Month: June 2014

The Properties of Drugs – Receptor Rationale

June 22, 2014 Pharmacology No comments , , , ,

The definition of drug, in the most general sense, is that a drug may be defined as any substance that brings about a change in biologic function through its chemical actions.

The Foundational Section

Generally, four primary factors affect drug-receptor interactions, including 1.drug’s affinity to the according receptor (with respect to Kd);2.the efficiency of the occupancy-response (determined by initial conformational change in the receptor and biochemical events that transduce receptor occupancy into cellular response); of spareness (the total number of receptors present compared with the number actually needed to elicit a maximal biologic response);and number of receptors (determining maximum effect, in the absence of point 3).

The Nature of Drugs

In the most general sense, a drug may be defined as any substance that brings about a change in biologic function through its chemical actions.

In most cases, the drug molecule interacts as an agonist or antagonist with a specific molecule (receptor) in the biologic system that plays a regulatory role. However, in a very small number of cases, drugs known as chemical antagonists may interact directly with other drugs, whereas a few drugs (osmotic agents) interact almost exclusively with water molecules. Also, physiologic antagonism where, for instance, several catabolic actions of the glucocorticoid hormones lead to increased blood sugar, an effect that is physiologically opposed by insulin which act on quite distinct receptor-effector system. Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus famously stated that “the dose makes the poison”, meaning that any substance can be harmful if taken in the wrong dosage. Toxins are usually defined as poisons of biologic origin, in contrast to inorganic poisons such as lead and arsenic. However, in some diseases (e.g., APL), poisons can be used to treat diseases, for instance, arsenic for acute promyelocytic leukemia.

Drug size, acid-base property, shape or stereoisomerism, and drug-receptor bonds all decide the characteristics of a drug. Most drugs have molecular weights between 100 and 1000. The lower limit of this narrow range is probably set by the requirements for specificity of action. The upper limit in molecular weight is determined primarily by the requirement that drugs must be able to move within the body (e.g., from the site of administration to the site of action).

Drug acid-base property and human body pH in different compartments impact the way these drugs are handled by the body (altering the degree of ionization of a drug). The shape of a drug molecule must be such as to permit binding to its receptor site via the bonds. Optimally, the drug’s shape is complementary to that of the receptor site in the same way that a key is complementary to a lock, which makes the effects of different chirality form of a same drug different.

Drug-receptor bonds include three major types: covalent, electrostatic, and hydrophobic. Covalent bonds are very strong and in many cases not reversible under biologic conditions. An example of covalent drug-receptor bond can be found here

Electrostatic bonding is much more common than covalent bonding in drug–receptor interactions. Electrostatic bonds vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces and similar phenomena. Nevertheless, electrostatic bonds are weaker than covalent bounds.

Hydrophobic bonds are usually quite weak and are probably important in the interaction of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor “prockets”. The significance of the type of drug-receptor bonds is that bind through weak bonds to their receptors are generally more selective than drugs that bind by means of very strong bonds. This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur (we call it the conformation change). Thus, in general, if we wished to design a highly selective short-acting drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose a molecule that forms weaker bonds.

Pharmacodynamic Principles and Drug-Receptor Binding

Agonist drugs bind to and activate the receptor in some fashion, which directly or indirectly brings about the effect. Receptor activation involves a change in conformation in the cases that have been studied at the molecular structure level.

Some receptors incorporate effector machinery in the same molecule, so that drug binding brings about the effect directly. Other receptors are linked through one or more intervening coupling molecules to a separate effector molecule and the binding brings about the effect indirectly.

Based on the maximal pharmacologic response that occurs when all receptors are occupied, agonists can be divided into full agonist and partial agonists. Partial agonists produce a lower response, at full receptor occupancy, than do full agonists.

Partial agonists produce concentration-effect curves that resemble those observed with full agonists in the presence of an antagonist that irreversibly blcoks some of the receptor sites (see below). It is important to emphasize that the failure of partial agonists to produce a maximal response is not due to decreased affinity for binding to receptors. Indeed, a partial agonist’s inability to cause a maximal pharmacologic response, even when present at high concentrations that saturate binding to all receptors, is indicated by the fact that partial agonists competitively inhibit the responses produced by full agonists.

Antagonist drugs bind to a receptor but do not activate receptor effectively, meanwhile antagonists compete with and prevent binding by other ligands (other drugs or endogenous regulatory molecules). They stabilize the receptor in its inactive state or some state other than activated state. Of note antagonist-receptor bind can be reversible or irreversible. However, face to antagonist, receptor activated effect could still be achieved by increased the dosage of the agonist.

Antagonists are divided into two classes depending on if or not they reversibly compete with agonists for binding to receptors. (see below for detail)

For competitive antagonists, the degree of inhibition produced by them depends on the concentration of antagonist. And, clinical response to a competitive antagonist also depends on the concentration of agonist that is competing for binding to receptors.

Irreversible antagonists bind to the receptor and this binding is irreversible or nearly irreversible. After occupancy of some proportion of receptors by such an antagonist, the number of remaining unoccupied receptors may be too low for the agonist (even at high concentrations) to elicit a response comparable to the previous maximal response. Therapeutically, irreversible antagonists present distinct advantages and disadvantages. Once the irreversible antagonist has occupied the receptor, it need not be present in unbound form to inhibit agonist responses, thus the duration of action is relatively independent of its own rate of elimination (pharmacokinetic parameter).

Drugs that bind to the same receptor molecule but do not prevent binding of the agonist are said to act allosterically and may enhance or inhibit the action of the agonist molecule. Allosteric inhibitioin is not overcome by increasing the dose of agonist. The drugs of this type modify receptor activity without blocking agonist binding.

Another form of drug-receptor interaction can be termed as ‘agonist that inhibit their binding molecules’. the acetylcholinesterase inhibitors are the classic example of these drugs. These drugs mimic agonist drugs by inhibiting the molecules responsible for terminating the action of an endogenous agonist.

At present, there is another theory that can explain the drug-receptor binding we have talked about above.

As indicated, the receptor is postulated to exist in the inactive, nonfunctional form (Ri) and in the activated form (Ra). Thermodynamic considerations indicate that even in the absence of any agonist, some of the receptor pool must exist in the Ra form some of the time and may produce the same physiologic effect as agonist-induced activity. This effect, occurring in the absence of agonist, is termed constitutive activity.

In this theory agonists are those drugs that have a much higher affinity for Ra configuration and stabilize it, so that a large percentage of the total pool resides in the Ra-D fraction and a large effect is produced. Again, based on the maximal pharmacologic response that occurs when all receptors are occupied, full agonists are drugs that shift of almost all of  the receptor pool to the Ra-D pool. Other drugs, called partial agonists, bind to the same receptors and activate them in the same way but do not evoke as great a response, no matter how high the concentration.

In the figure at left side, partial agonist do not stabilize the Ra configuration as fully as full agonists, so that a significant fraction of receptors exists in the Ri-D pool (in the setting of all receptors have been occupied). Such drugs are said to have low intrinsic efficacy. Thus, these drugs may act either as an agonist (if no full agonist is present) or as an antagonist (if a full agonist is present). Note that intrinsic efficacy is independent of affinity for the receptor. That is the failure of partial agonists to produce a maximal response is not due to decreased affinity for binding to receptors. Indeed, a partial agonist’s inability to cause a maximal pharmacologic response, even when present at high concentrations that saturate binding to all receptors, is indicated by the fact that partial agonists competitively inhibit the responses produced by full agonist (if a full agonist is present).

In the same model, conventional antagonist action can be explained as fixing the fractions of drug-bound Ri and Ra in the same relative amounts as in the absence of any drug. In this situation, no change will be observed, so the drug will appear to be without effect. However, the presence of the antagonist at the receptor site will block access of agonists to the receptor and prevent the usual agonist effect. Such blocking action can be termed neutral antagonism.

If a drug has much stronger affinity for the Ri than Ra state and stabilizes a large fraction in the Ri-D pool, the drug would reduce any constitutive activity, thus resulting in effects that are the opposite of the effects produced by conventional agonists at that receptor. The drug inducing this phenomenon is termed inverse agonists.

Other Mechanisms of Drug Antagonism

The antagonism we have discussed above firstly belongs to chemical antagonism, in that, a antagonist acts simply by ionic binding the receptor and results in the receptor unavailable for interactions with other drugs.

Another type of antagonism is physiologic antagonism between endogenous regulatory pathways mediated by different receptors. For example, several catabolic action of the glucocorticoid hormones lead to increased blood sugar, an effect that is physiologically opposed by insulin. Although glucocorticoids and insulin act on quite distinct receptor-effector system, the clinician must sometimes administer insulin to oppose the hyperglycemic effects of a glucocorticoid hormone, whether the latter is elevated by endogenous synthesis (e.g., a tumor of the adrenal cortex) or as a result of glucocorticoid therapy.

In general, use of a drug as physiologic antagonist produces effects that are less specific and less easy to control than are the effects of a receptor-specific antagonist (chemical antagonist).

Characteristics of Drug-Receptor Binding

Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects. The receptor’s affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors may limit the maximal effect a drug may produce.

Receptors are responsible for selectivity of drug action. The molecular size, shape, and electrical charge of a drug determine whether-and with what affinity-it will bind to a particular receptor among vast array of chemically different binding sites available in a cell, tissue, or patient. Accordingly, changes in the chemical structure of a drug can dramatically increase or decrease a new drug’s affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects.

Receptors mediates the actions of pharmacologic agonists and antagonists. Some drugs and many natural ligands regulate the function of receptor macromolecules as agonists; this means that they activate the receptor to signal as a direct result of binding to it. Some agonists activate a single kind of receptor to produce all their biologic function, whereas others selectively promote one receptor function more than another. Antagonists bind to receptors but do not activate generation of a signal; consequently, they interfere with the ability of an agonist to activate the receptor. The effect of so-called “pure” antagonist on a cell or in a patient depends entirely on its preventing the binding of agonist molecules and blocking their biologic actions. Others, in addition to prevent agonist binding, suppress the basal signaling (“constitutive”) activity of receptors.

Duration of Drug Action

Termination of drug action is a result of one of several processes. In some cases, the effect lasts only as long as the drug occupies the receptor, and dissociation of drug from the receptor automatically terminates the effect. In many cases, however, the action may persist after the drug has dissociated because, for example, some coupling molecule is still present in activated form. In the case of drugs that bind covalently to the receptor site, the effect may persist until the drug-receptor complex is destroyed and new receptors or enzymes are synthesized.

In addition, many receptor-effector systems incorporate desensitization mechanisms for prevent excessive activation when agonist molecules continue to be present for long periods.

Inert Binding Sites

The body contains a vast array of molecules that are capable of binding drugs, however, and not all of these endogenous molecules are regulatory molecules. Binding of a drug to a nonregulatory molecule such as plasma albumin will result in no detectable change in the function of the biologic system, so this endogenous molecule can be called an inert binding site. However, such binding is clinical significant since it affects the distribution of the drug within the body, which belongs to pharmacokinetics and beyond the scope of this thread.

Relation Between Drug Concentration and Response

The relation between dose of a drug and the clinically observed response may be complex (actually it is true). The below relation between drug concentration and drug response is in carefully controlled systems in vitro.

Concentration-Effect Curves & Receptor Binding of Agonists

Responses to low doses of a drug usually increase in direct proportion to dose. As doses increase, however, the response increment diminishes; finally, doses may be reached at which no further increase in response can be achieved. In ideal or in vitro systems, the relation between drug concentration and effect is described by a hyperbolic curve. The formula for this curve is as follow.

E = ( Emax × C ) ÷ ( C + EC50 )

where E is the effect observed at concentration C, Emax is the maximal response that can be produced by the drug, and EC50 is the concentration of drug that produce 50% of maximal effect. Similarly, the relation between drug-receptor binding and drug concentration could be described by the hyperbolic curve too.

B = ( Bmax × C ) ÷ (C + Kd )

where Bmax indicates the total concentration of receptor sites, and Kd represents the concentration of free drug at which half-maximal binding is observed. This constant characterizes the receptor’s affinity for binding the drug in reciprocal fashion: If the Kd is low, binding affinity is high, and vice versa.

The EC50 and Kd may be identical, but need not be. Dose-response data are often presented as a plot of the drug effect (ordinate) against the logarithm of the dose or concentration (abscissa), which transforms the hyperbolic curve as described above into a sigmoid curve with a linear midportion.

PS: attention must be paid that not only the affinity of the receptor for binding the agonist but also the degree of spareness (see below) – the total number of receptors present compared with the number actually needed to elicit a maximal biologic response determine the sensitivity of a cell or tissue to a particular concentration of agonist.

Receptor-Effector Coupling & Spare Receptors

When a receptor is occupied by an agonist, the resulting conformational change is only the first of many steps usually required to produce a pharmacologic response. The transduction process that links drug occupancy of receptors and pharmacologic response is often termed coupling.

Coupling efficiency is relative to if the agonist is full or partial agonist, which determine the conformational change in the receptor; also, coupling efficiency is determined by the biochemical events that transduce receptor occupancy into cellular response. Sometimes the biologic effect of the drug is linearly related to the number of receptors bound. In other cases, the biologic response is a more complex function of drug binding to receptors. This is often true for receptors linked to enzymatic signal transduction cascades.

Many factors can contribute to nonlinear occupancy-response coupling, and often these factors are only partially understood. The concept of “spare” receptors, regardless of the precise biochemical mechanism involved, can help us to think about these effects. Receptors are said to be “spare” for a given pharmacologic response if it is possible to elicit a maximal biologic response at a concentration of agonist that does result in occupancy of the full complement of available receptors. The figure at left show drug concentration-response curve and the phenomenon of spare receptors.

The mechanism of spare receptor are described below. In example of beta adrenoceptor, receptor activation promotes binding of guanosine triphosphate to an intermediate signaling protein and activation of the signaling intermediate may greatly outlast the agonist-receptor interaction. In such case, the “spareness” of receptors is temporal. Maximal response can be elicited by activation of relatively few receptors because the response initiated by an individual ligand-receptor binding event persists longer than the binding event itself.

In other cases, in which the biochemical mechanism is not understood, we imagine that the receptors might be spare in number. If the concentration or amount of cellular components other than the receptors limits the coupling of receptor occupancy to response, then a maximal response can occur without occupancy of all receptors.

Competitive & irreversible antagonists

The concentration (C’) of an agonist required to produce a given effect in the presence of a fixed concentration ([I]) of competitive antagonist is greater than the agonist concentration (C) required to produce the same effect in the absence of the antagonist. The ratio of these two agonist concentrations (dose ratio) is related to the dissociation constant (Ki) of the antagonist by the Schild equation:

C’ / C = 1 + [I] ÷ Ki

Mechanism of Thermoregulation

June 17, 2014 Physiology and Pathophysiology, Uncategorized No comments , , ,

Flag_of_the_United_States_Public_Health_Service.svgThe normal body core temperature is 36.6℃ to 38.3℃ (via rectal), 36 to 37.7℃ (via oral), respectively. The temperature is fluctuating, with lowest in the early morning and highest in the late afternoon or early evening. Even in patients with fever, this diurnal variation of body temperature still exists.

The thermoregulation is based on heat production and heat loss, meanwhile the heat is produced by active tissues supplied by blood and redistributing of blood can increase or decrease heat loss from the body.

Heat Production

Body heat is produced by: 1.basic metabolic processes; intake;and 3.muscular activity.

A variety of basic chemical reactions contribute to body heat production at all times. Ingestion of food increases heat production. But, the major source of heat is the contraction of skeletal muscle.

Heat Loss

Heat can lose from body via conduction, radiation, vaporization of sweat, respiration, urination, and defecation. Each way of heat loss take certain percentage of total heat loss, but the percentage is not always constant and change change, i.e., under different environment temperature, sporting like basketball, etc. At 21℃, vaporization is a minor component in humans at rest. As the environmental temperature approaches body temperature, radiation lossess decline and vaporization losses increase.

When the environmental temperature is below body temperature, heat can lose by conduction and radiation. Conduction is heat exchange between objects or substances at different temperatures that are in contact with one another. For example, when someone is at fever, care givers often put a wet wash on the patient's head. That is, to enhance the heat exchange from the patient to the wet wash via conduction. Note that heat must be exchanged between objects (the skin and environment) that in contact with each other.

In conduction, a basic characteristic of matter is that its molecules are in motion, with the amount of motion proportional to the temperature. These molecules collide with the molecules in cooler objects, transferring thermal energy to them. The amount of heat transferred is proportional to the temperature difference between the objects in contact (thermal gradient). Conduction is aided by convection, the movement of molecules away from the area of contact. Thus, for example, an object in contact with air at a different temperature changes the specific gravity of the air, and because warm air rises and cool air falls, a new supply of air is brought into contact with the object. Of course, convection is greatly aided if the object moves about in the medium or the medium moves past the object, for example, if a subject swims through water or a fan blows air through a room.

Note that heat that is transferred from skin to environment can be trapped by hair and clothing. That is, heat is conducted from the skin to the air trapped in the layer of hair or clothing, then from the trapped air to the exterior. When the thickness of the trapped layer is increased by erection of the hairs (horripilation), heat transfer across the layer is reduced and heat losses are decreased.

Because conduction occurs from the surface of one object to the surface of another, the temperature of the skin determines to a large extent the degree to which body heat is lost or gained. That is, the dilation or constriction of capillaries in the skin change the amount of blood flow from deep tissues to the skin, so resulting in varies of skin temperature and final the degree of heat conduction between body and environment. The rate at which heat is transferred from the deep tissues to the skin is called the tissue conductance.

Radiation is the transfer of heat by infrared electromagnetic radiation from one object to anther at a different temperature with which it is not in contact. When an individual is in a cold environment, heat is lost by conduction to the surrounding air and by radiation to cool objects in the vicinity. Conversely, of course, heat is transferred to an individual and the heat load is increased by these processes when the environmental temperature is above body temperature. Note that because of radiation, an individual can feel chilly in a room with cold walls even through the room is relatively warm. On a cold but sunny day, the heat of the sun reflected off bright objects exerts an appreciable warming effect. It is the heat reflected from the snow, for example, that in part makes it possible to ski in fairly light clothes even though the air temperature is below freezing.

Sweat is another major process transferring heat from the body in humans. Vaporization of water on the skin and mucous membranes of the mouth and respiratory passages takes away heat, by which vaporization of 1 g of water removes about 0.6 kcal of heat. A certain amount of water is vaporized at all times, which is insensible water vaporizing at a rate of approximately 50 mL/h in humans. When sweat secretion is increased, the degree to which the sweat vaporizes depends on the humidity of the environment, where in humidity environment the degree of vaporization of sweat is decreased.

Temperature-Regulating Mechanisms

Information of temperature to the brain and temperature receptors

The hypothalamus is said to integrate body temperature information from sensory receptors (primarily cold receptors) in the skin, deep tissues, spinal cord, extrahypothalamic portions of the brain, and the hypothalamus itself. Each of these five inputs contributes about 20% of the information that is integrated.


The reflex and semireflex thermoregulatory responses in humans include autonomic, somatic, endocrine, and behavioral changes. Generally, one group of responses increases heat loss and decrease heat production (stimulated by exposure to heat);whereas, the other group of responses decrease heat loss and increase heat production (stimulated by exposure to cold).

The main temperature-regulating responses are shown in the figure at left. The reflex responses activated by cold are controlled from the posterior hypothalamus. Those activated by warmth are controlled primarily from the anterior hypothalamus. Note that some thermoregulati `on against heat still occurs after decerebration at the level of the rostral midbrain.

The thermostat

In the hypothalamus there is a thermostat, which controls and maintains the temperature of the individual. If the thermostat has been reset to a new point different from the normal value, the body would sense the difference between true body temperature and the new thermostat via temperature receptors, and after the signal being transmitted into the hypothalamus, the ratio of heat production to heat loss will be changed accordingly via temperature-regulating responses to make the body core temperature the same as the new thermostat. For example, if the thermostat had been reset to above 37℃, the temperature receptors then signal that the actual temperature is below the new set point, and the temperature-raising mechanisms are activated. Then the ratio of heat production to heat loss would increases and the actual body temperature starts to increase until the value equaling the new set point.

Update on Dec 31st 2015

Mechanisms of Heat Loss or Gain

Most of the gain or loss of heat between the body and the environment is through the skin. Heat is mainly transferred to the skin from the internal environment by the circulatory system. There are four general mechanisms of heat transfer between the body and the environment. Radiation is the emission of heat to and from the skin by electromagnetic waves – the rate of the temperature transfer by radiation is proportional to the temperature difference between the body surface and the environment. Conduction is intermolecular thermal heat transfer and usually occurs between the skin and air. One loses heat more rapidly when immersed in water because conduction between the skin and water is faster than that between skin and air. Convection is the loss or gain of heat by the movement of air or water over the body. Because heat rises, air carries heat away from the body by convection. Finally, evaporation of water from the skin and the respiratory tract can carry a large amount of heat generated by the body because of the amount of heat required to transform water from the liquid to the gas phase.

Heat production in humans is usually by metabolism. The basal metabolic rate can be altered by circulating thyroid hormone, and by shivering thermogenesis, driven by innervation of skeletal muscle. Shivering is the rhythmic, involuntary contraction and relaxation of skeletal muscles that generates heat due to increase metabolic rate. Of course, one can voluntarily increase heat production from skeletal muscle with movement.

The Autoregulation of Renal Blood Flow

June 4, 2014 Physiology and Pathophysiology 1 comment , ,

Part I

The capacity of tissues to regulate their own blood flow is referred to as autoregulation. Most vascular beds have an intrinsic capacity to compensate for moderate changes in perfusion pressure by changes in vascular resistance, so that blood flow remains relative constant. This capacity is well developed in the kidneys (see Part II), but it has also been observed in the mesentery, skeletal muscle, brain, liver, and myocardium.

The intrinsic capacity of autoregulation is probably due to in part to the intrinsic contractile response of smooth muscle to stretch (myogenic theory of autoregulation). As the pressure rises, the blood vessels are distended and the vascular smooth muscle fibres that surround the vessels contract. If it is postulated that the muscle responds to the tension in the vessel wall, this theory could explain the greater degree of contraction at higher pressures; the wall tension is proportional to the distending pressure times the radius of the vessel (law of Laplace), and the maintenance of a given wall tension as the pressure rises would require a decrease in radius.

Second, vasodilator substances tend to accumulate in active tissues, and these “metabolites” also contribute to autoregulation (metabolic theory autoregualtion). When blood flow decreases, they accumulate and the vessels dilate; when blood flow increases, they tend to be washed away.

Figure 1 Law of Laplace

Part II

To understand the autoregulation of renal blood flow, firstly, we need to know the normal blood vessels, the innervation of the renal vessels, and the normal renal circulation.

Renal Blood Vessels and Renal Circulation

Renal blood vessels

The renal circulation is diagrammed in Figure 37-3. The afferent arterioles are short, straight branches of the interlobular arteries. Each divides into multiple capillary branches to form the tuft of vessels in the glomerulus. The capillaries coalesce to form the efferent arteriole, which in turn breaks up into capillaries that supply the tubules (peritubular capillaries) before draining into the interlobular veins. There is relatively little smooth muscle in the efferent arterioles.

PS: the arterial segments between glomeruli and tubules are technically a portal system.

The capillaries draining the tubules of the cortical nephrons form a  peritubular network, whereas the efferent arterioles from the juxtamedullary glomeruli drain not only into peritubular network, but also into vessels that form hairpin loops (the vasa recta). These loops dip into the medullary pyramids alongside the loops of Henle. The descending vasa recta have a nonfenestrated endothelium that contains a facilitated transporter for urea, and the ascending vasa recta have a fenestrated endothelium, consistent with their function in conserving solutes.

The efferent arteriole from each glomerulus breaks up into capillaries that supply a number of different nephrons. Thus, the tubule of each nephron dose not necessarily receive blood solely from the efferent arteriole of the same nephron. In humans, the total surface of the renal capillaries is approximately equal to the total surface area of the tubules, both being about 12 m2. The volume of blood in the renal capillaries at any given time is 30-40 mL.

In normal status, the renal blood flow per minute is approximately 1273 mL/min.

Screen Shot 2015-01-08 at 6.44.31 PM

The macula, the neighbouring lacks cells, and the renin-secreting granular cells in the afferent arteriole form the juxtaglomerular apparatus.

Autoregulation of Renal Blood Flow

Function of the renal nerves

Stimulation of the renal nerves increases renin secretion by a direct action of released norepinephrine on β1-adrenergic receptors on the juxtaglomerular cells and it increases Na+ reabsorption, probably by a direct action of norepinephrine on renal tubular cells. The proximal and distal tubules and the thick ascending limb of the loop of Henle are richly innervated (more accurately, the blood vessels of the proximal and distal tubules). When the renal nerves are stimulated to increasing extents in experimental animals, the first response is an increase in the sensitivity of the granular cells in the juxtaglomerular apparatus, followed by increased renin secretion, then increased Na+ reabsorption, and finally, at the highest threshold, renal vasoconstriction with decreased glomerular filtration and renal blood flow. It is still unsettled whether the effect on Na+ reabsorption is mediated via α- or β-adrenergic receptors, and it may be mediated by both. The physiologic role of the renal nerves in Na+ homeostasis is also unsettled, in part because most renal functions appears to be normal in patients with transplanted kidneys, and it takes some time for transplanted kidneys to acquire a functional innervation.

The factors affecting rennin secretion is at thread here .Generally, the stimulation of the renal nerves causes: 1. increased rennin secretion;2. increased Na+ reabsorption;3. renal vasoconstriction;and 4. decreased renal blood flow and GFR.

Regulation of the renal blood flow

Norepinephrine constricts the renal vessels, with the greatest effect of injected norepinephrine being exerted on the interlobular arteries and the afferent arterioles. Dopamine is made in the kidney and causes renal vasodilation and natriuresis (however, controlled trials of dopamine have failed to show a protective effect on renal function). AngII exerts a constrictor effect on both the afferent and efferent arterioles (AngII can try to maintain GFR by constricting the efferent arterioles [when efferent arteriolar constriction is greater than afferent constriction]). Prostaglandins increase blood flow in the renal cortex and decrease blood flow in the renal medulla. Acetylcholine also produces renal vasodilation. A high-protein diet raises glomerular capillary pressure and increase renal blood flow.

Autoregulation of renal blood flow

When the kidney is perfused at moderate pressures (90-220 mm Hg in the dog), the renal vascular resistance varies with the pressure so that renal blood flow is relatively constant (see figure below).

Autoregulation of this type occurs in other organs, and several factors contribute to it (for detail about autoregulation please see the comment after this post). Renal autoregulation is present in denervated and in isolated, perfused kidneys, but is prevented by the administration of drugs that paralyze vascular smooth muscle. It is probably produced in part by a direct contractile response to stretch of the smooth muscle of the afferent arteriole. NO may also be involved.

The main function of the renal cortex is filtration of large volumes of blood through the glomeruli, so it is not surprising that the renal cortical blood flow is relatively great and little oxygen is extracted from the blood (see Table 3.1 below). However, metabolic work is being done, particularly to reabsorb Na+ in the thick ascending limb of Henle, so relative large amounts of O2 are extracted from the blood in the medulla (The PO2 of the cortex is about 50 mm Hg, whereas in medulla it is about 15 mm Hg). I think the reason for the relative high extracting rate includes both relative low blood flow in the medulla and the load of metabolic work. Thus, this makes the medulla vulnerable to hypoxia if flow is reduced further. NO, prostaglandins, and many cardiovascular peptides in this region function in a paracrine fashion to maintain the balance between low blood flow and metabolic needs.

PS: Oxygen Extracted from Various Organs While The Body is at Rest.

Extracted O2 as Percentage of O2 Available

Pathophysiology of Selected Vascular Disorders

June 2, 2014 Cardiology, Physiology and Pathophysiology 1 comment , , , ,


A condition that afflicts the large and medium-sized arteries of almost every human, at least in societies in which cholesterol-rich foodstuffs are abundant and cheap, is atherosclerosis. This condition begins in childhood and, in the absence of acelerating factors, develops slowly until it is widespread in old age. However, it is accelerated by a wide variety of genetic and environmental factors.

Atherosclerosis is characterized by localized fibrous thickenings of the arterial wall associated with lipid-infiltrated plagques that may eventually calcify. Old plaques are also prone to ulceration and rupture, triggering the formation of thrombi that obstruct flow.

Risk Factors Accelerating Atherosclerosis

First let see the risk factors that accelerate the progression of atherosclerosis, since treating the accelerating conditions that are treatable and avoiding those that are avoidable should reduce the incidence of myocardial infarctions, strokes, and other complications of atherosclerosis.

Detail mechanisms of lipid metabolism can be found here


Estrogen increases cholesterol removal by the liver, and the progression of atherosclerosis is less rapid in premenopausal women than in men. In addition, epidemiologic evidence shows that estrogen replacement therapy protects the cardiovascular system in postmenopausal women. But, in several studies, estrogen treatment of postmenopausal women failed to prevent second heart attacks (note here, it was secondary prevention, not primary prevention).

Homocysteine and related molecules

The effect of increased plasma levels of homocysteine and related molecules such as homocystine and homocysteine thiolactone, a condition sometimes called hyperhomocystinemia, deserves emphasis. These increases are assoicated with accelerated atherosclerosis, and the magnitude of the plasma elevation is positively correlated with the severity of the atherosclerosis. Markedly elevated levels resulting from documented mutations of relevant genes are rare, but mild elevations occur in 7% of the general population.

The mechanism responsible for the accelerated vascular damage is unsettled, but homocysteine is a significant source of H2O2 and other reactive forms of oxygen, and this may accelerate the oxidation of LDL.

Cholesterol and triglyceride

Evidence is now overwhelming that lowering plasma cholesterol and triglyceride levels and increasing plasma HDL levels slows, and in some cases reverses, the atherosclerotic process. For the ways to lowering serum cholesterol and triglyceride (including how to elevate HDL) please refer the thread describing the management of dyslipidemia.


Men who smoke a pack of cigarettes a day have a 70% increase in death rate from ischemic heart disease compared with nonsomokers, and there is also an increase in women. The deleterious effects of smoking include endothelial damage caused by carbon monoxide-induced hypoxia. Other factors may also be involved. In general, these deleterious increase the risk of atherosclerosis.

Blood pressure

Because of the increased shear stress imposed on the endothelium by an elevated blood pressure, hypertension is another important modifiable risk factor for atherosclerosis.


In diabetes, there are microvascular complications and macrovascular complications. These complications are shown below:


The nephrotic syndrome and hypothyroidism also accelerate the progression of atherosclerosis.

Pathogenesis of Atherosclerosis

The initial event in atherosclerosis is infiltration of LDLs into the subendothelial region. The endothelium is subject to shear stress, the tendency to be pulled along or deformed by flowing blood. This is most marked at points where the arteries brach, and this is where the lipids accumulate to the greatest degree.

The LDLs are oxidized or altered in other ways. Thus, altered LDLs activate various components of innate immune system including macrophages, natural antibodies, and innate effector proteins such as C-reactive protein and complement. Altered LDLs are recognized by a family of scavenger receptors expressed on macrophages. These scavenger receptors mediate uptake of the oxidized LDL into macrophages and the formation of foam cells. The foam cells form fatty streaks.

The streaks appear in the aorta in the first decade of life, in the coronary arteries in the second decade, and in the cerebral arteries in the third and fourth decades.

Oxidized LDLs have a number of deleterious effects, including stimulation of the release of cytokines and inhibition of NO production. Vascular smooth muscle cells in the vicinity of foam cells are stimulated and move from the media to the intima, where they proliferate, lay down collagen and other matrix molecules, and contribute to the bulk of the lesion. Smooth muscle cells also take up oxidized LDL and become foam cells.

Lipids accumulate both intracellularly and extracellularly.Screen Shot 2015-10-18 at 1.31.03 PM

As the atherosclerotic lesions age, T cells of the immune system as well as macrophages are attracted to them. The intercellular “soup” in the plaques contains a variety of cell-damaging substances, including ozone. Overally, the lesions have been shown to have many of the characteristics of a low-grade infection.

Growth factors and cytokines involved in cell migration and proliferation are also produced by smooth muscle cells and endothelial cells, and there is evidence for shear stress response elements in the flanking DNA of relevant genes in the endothelial cells. Major investigations found bacteria in plaques – Chlamydophila pneumoniae, whereas other organisms have also been found.

As plaques mature, a fibrous cap forms over them. The plaques with defective or broken caps are most prone to rupture. The lesions alone may distort vessels to the point that they are occluded, but it is usually rupture or ulceration of plaques that triggers thrombosis, blocking blood flow.

A characteristic of atherosclerosis that is currently receiving considerable attention is its association with deficient release of NO and defective vasodilation. As noted, oxidized LDLs inhibit NO production. If acetylcholine is infused via catheter into normal coronary arteries, the vessels dialte; however, if it is infused when atherosclerosis is present, the vessels constrict. This indicates that endothelial secretion of NO is defective.

PS: Acetylcholine (ACh) can effect vasodilation by several mechanisms, including activation of endothelial nitric oxide (NO) synthase and prostaglandin (PG) production[1].


1.Kellogg DL Jr1, Zhao JL, Coey U, Green JV. Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin. J Appl Physiol (1985). 2005 Feb;98(2):629-32. [PMID: 15649880]


Current guidelines of Joint Natinal Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure define normal blood pressure as systolic pressure of <120 mm Hg and diastolic pressure of <80 mm Hg. Hypertension is defined as an arterial pressure greater than 140/90 mm Hg in adults on at least three consecutive visits to the doctor’s office.

The most common cause of hypertension is increased peripheral vascular resistance. However, because blood pressure equals total peripheral resistance times cardiac output, prolonged increase in cardiac output can also cause hypertension. These are seen, for example, in hyperthyroidism and beriberi.

In addition, increased blood volume causes hypertension (see below), especially in individuals with mineralocorticoid excess or renal failure; and increased blood viscosity (blood resistance increases with viscosity), if it is marked, can increase arterial pressure.

PS: Cardiac output is a function of stroke volume, heart rate, and venous capacitance. Increased blood volume increase cardiac preload, which causes increase in stroke volume, and finally the cardiac output and arterial pressure.

Pathogenesis of Hypertension