sides of the membrane If a substance is lipid soluble, it can diffuse directly through the cell membranes of the capillary without having to go through the pores. Such substances include oxygen and carbon dioxide. Because these substances can permeate all areas of the capillary membrane, their rates of transport through the capillary membrane are many times faster than the rates for lipid-insoluble substances, such as sodium ions and glucose that can go only through the pores. c. Capillary density: increase capillary density increase diffusion because increase surface area. اتجاه انتمال المواد *الدم ثم السايل ب ن الخلوي interstitial fluid ثم الى الخال ا العوامل المإثرة ف ficks law 1- ذايب تهوا فو الودهون لعبوور جودار الخل وة مثوال غواز االكسوج ن و ثوان اكسو د الكربون 2- فرق الترك ز ب ن الدم و السايل ب ن الخلوي ظش ا كم يا صاد فشق انتشك ض صاد اال تشاس ك ا ف االكسج حا اكس ذ انكشت تشك ض االكسج ف انذو ػان ف تمم ان انخال ا انت تشك ضاالكسج ف ا الم ف تمم ي انتشك ض ان شتفغ ان ان خفط ايا ف حا اكس ذ انكشت فثانؼكس تمم ي انخال ا انت ك ف ا تشك ض يشتفغ ان انذو انز ك ف انتشك ض الم نك ف اياك يحذد ف انجسى ي ك ا حذث ال diffusion سغى ا انفشق له م يخال ي ك ف تؼط االياك ا تت تمم ان اد ي انتشك ض انؼان ان ان خفط ن كا انفشق تس ػ يخال : سثح تشثغ االكسج ف انذو Hgmm100 ف انذو ايا ف اال سجح "ف حانح انشاحح" ف 55 ار انفشق 25 ايا ف حا اكس ذ انكشت ف ك سثت 46 ف انذو ايا سثت ايا 45 ف اال سجح انفشق 6 تمم كثافة الشع رات الدمو ة diffusion كلما زادت الشع رات زادة مساحة التبادل للمواد و تزداد ال Water-Soluble, Non Lipid-Soluble Substances Diffuse Through A. Intercellular Pores in the Capillary Membrane (Fenestrated capillaries):

12 Fenestrated capillaries (fenstra: window) have pores in the endothelial cells (60-80 nm in diameter) that are spanned byامتووداد a diaphragm of radially orientedشوعاع fibrils and allow small molecules and limited amounts of protein to diffuse. بعض من انواع الشع رات مثمبة ولكن هذه الثموب موطاه بوشاء سمح بانتمال المواد الذايبوة فو الماء و نتشر ف الكل ة B. Intercellular clefts between the endothelial cells (continuous capillaries): Many substances needed by the tissues are soluble in water but cannot pass through the lipid membranes of the endothelial cells; such substances include water molecules, sodium ions, chloride ions, and glucose. Although only 1/1000 of the surface area of the capillaries is represented by the intercellular clefts between the endothelial cells, the velocity of thermal molecular motion in the clefts is so great that even this small area is sufficient to allow tremendous diffusion of water and water-soluble substances through these cleft-pores. To give one an idea of the rapidity with which these substances diffuse, the rate at which water molecules diffuse through the capillary membrane is about 80 times as great as the rate at which plasma itself flows linearly along the capillary. That is, the water of the plasma is exchanged with the water of the interstitial fluid 80 times before the plasma can flow the entire distance through the capillary. هذه الفراغات تسمح بانتمال ا ونات الماء وما ذاب ف المواء مثول ال ور وا و الجلوكووز و الكلوور والصود وم الموواء سوووف عبوور جوودار الشووع رات و تبووادل المووواد مووع االنسووجة ثووم عووود محموول بووالمواد و الفضالت 01 مرة عبر هذه الفراغات رغم ان هذا الفراغ الصو ر كوون 1111/1 مون مسواحة سطح الخل ة مما عن ان مكونات ال interstitial fluid تنوسل 01 مرة

13 Effect of Molecular Size on Passage through the Pores. The width of the capillary intercellular cleft-pores, 6 to 7 nanometers, is about 20 times the diameter of the water molecule, which is the smallest molecule that normally passes through the capillary pores. The diameters of plasma protein molecules, however, are slightly greater than the width of the pores. Other substances, such as sodium ions, chloride ions, glucose, and urea, have intermediate diameters. Therefore, the permeability of the capillary pores for different substances varies according to their molecular diameters. commonly encountered, demonstrating, for instance, that the permeability for glucose molecules is 0.6 times that for water molecules, whereas the permeability for albumin molecules is very slight only 1/1000 that for water molecules. A word of caution must be issued at this point. The capillaries in various tissues have extreme differences in their permeabilities. For instance, the membranes of the liver capillary sinusoids are so permeable that even plasma proteins pass through these walls, almost as easily as water and other substances. Also, the permeability of the renal glomerular membrane for water and electrolytes is about 500 times the permeability of the muscle capillaries, but this is not true for the plasma proteins; for these proteins, the capillary permeabilities are very slight, as in other tissues and organs. When we study these different organs later in this text, it should become clear why some tissues require greater degrees of capillary permeability than do other tissues. For example, greater degrees of capillary permeability are required for the liver to transfer tremendous amounts of nutrients between the blood and liver parenchymal cells and for the kidneys to allow filtration of large quantities of fluid for the formation of urine. Effect of Concentration Difference on Net Rate of Diffusion through the Capillary Membrane.

14 The net rate of diffusion of a substance through any membrane is proportional to the concentration difference of the substance between the two sides of the membrane. That is, the greater the difference between the concentrations of any given substance on the two sides of the capillary membrane, the greater the net movement of the substance in one direction through the membrane. For instance, the concentration of oxygen in capillary blood is normally greater than in the interstitial fluid. Therefore, large quantities of oxygen normally move from the blood toward the tissues. Conversely, the concentration of carbon dioxide is greater in the tissues than in the blood, which causes excess carbon dioxide to move into the blood and to be carried away from the tissues. The rates of diffusion through the capillary membranes of most nutritionally important substances are so great that only slight concentration differences suffice to cause more than adequate transport between the plasma and interstitial fluid. For instance, the concentration of oxygen in the interstitial fluid immediately outside the capillary is no more than a few percent less than its concentration in the plasma of the blood, yet this slight difference causes enough oxygen to move from the blood into the interstitial spaces to provide all the oxygen required for tissue metabolism often as much as several liters of oxygen per minute during very active states of the body. However, in a state of acute or chronic inflammation, ischemia reperfusion, atherosclerosis, sepsis, diabetes, thermal injury, angiogenesis or tumor metastasis, mediators such as histamine, serotonin, thrombin, bradykinin, substance P, Platelet-activating factor (PAF), cytokines, growth factors such as vascular endothelial growth factor (VEGF) and reactive oxygen species induce endothelial cell retraction, which increases the intercellular space and subsequently the permeability to solute and plasma proteins. مسافة هذا الفراغ الب ن خلوي من 7-6 نانو م تر وه 21 مرة اكبر من حجم ذرة الماء المواد الت تر د العبر من هذا الفراغ جب ان تناسب حجمها مع حجم هوذا الفوراغ وال تسوتط ع ان تسمح لمواد كب ورة بوالعبور مثوال بوروت ن ال albumin ال سوتط ع المورور لكون الموواد مثول الجلوكوز و ال ور ا و الصود وم و البوتاس وم و الكلور تعبر الن االلبوم ن اكبور مون المواء بوال 1111 ضعف اما الجلوكوز فهو 1.6 من حجم الماء وهوذا الكوالم ال نطبوك فو جم وع الشوع رات مثول تلون الموجوودة بالكبود حتوى تسومح لول البووم ن بالخروج منه و مثل االوع ة ف الكل ة كب رة بشكل كاف للسوما للفضوالت بوالخروج والكون ال تسومح لخال وا الدم الحمراء و البروت نات بالخروج ف حاالت المرض خال ا ال endothelium تنكم و الفوراغ ز ود فو الحواالت However, in a state of acute or chronic inflammation, ischemia reperfusion, atherosclerosis, sepsis, diabetes, thermal injury, angiogenesis or tumor metastasis

15 الموواد التو تسوبب انكمواخ الخال وا هو bradykinin, as histamine, serotonin, thrombin, substance P, Platelet-activating factor (PAF), cytokines, growth factors such as vascular endothelial growth factor (VEGF) and reactive oxygen species 3. Transcytosis (Vesicular Transport) Vesicular transport is involved in the translocation of macromolecules across capillary endothelium by endocytosis and exocytosis Transcytosis, blood substances move into the cell by endocytosis then across the endothelial cells that compose the capillary structure. Finally, these materials exit by exocytosis, process in which vesicles go out from a cell to the interstitial space. Transcytosis is mainly used by large molecules that are lipid-insoluble, such as the insulin hormone. A minimum amount of substances cross by transcytosis. Once vesicles exit the capillaries, they go to the interstitium. Sometimes vesicles can merge with other vesicles, so their contents are mixed, or can directly go to a specific tissue. This material intermixed increases the functional capability of the vesicle. Sometimes vesicles fuses with each other forming vesicular channels Present in the endothelial cells are many minute plasmalemmal vesicles, also called caveolae (small caves). These plasmalemmal vesicles form from oligomers

16 of proteins called caveolins that are associated with molecules of cholesterol and sphingolipids. Although the precise functions of caveolae are still unclear, they are believed to play a role in endocytosis (the process by which the cell engulfs material from outside the cell) and transcytosis of macromolecules across the interior of the endothelial cells. The caveolae at the surface of the cell appear to imbibe proteins. smallشورب packets of plasma or extracellular fluid that contain plasma These vesicles can then move slowly through the endothelial cell. Some of these vesicles may coalesce to form vesicular channels all the way through the endothelial cell تتك ز ان الم ػ ذ دخ ل يادج كث شج يخلم تلش ت ػل غش لك ال endocytosis فو االذرع الكاذبوة فتلتمو و تكوون vesicle تثووم بنملهوا عبور الجودار و حصول exocytosis و تخورج هوذه البروت نوات الوى اماكنهوا وفو بعوض االح وان تلتمو عوذه vesicles موع نوالول اخورى مثول ال lysosomes الت تحتوي على مواد هاضمة و ممكن انت تلتم مع نوالل اخرى لتكون لنوات مثال نوع من انواع المنوات ف ال smooth muscle سومى ال caveolae و تعنو الكهوف الصوو ر و هوووو تكوووون مووون موووادة تسووومى ال caveolins و موجوووود معهوووا موووواد cholesterol and caveolae لتكون ال phospholipid sphingolipids وال caveolae وظ فتهووا تشووبه وظ فووة ال vesicles فهوو تلتموو مووع receptor و تموووم بووال endocytosis ثووم تنتموول الووى الجانووب االخوور موون الوشوواء و تخوورج مكونووات النالوول عبوور exocytosis Interstitium & interstitial fluid About one sixth of the total volume of the body consists of spaces between cells, which collectively are called the interstitium. The fluid in these spaces is called the interstitial fluid.

17 The structure of the interstitium contains two major types of solid structures: (1) collagen fiber bundles The collagen fiber bundles extend long distances in the interstitium. The collagen fiber are extremely strong and therefore provide most of the tensional strength of the tissues. (2) Proteoglycan filaments. The proteoglycan filaments, however, are extremely thin coiled or twisted molecules composed of about 98 percent hyaluronic acid and 2 percent protein. These molecules are so thin that they cannot be seen with a light microscope and are difficult to demonstrate even with the electron microscope. Nevertheless, they form a mat of very fine reticular filaments aptly described as a brush pile. تكون الفراغ ب ن الخال ا من ترك بات منها 1- Collagen : ال اف الكوالج ن من الوى االل اف ف جسمناو ه الوى من ال اف الحد د المستخدم ف البناء -2 Proteoglycan : تكون من hyaluronic acid بنسبة %80 و من %2 بروت ن هووذه الترك بووة توورى بصووعوبة فوو المجهوور االلكترونوو و تشووبه الفرشوواة و لووذلن تسوومى brush pile

18 وظ فتها االساس ة ه التحد د من انتمال الماء وال ع ك انتمال المواد عبر interstitium فلذلن المواد تنتمل بسهولة و الماء نتمل بصعوبة بس وجوده Gel in the Interstitium. The fluid in the interstitium is derived by filtration and diffusion from the capillaries. It contains almost the same constituents as plasma except for much lower concentrations of proteins because proteins do not easily pass outward through the pores of the capillaries. The interstitial fluid is entrapped mainly in the minute spaces among the proteoglycan filaments. This combination of proteoglycan filaments and fluid entrapped within them has the characteristics of a gel and therefore is called tissue gel. Because of the large number of proteoglycan filaments, it is difficult for fluid to flow easily through the tissue gel. Instead, fluid mainly diffuses through the gel; that is, it moves molecule by molecule from one place to another by kinetic, thermal motion rather than by large numbers of molecules moving together. Diffusion through the gel occurs about 95 to 99 percent as rapidly as it does through free fluid. For the short distances between the capillaries and the tissue cells, this diffusion allows rapid transport through the interstitium not only of water molecules but also of electrolytes, small molecular weight nutrients, cellular excreta, oxygen, carbon dioxide, and so forth. Free Fluid in the Interstitium. Although almost all the fluid in the interstitium normally is entrapped within the tissue gel, occasionally small rivulets of free fluid and small free fluid vesicles are also present, which means fluid that is free of the proteoglycan molecules and therefore can flow freely. When a dye is injected into the circulating blood, it often can be seen to flow through the interstitium in the small rivulets, usually coursing along the surfaces of collagen fibers or surfaces of cells. The amount of free fluid present in normal tissues is slight usually less than 1 percent. Conversely, when the tissues develop edema, these small pockets and rivulets of free fluid expand tremendously until one half or more of the edema fluid becomes freely flowing fluid independent of the proteoglycan filaments. وجود الماء الماء كون محدود ضمن ال interstitium وال خرج منه المواء الصواف موجوود بنسوبة %1 وال ز ود الوى فو الحواالت المرضو ة مثول ال edema او الودمة وه انتفاخ الجسم بسبب الماء و البال موجود ف ال gell الذي تكون مون المواء و الموواد الذايبوة ف وه و ال collagen amd the proteoglycan