Month: July 2015

Arteriolar Tone and Its Regulation (Local Mechanisms)

July 17, 2015 Cardiology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , ,


I.Arteriolar Tone

A.Basal tone


C.Adrenal Glands


1.Metabolic substances

2.Endothelial cells secretion

3.Other local chemical influences

4.Transmural pressure (myogenic response)

II.Venous Tone

A.Basal tone (little)


C.Adrenal glands

D.Internal pressure (recall deltaV/deltaP = C)

E.External compression (muscle pump)

Because the body's needs are continually changing, the cardiovascular system must continually make adjustments in the diameter of its vessels. The purposes of these vascular change are efficiently distribute the cardiac output among tissues with different current needs (the job of arterioles) and regulate the distribute of blood volume and cardiac filling (the job of veins). So besides central regulatory mechanisms for vascular system (CNS, autonomic nerves system) and hormonal regulatory mechanisms (RAAS/angII and vasopressin, natriuretic hormone, insulin resistance and hyperinsulinemia, circulating catecholamines), there are another vascular regulatory mechanism – peripheral regulatory mechanisms/local mechanisms.

Total peripheral resistance (TPR) is determined by resistances of each primary organs and tissues, whereas resistance of an single organ or tissue region is primarily determined by resistances of arterioles that distribute within this organ or tissue. Therefore, TPR is determined primarily by resistance of arterioles. According to the famous Hagen–Poiseuille equation, resistance to flow is inversely and directly related to the radius of the vessel.

(Note: Q = ΔP/R, and R is resistance of the vessel)

Because resistances of arterioles are so important for TPR and the resultant blood flow (Q), we need to study the characteristics of arteriolar resistance carefully. Vascular tone is a term commonly used to characterize the general contractile state (so the radius of the vessel) or a vascular region. The "vascular tone" of a region can be taken as an indication of the "level of activation" of the individual smooth muscle cells in that region. Because the blood flow through any organ is determined largely by its vascular resistance, which dependent primarily on the diameter of its arterioles, thus an organ's flow is controlled by factors that influence the arteriolar smooth muscle tone.

Arterioles remain in a state of partial constriction even all external influences on them are removed; hence, they are said to have a degree of basal tone. The understanding of the mechanism is incomplete, but basal arteriolar tone may be a reflection of the fact that smooth muscle cells inherently and actively resist being stretched as they continually are in pressurized arterioles. Another hypothesis is that the basal tone of arterioles is the result of a tonic production of local vasoconstrictor substances by the endothelial cells that line their inner surface. Nevertheless, the arterioles have basal tone, and several factors externally influence it, including local influences, neural influences, and hormonal influences.


The capacity of tissues to regulate their own blood flow is referred to as auto regulation. Most vascular beds have an intrinsic capacity to compensate for moderate changes in perfusion pressure by change in vascular resistance, so that blood flow remains relatively constant. The ability of vascular autoregulation is probably due in part to the intrinsic contractile response of smooth muscle to stretch (myogenic theory of autoregulation). That is, as the perfusion pressure rises, the blood vessels are distended and the vascular smooth muscle fivers that surround the vessels contract, which increases the vascular resistance so that the blood flow remains constant (Q = ΔP/R). At the last section of this thread you can find more detail information for the mechanisms and rationales about vascular autoregulation.

General Mechanisms for Activation of the Vascular Smooth Muscle

The task of the vascular smooth muscle is unique, because to maintain a certain vessel diameter in the face of the continual distending pressure of the blood within it, the vascular smooth muscle must be able to sustain active tension for prolonged periods. Compared with other muscle types, smooth muscle cells have these different characteristics, including:

1.Contract and relax much more slowly;

2.Can change their contractile activity as a result of either action potentials or changes in resting membrane potential;

3.Can change their contractile activity in the absence of any change in membrane potential;

4.Can maintain tension for prolonged periods at low energy cost;


5.Can be activated by stretch.

Local Influences on Basal Tone

Local factors influencing arteriolar basal tone (and the diameter of arterioles) include metabolic influences, endothelial cells, other chemical influences, and transmural pressure.

Metabolic Substances. The arterioles that control flow through a given organ lie within the organ tissue itself. Thus, arterioles and the smooth muscle in their walls are exposed to the chemical composition of the interstitial fluid of the organ they serve. The interstitial concentrations of many substances reflect the balance between the metabolic activity of the tissue and its blood supply. Exposure to low oxygen, and metabolic substances such as high H+, high K+, high CO2, high osmolarity, and adenosine, cause reduced arteriolar tone and vasodilation. By contrary, exposure to high oxygen and low metabolic substances induce increased arteriolar tone and vasoconstriction. When metabolic activity is over the blood supply, oxygen pressure in that tissue gets lower and the metabolic wastes accumulate in the tissue, which cause vasodilation of arterioles. As a result of arteriolar vasodilation, the blood supply to that tissue is improved and oxygen pressure gets back to normal or even higher, whereas increased amount of metabolic wastes are washed away by the improved blood flow therefore the accumulation of metabolic wastes is resolved. Finally, the basal tone gets back to normal.

Endothelial cells cover the entire inner surface of the cardiovascular system. A large number of studies have shown that the blood vessels respond very differently to certain vascular influences when their endothelial lining is missing. In the case of the vasodilator effect of infusing acetylcholine through intact vessels, the vasodilator influence produced by endothelial cells has been identified as nitric oxide. Nitric oxide is produced within endothelial cells from the amino acid, L-arginine, by the action of an enzyme, nitric oxide synthase. Nitric oxide synthase is activated by a rise in the intracellular level of the Ca2+. And nitric oxide is a small lipid-soluble molecule that, once formed, easily diffuses into adjacent smooth muscle cells where it causes relaxation by stimulating cGMP production.

Acetylcholine and several other agents such as bradykinin, vasoactive intestinal peptide, and substance P stimulate endothelial cell nitric oxide production because their receipts on endothelial cells are linked to receptor-operated Ca2+ channels. Probably more importantly from a physiological standpoint, flow-related shear stresses on endothelial cells stimulate their nitric oxide production presumably because stretch-sensitive channels for Ca2+ are activated. Such flow-related endothelial cell nitric oxide production may explain why, for example, exercise and increased blood flow through muscles of the lower leg can cause dilation of the blood-supplying femoral artery at points far upstream of the exercising muscle itself.

One general unresolved issue with the concept that arteriolar tone is regulated by factors produced by arteriolar endothelial cells is how these cells could know what the metabolic needs of the downstream tissue are. This is because the endothelial cells lining arterioles are exposed to arterial blood whose composition is constant regardless of flow rate or what is happening downstream. One hypothesis is that there exists some sort of communication system between vascular endothelial cells. That way, endothelial cells in capillaries or venules could telegraph upstream information about whether the blood flow is indeed adequate.

Other local chemical influences. Many specific locally-produced and locally-reacting chemical substances have been identified that have vascular effects and therefore could be important in local vascular regulation in certain instances. In most cases, however, definite information about the relative importance of these substances in cardiovascular regulation is lacking. Prostaglandins are a group of several chemically related products of the cyclooxyrgenase pathways of arachidonic acid metabolism, which have vasoactive effects. Certain prostaglandins are potent vasodilators, while some are potent vasoconstrictors. However, despite the vasoactive potency of the prostaglandin and the fact that most tissues are capable of synthesizing prostaglandins, it has not been demonstrated convincingly that prostaglandins play a crucial role in the normal vascular control.

Histamine is synthesized and stored in high concentrations in secretory granules of tissue mast cells and circulating basophils. When released, histamine produces arteriolar vasodilation (via the cAMP pathway) and increases vascular permeability (by causing separations in the junctions between the endothelial cells that line the vascular system), which leads to edema formation and local tissue swelling. Other effects that histamine plays include stimulation of sensory nerve endings to produce itching and pain sensation.

Bradykinin is a small polypeptide that has approximately ten times the vasodilator potency of histamine on a molar basis. It also acts to increase capillary permeability by opening the junctions between endothelial cells. Bradykinin is formed from certain plasma globulin substances by the action of an enzyme, kvllikrein, and is subsequently rapidly degraded into inactive fragments by various tissue kinases.

Transmural pressure. The effect of transmural pressure on arteriolar diameter is more complex because arterioles respond both passively and actively to changes in transmural pressure. For example, a sudden increases in the internal pressure within an arteriole produces: 1.first an initial slight passive mechanical distention, and 2.then an active constriction that, within seconds, may completely reverse the initial distention. A sudden decrease in transmural pressure elicits essentially the opposite response, that is, an immediate passive decrease in diameter followed shortly by a decrease in active tone, which returns the arteriolar diameter to near that which existed before the pressure change. The active phase of such behavior is referred to as a myogenic response, because it seems to originate within the smooth muscle itself. The mechanism of the myogenic response is not known for certain, but stretch-sensitive ion channels on arteriolar vascular smooth muscle cells are likely candidates for involvement.

Examples of Local Regulation

Active Hyperemia – In organs with a highly variable metabolic rate, such as skeletal and cardiac muscles, the blood flow closely follows the tissue's metabolic rate. For example, skeletal muscle blood flow increases within seconds of the onset of muscle exercise and returns to control values shortly after exercise ceases. This phenomenon, which is illustrated in Figure 7-3A, is known as exercise or active hyperemia. Active hyperemia could be explained by mechanisms related to local metabolic theory and to local flow-related shear stresses theory.Screen Shot 2015-07-17 at 8.11.32 PM

Reactive Hyperemia – In this case, the higher-than-normal blood flow occurs transiently after the removal of any restriction that has caused a period of lower-than-normal blood flow and is sometimes referred to as post occlusion hyperemia. The phenomenon is illustrated in Figure 7-3B. For example, flow through an extremity is higher than normal for a period after a tourniquet is removed from the extremity. Both local metabolic and myogenic mechanisms may be involved in producing reactive hyperemia.

Autoregulation talks about the arterioles' reaction to the changes of the perfusion pressure. Except when displaying active and reactive hyperemia, nearly all organs tend to keep their blood flow constant despite variations in arterial pressure – that is, they autoregulate their blood flow. For example, an abrupt increase in arterial pressure is normally accompanied by an initial abrupt increase in organ blood flow that then gradually returns toward normal despite the sustained elevation in arterial pressure. The later autoregulation that returns the flow toward the normal level is caused by a gradual increase in active arteriolar tone and resistance to blood flow. Ultimately, a new steady state is reached with only slightly elevated blood flow because the increased driving pressure is counteracted by a higher-than-normal vascular resistance. The mechanisms for autoregulation are believed to be both local metabolic feedback theory and myogenic theory. Also, tissue pressure hypothesis of blood flow auto regulation for which it is assumed that an abrupt increase in arterial pressure causes transcapillary fluid filtration and thus leads to a gradual increase in interstitial fluid volume and pressure. Presumably the increase in extravascular pressure would cause a decrease in vessel diameter by simple compression. This mechanism might be especially important in organs such as the kidney and brain whose volumes are constrained by external structures.


Vascular Resistances and Compliance, MAP and Pulse Pressure

July 9, 2015 Cardiology, Physiology and Pathophysiology No comments , , , , , , ,

Resistances In A Single Organ

In an organ, the consecutive vascular segments are arranged in series within an organ. Therefore, the overall vascular resistance of the organ must equal the sum of the resistances of its consecutive vascular segments,

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Because arterioles have a large vascular resistance in comparison to the other vascular segments (see above), the overall vascular resistance of any organ is determined to a very large extent by the resistance of its arterioles. And according to its histologic characteristics, we can change the diameter of arterioles either spontaneously or with will (i.e., arterioles inside the penis). Thus, the blood flow through an organ is primarily regulated by adjustments in the internal diameter of arterioles caused by contraction or relaxation of their muscular arteriolar walls.

When the arterioles of an organ change diameter, not only does the flow (in general flow is decreased) to the organ change but also the manner in which the pressures drop within the organ is also modified. Arteriolar constriction causes a greater pressure drop  across the arterioles, and this tends to increase the arterial pressure while it decreases the pressure in capillaries and veins. Conversely, increased organ blood flow caused by arteriolar dilation is accompanied by decreased arterial pressure and increased capillary pressure. Because of the changes in capillary hydrostatic pressure, arteriolar constriction tends to cause transcapillary fluid reabsorption, whereas arteriolar dilation tends to promote transcapillary fluid filtration (see thread Transcapillary Transport at
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Resistances In A Whole Body

The overall resistance to flow through the entire systemic circulation is called the total peripheral resistance. Because the systemic organs are generally arranged in parallel, the vascular resistance of each organ contributes to the total peripheral resistance according to the following  parallel resistance equation:

Screen Shot 2015-07-08 at 10.51.03 PMAccording to the parallel vascular model, the TPR must always be less than that of any of the elements in the network (organ1, organ2, …, organn).

Compliance of Vassels

As indicated earlier, arteries and veins contribute only a small portion to the overall resistance to flow through a vascular bed. Therefore, changes in their diameters have no significant effect on the blood flow through systemic organs. The elastic behavior of arteries and veins is however every important to overall cardiovascular function because they can act as reservoirs and substantial amounts of blood can be stored in them.

Arteries or veins behave more like balloons with one pressure throughout rather than as resistive pipes with a flow-related pressure difference from end to end. Thus, we often think of an “arterial compartment” and a “venous compartment,” each with an internal pressure that is related to the volume of blood within it at any instant and how elastic its walls are.

The elastic nature of a vascular region is characterized by a parameter called compliance that describes how much its volume changes (ΔV) in response to a given change in distending pressure (ΔP): C = ΔV/ΔP. Distending pressure is the difference between the internal and external pressures on the vascular walls. The volume-pressure curves for the systemic arterial and venous compartments are shown in Figure 6-8. It is immediately apparent from the disparate slopes of the curve in this figure that the elastic properties of arteries and veins are very different. For the arterial compartment, the ΔV/ΔP measured near a normal operating pressure of 100 mm Hg indicates a compliance of approximately 2 mL/mm Hg. By contrast, the venous pool has a compliance of more than 100 mL/mm Hg near its normal operating pressure of 5 to 10 mm Hg.

Besides, arterial compliance also decreases with increasing MAP. Otherwise, arterial compliance is a relatively stable parameter.
Screen Shot 2015-07-09 at 8.35.11 PM

Because veins are so compliant, even small changes in peripheral venous pressure can cause a significant amount of the circulation blood volume to shift into or out of the peripheral venous pool. Standing upright, for example, increases venous pressure in the lower extremities, distends the compliant veins, and promotes blood accumulation (pooling) in these vessels, as might be represented by as shift from point A to point B in Figure 6-8. Fortunately, this process can be counteracted by active venous constriction. The dashed line in Figure 6-8 shows the venous volume-pressure relationship that exists when veins are constricted by activation of venous smooth muscle. In constricted veins, volume may be normal (point C) or even below normal (point D) despite higher-than-normal venous pressure. Peripheral venous constriction tends to increase peripheral venous pressure and shift blood out of the peripheral venous compartment.

Mean Arterial Pressure

Mean arterial pressure is a critically important cardiovascular variable because it is the average effective pressure that drives blood through the systemic organs. One of the most fundamental equations of cardiovascular physiology is that which indicates how mean arterial pressure is related to cardiac output and total peripheral resistance:

Screen Shot 2015-07-09 at 9.17.06 PM

This equation is simply a rearrangement of the basic flow equation (Q = ΔP/R) applied to the entire systemic circulation with the single assumption that central venous pressure is approximately zero so that ΔP = MAP. Of note is that all changes in MAP result from changes in either cardiac output or total peripheral resistance.

Arterial Pulse Pressure

The arterial pulse pressure (PP) is defined simply as systolic pressure minus diastolic pressure,

Screen Shot 2015-07-09 at 8.46.59 PM

To be able to use pulse pressure to deduce something about how the cardiovascular system is operating, one must do more than just define it. It is important to understand what determines pulse pressure; that is, what causes it to be what it is and what can cause it to change. As a consequence of the compliance of the arterial vessels, arterial pressure increases as arterial blood volume is expanded during cardiac ejection. The magnitude of the pressure increase (ΔP) caused by an increase in arterial volume depends on how large the volume change (ΔV) is and on how compliant (CA) the arterial compartment is: ΔP = ΔV/CA. If, for the moment, the fact that some blood leaves the arterial compartment during cardiac eject is neglected, then the increase in arterial volume during each heartbeat is equal to the stroke volume (SV). Thus, pulse pressure is, to a first approximation, equal to stoke volume divided by arterial compliance:

Screen Shot 2015-07-09 at 8.58.07 PM

If the stoke volume of a normal resting young man is approximately 80 mL and the arterial compliance is approximately 2 mL/mm Hg, arterial pulse should be approximately 40 mm Hg, according to the equation above. Because the compliance of arteries decrease as age grows, the arterial pulse pressure increases as age grows. Of note, arterial blood volume and mean arterial pressure tend to increase with age. The increase in mean arterial pressure is not caused by the decreased arterial compliance because compliance changes do not directly influence either cardiac output or total peripheral resistance, which are the sole determinants of MAP. And, the decrease in arterial compliance is sufficient to cause increased pulse pressure even through stroke volume tends to decrease with age.

In addition, MAP tends to increase with age because of an age-dependent increase in total peripheral resistance, which is controlled primarily by arterioles, not arteries.

The preceding equation for pulse pressure is a much-simplified description of some very complex hemodynamic processes. It correctly identifies stroke volume and arterial compliance as the major determinants of arterial pulse pressure but is based on the assumption that no blood leaves the aorta during systolic ejection. Obviously, this is not strictly correct. It is therefore not surprising that several factors other than arterial compliance and stroke volume have minor influences on pulse pressure. For example, because the arteries have viscous properties as well as elastic characteristics, faster cardiac ejection caused by increased myocardial contractility tends to increase pulse pressure somewhat even if stroke volume remains constant. Changes in peripheral resistance, however, have little or no effect on pulse pressure, because a change in total peripheral resistance causes parallel change in both systolic and diastolic pressures.

The Theories and the Risk Factors for Urinary Stones

July 6, 2015 Urology No comments , , ,



I would like to dedicate this thread to my dad, Cheney Hsiung, who devote his life to my mom, myself, and his many students over the years at 49th Middle School in Chengdu, Sichuan.



Mineralization in all biologic systems has a common theme in that the crystals and matrix are intertwined. Urinary stones are no exception; they are polycrystalline aggregates composed of varying amounts of crystalloid and organic matrix. But, theories to explain urinary stone disease are incomplete.

Stone formation requires supersaturated urine. Supersaturation depends on urinary pH, ionic strength, solute concentration, and complexation. Urinary constituents may change dramatically during different physiologic states from a relatively acid urine in a first morning void to an alkaline tide noted after meals. Ionic strength is determined primarily by the relative concentration of monovalent ions. As ionic strength increases, the activity coefficient decreases. The activity coefficient reflects the availability to a particular ion.

The calculation of activity product from urinary stone risk factors is briefly described here, illustrated for calcium oxalate. It should be noted that the urinary saturation of calcium oxalate is defined by the activity product (alpha Ca2+ times alpha Ox2-), not by the product of total or ionic calcium and oxalate concentrations.


where alpha Ca2+ is the activity of calcium ion, alpha Ox2- is activity of oxalate ion, [Ca2+] the concentration of calcium ion, [Ox2-] concentration of oxalate ion, and gamma is the activity coefficient. [Ca2+] is the total calcium concentration minus the concentration of soluble complexes principally of calcium-oxalate and calcium-citrate. [Ox2-] is the total oxalate concentration minus the concentration of soluble calcium-oxalate complexes. gamma is an inverse function of ionic strength that is determined by the amount of cations and anions. Alpha Ca2+ is defined by the product of [Ca2+] and gamma. Alpha Ox2- is obtained as the product of [Ox2-] and gamma1.

The role of solute concentrations is clear: The greater the concentration of two ions, the more likely they are to precipitate. Low ion concentrations result in undersaturation and increased solubility. As ion concentrations increases, their activity product reaches a specific point termed the solubility product (Ksp).  Concentrations above this point are metastable and are capable of initiating crystal growth and heterogeneous nucleation. As solutions become more concentrated, the activity product eventually reaches the formation product (Kfp). Supersaturation levels beyond this point are unstable, and spontaneous homogeneous nucleation may occur.

Multiplying two ion concentrations reveals the concentration product. The concentration products of most ions are greater than established solubility products (Ksp). Other factors must play major roles in the development of urinary calculi, including complexation. Complexation influences the availability of specific ions. For instance, sodium complexes with oxalate and decrease it free ionic form, while sulfates can complex with calcium. Crystal formation is modified by a variety of other substances found in the urinary tract, including magnesium, citrate, pyrophosphate, and a variety of trace metals. These inhibitors may act at the active crystal growth sites or as inhibitors in solution (as with citrate).

The nucleation theory suggests that urinary stones originate from crystals or foreign bodies immersed in supersaturated urine. This theory is challenged by the same arguments that support it. Stones do not always form in patients who are hyperexcretors or who are at risk for dehydration. Additionally, up to a third of stone formers’s 24-hour urine collections are completely normal with respect to stone-forming ion concentrations.

The crystal inhibitor theory claims that calculi form due to the absence or low concentration of natural stone inhibitors including magnesium, citrate, pyrophosphate, and a variety of trace metals.

Crystal Component

Stones are composed primarily of a crystalline component. Crystals of adequate size and transparency are easily identified under a polarizing microscope. X-ray diffraction is preferred to assess the geometry and architecture of calculi. A group of stones from the same geographic location or the same historical time period typically have crystalline constituents that are common.

Multiple steps are involved in crystal formation, including nucleation, growth, and aggregation. Nucleation initiates the stone process and may be induced by a variety of substances, including proteinaceous matrix, crystals, foreign bodies, and other particulate tissues. Heterogeneous nucleation, which requires less energy and may occur in less saturated urine, is a common theme in stone formation. It should be suspected whenever an oriented conglomerate is found. A crystal of one type thereby serves as a nidus for the nucleation of another type with a similar crystal lattice. This is frequently seen with uric acid crystals initiating calcium oxalate formation. It takes time for these early nidi to grow or aggregate to form a stone incapable of passing with ease through the urinary tract.

How these early crystalline structures are retained in the upper urinary tract without uneventful passage down the ureter is unknown. The theory of mass precipitation or intranephronic calculus’s suggests that the distal tubules or collecting ducts, or both, become plugged with crystals, thereby establishing an environment of stasis, ripe for further stone growth. This explanation is unsatisfactory; tubules are conical in shape and enlarge as they enter the papilla (ducts of Bellini), thereby reducing the possibility of ductal obstruction. In addition, urine transit time from the glomerulus into the renal pelvis is only a few minutes, making crystal aggregation and growth within the uriniferous tubules unlikely.

The fixed particle theory postulates that formed crystals are somehow retained within cells or beneath tubular epithelium. Alexander Randall noted whitish-yellow precipitations of crystalline substances occurring on the tips of renal papillae as submucosal plaques. These plaques are associated with both the vasa recta and the urinary collecting ducts and grow deep within the papilla. The tips of the plaques can be appreciated during endoscopy of the upper urinary tract. Carr hypothesized that calculi form in obstructed lymphatics and then rupture into adjacent fornices of a calyx. Arguing against Carr’s theory are the grossly visible early stone elements in areas remote from fornices.

Matrix Component

The amount of the noncrystalline, matrix component of urinary stones varies with stone type, commonly ranging from 2% to 10% by weight. It is composed predominantly of protein, with small amounts of hexose and hexosamine. An unusual type to stone called a matrix calculus can be associated with previous kidney surgery or chronic urinary tract infections and has a gelatinous texture. Histologic inspection reveals laminations with scant calcifications. On plain abdominal radiographs, matrix calculi are usually radiolucent and can be confused with other filling defects, including blood clots, upper-tract tumors, and fungal bezoars. Noncontrast computed tomography reveals calcifications and can help to confirm the diagnosis.

The role of matrix in the initiation of ordinary urinary stones as well as matrix stones is unknown. It may serve as a nidus for crystal aggregation or as a naturally occurring glue to adhere small crystal components and thereby hinder uneventful passage down the urinary tract. Alternatively, matrix may have an inhibitory role in stone formation or may be an innocent bystander, playing no active role in stone formation.

Risk Factors


Crystalluria is a risk factor for stones. Stone formers, especially those with calcium oxalate stones, frequently excrete more calcium oxalate crystals, and those crystals are larger than normal (>12 μm). The rate of stone formation is proportional to the percentage of large crystals and crystal aggregates. Crystal production is determined by the saturation of each salt and the urinary concentration of inhibitors and promoters.

Socioeconomic Factors

Renal stones are more common in affluent, industrialized countries. Immigrants from less industrialized nations gradually increase their stone incidence and eventually match that of the indigenous population. Use of soft water does not decrease the incidence of urinary stone.


Diet may have a significant impact no the incidence of urinary stones. As per capita income increases, the average diet changes, with an increase in saturated and unsaturated fatty acids; an increase in animal protein and sugar; and a decrease in dietary fiber, vegetable protein, and unrefined carbohydrates. A less energy-dense diet may decrease the incidence of stones. This fact has been documented during war years when diets containing minimal fat and protein resulted in a decreased incidence of stones. Vegetarians may have a decreased incidence of urinary stones. High sodium intake is associated with increased urinary sodium, calcium, and pH and a decreased excretion of citrate; this increases the likelihood of calcium salt crystallization because the urinary saturation of monosodium urate and calcium phosphate (brushite) is increased. Fluid intake and urine output may have an effect on urinary stone disease. The average daily urinary output in stone former is 1.6 L/d.


Occupation can have an impact on the incidence of urinary stones. Physicians and other white-collar workers have an increased incidence of stones compared with manual laborers. This finding may be related to differences in diet but also may be related to physical activity; physical activity may agitate urine and dislodge crystal aggregates. Individuals exposed to high temperatures may develop higher concentrations of solutes owing to dehydration, which may have an impact on the incidence of stones.


Individuals living in hot climates are prone to dehydration, which results in an increased incidence of urinary stones, especially uric acid calculi. Although heat may cause a higher fluid intake, sweat loss results in lowered voided volumes. Hot climates usually expose people to more ultraviolet light, increasing vitamin D3 production. Increased calcium and oxalate excretion has been correlated with increased exposure time to sunlight. This factor has more impact on light-skinned people and may help explain why African Americans in the United States have a decreased stone incidence. Global warming may increase the incidence of urinary stone disease.

Family history

A family history of urinary stones is associated with an increased incidence of renal calculi. A patient with stones is twice as likely as a stone-free cohort to have at least one first-degree relative with renal stones (30% vs 15%). Those with a family history of stones have an increased incidence of multiple and early recurrences. Spouses of patients with calcium oxalate stones have an increased incidence of stones; this may be related to envi- ronmental or dietary factors. Large studies of identical twins have found that >50% of stones have a significant genetic component. New evidence is finding a significant association between urinary stones and cardiovascular disease.


A thorough history of medications taken may provide valuable insight into the cause of urinary calculi. The antihypertensive medication triamterene is found as a component of several medications, including Dyazide, and has been associated with urinary calculi with increasing frequency. Long-term use of antacids containing silica has been associated with the development of silicate stones. Car- bonic anhydrase inhibitors may be associated with urinary stone disease (10–20% incidence). The long-term effect of sodium- and calcium-containing medications on the devel- opment of renal calculi is not known. Protease inhibitors in immunocompromised patients are associated with radiolu- cent calculi.


1.Charles Y C Pak1, Clarita V Odvina1, Margaret S Pearle, et. al. Effect of dietary modification on urinary stone risk factors. Kidney International (2005) 68, 2264–2273.

Transcapillary Transport

July 2, 2015 Cardiology, Critical Care, Physiology and Pathophysiology No comments , , , , , ,

One of the primary functions of capillary is to provide exchanges, so that oxygen and nutrients could be provided to tissues while carbon dioxide and wastes could be taken away from tissues. Other functions that capillary plays include innate and adaptive immune where leukocytes and other cells could recruit to the site of infection/inflammation, hemostasis where platelet and coagulants could reach the site of bleeding, fluids regulation of endocrine that various hormone could play their actions on distal target tissues, and so on. In this thread we only discuss the transcapillary transport, including transcapillary solute diffusion and transcapillary fluid movement.

Transcapillary Solute Diffusion

Capillaries act as efficient exchange sites where most substances cross the capillary walls simply by passively diffusing from regions of high concentration to regions of low concentration. As in any diffusion situation, there are four factors that determine the diffusion rate of a substance between the blood and the interstitial fluid: 1.the concentration difference; 2.the surface area for exchange (being maximized); 3.the diffusion distance (being minimized); and 4.the permeability of the capillary wall to the diffusing substance. The ease with which a particu­lar solute crosses the capillary wall is expressed in a parameter called its capillary permeability. Permeability takes into account all the factors (diffusion coefficient, diffusion distance, and surface area)- except concentration difference-that affect the rate at which a solute crosses the capillary wall.

PS: Pick’s first law of diffusion, Xd = D*A*(Δ[X]/ΔL), whereas,

D: diffusion coefficient

A: surface area

Δ[X]: concentration difference

ΔL: diffusion distance

Permeability: A + D + 1/ΔL

Capillary beds allow huge amounts of materials to enter and leave blood because they maximize the are across which exchange can occur while minimizing the distance over which the diffusing substances must travel. Capillaries are extremely fine vessels with a lumen (inside) diameter of approximately 5 μm, a wall thickness of approximately 1 μm, and an average length of perhaps 0.5 mm.

Capillaries are distributed in incredible numbers in organs and communicate intimately with all regions of the interstitial space. It is estimated that there are approximately 1010 capillaries in the systemic organs with a collective surface area of approximately 100 m2. That is roughly the area of one player’s side of a single tennis court.

Diffusion is a tremendously powerful mechanism for material exchange when operating over such a short distance and through such a large area. We are far from being able to duplicate – in an artificial lung or kidney, for example – the favorable geometry for diffusional exchange that exist in our own tissue.

As illustrated in Figure 6-1, the capillary wall itself consists of only a single thickness of endothelial cells joined to form a tube. The ease with which a particular solute crosses the capillary wall is expressed in a parameter called its capillary permeability. Permeability takes into account all the factors (diffusion coefficient, diffusion distance, and surface area) – except concentration difference – that affect the rate at which a solute crosses the capillary wall.Screen Shot 2015-06-30 at 8.21.23 PM

Careful experimental studies on how rapidly different substances cross capillary walls indicate that two fundamentally distinct pathways exist for transcapillary exchange. Lipid-soluble substances, such as the gases oxygen and carbon dioxide, cross the capillary wall easily. Because the lipid endothelial cell plasma membranes are not a significant diffusion barrier for lipid-soluble substances, transcapillary movement of these substances can occur through the entire capillary surface area.

The capillary permeability to small polar particles such as sodium and potassium ions is approximately 10,000-fold less than that for oxygen. Nevertheless, the capillary permeability to small ions is several orders of magnitude higher than the permeability that would be expected if the ions were forced to move through the lipid plasma member. It is therefore postulated that capillaries are somehow perforated at intervals with water-filled channels or pores.

Calculation from diffusion data indicate that the collective cross-sectional area of the pores relative to the total capillary surface area varies greatly between capillaries in different organs. Brain capillaries appear to be very tight (have few pores), whereas capillaries in the kidney and fluid-producing glands are much more leaky. On an average, however, pores constitute only a very small fraction of total capillary surface area – perhaps 0.01%. This area is, nevertheless, sufficient to allow very rapid equilibration of small water-soluble substances between the plasma and interstitial fluids of most organs. Thus, the concentrations of inorganic ions measured in a plasma sample can be taken to indicate their concentrations throughout the entire extracellular space.

Transcapillary Fluid Movement

In addition to providing a diffusion pathway for small charged molecules, the water-filled channels that traverse capillary walls permit fluid flow through the capillary wall. Net shifts of fluid between the blood and the interstitial compartments are important for a host of physiological functions, including the maintenance of circulating blood volume, intestinal fluid absorption, tissue edema formation, and saliva, sweat, and urine production. Net fluid movement out of capillaries is referred to as filtration, and fluid movement into capillaries is called reabsorption.

Fluid movement = Kf[(Pc – Pi) – (πc – πi)] [Equation 1]

  • Pc is about 25 mm Hg
  • Pi is about 0 mm Hg or negative values
  • πc is about 25 mm Hg
  • πi is nearly 0 mm Hg

PS: Actually, Rate of filtration = hydraulic permeability × surface area × NFP. As it is difficult to estimate the surface area of a capillary bed, a parameter called the filtration coefficient (Kf) is used to denote the product of the hydraulic permeability and surface area.

NFP: Net filtration pressure

Fluid flows through transcapillary channels in response to pressure differences between the interstitial and intracapillary fluids according to the basic flow equation. However, both hydrostatic and osmotic pressures influence transcapillary fluid movement. The intravascular hydrostatic pressure provides the driving force for causing blood flow along vessels. For example, the hydrostatic pressure inside capillaries, Pc, is approximately 25 mm Hg and is the driving force that causes blood to return to the right side of the heart from the capillaries of systemic organs. In addition, however, the 25-mm Hg hydrostatic intracapillary pressure tends to cause fluid to flow through the transcapillary pores into the interstitium where the hydrostatic pressure (Pi) is near or below 0 mm Hg. Thus, there is normally a large hydrostatic pressure difference favoring fluid filtration across the capillary wall. Our entire plasma volume would soon be in the interstitial if there were not some counteracting force tending to draw fluid into the capillaries. The balancing force is an osmotic pressure that arises from the fact that plasma has a higher protein concentration than does interstitial fluid.

Plasma has a total osmotic pressure of approximately 5000 mm Hg – nearly all of which is attributable to dissolved mineral salts such as NaCl and KCl. As discussed in the section of transcapillary solute diffusion, the capillary permeability to small ions is very high. Their concentrations in plasma and interstitial fluid are very nearly equal and, consequently, they do not affect transcapillary fluid movement.

There is however a small but important difference in the osmotic pressures of plasma and interstitial fluid that is due to the presence of albumin and other large proteins in the plasma, which are normally absent from the interstitial fluid. A special term, oncotic pressure (or colloid osmotic pressure), is used to denote the portion of a solution’s total osmotic pressure that is due to particles that do not move freely across capillaries. Because of the plasma proteins, the oncotic pressure of plasma (πc) is approximately 25 mm Hg. Because of the absence of protein, the oncotic pressure of the interstitial fluid (πi) is nearly 0 mm Hg. Thus, there is normally a large osmotic force for fluid reabsorption into capillaries that counteracts the tendency for intracapillary hydrostatic pressure to drive fluid out of capillaries.

So what is the true fact for the movement of fluid between capillary and interstitum? Fluid balance within a tissue (the absence of net transcapillary water movement) occurs when the bracketed term in [Equation 1] is zero. This equilibrium may be upset by alterations in any of the four pressure terms. The pressure imbalances that cause capillary filtration and reabsorption are indicated on the right side of Figure 6-2.

Screen Shot 2015-07-02 at 7.42.48 PMIn most tissues, rapid net filtration of fluid is abnormal and cause tissue swelling as a result of excess fluid in the interstitial space (edema). For example, a substance called histamine (in inflammation) is often released in damaged tissue. One of the actions of histamine is to increase capillary permeability to the extent that protein leak into the interstitum. Net filtration and edema accompany histamine release, in part, because the oncotic pressure difference (πc – πi) is reduced below normal.

Transcapillary fluid filration is not always detrimental. Indeed, fluid-producing organs such as salivary glands and kidneys utilize high intracapillary hydrostatic pressure to produce continual net filtration. Moreover, in certain abnormal situations, such as severe loss of blood volume through hemorrhage, the net fluid reabsorption accompanying diminished intracapillary hydrostatic pressure helps restore the volume of circulating fluid.