Control of Blood Pressure Changes in blood pressure are routinely made in order to direct appropriate amou nts of oxygen

and nutrients to specific parts of body. For example, when exercis e demands additional supplies of oxygen to skeletal muscles, blood delivery to t hese muscles increases, while blood delivery to the digestive organs decreases. Adjustments in blood pressure are also required when forces are applied to your body, such as when starting or stopping in an elevator. Blood pressure can be adjusted by producing changes in the following variables: Cardiac output can be altered by changing stroke volume or heart rate. Resistance to blood flow in the blood vessel is most often altered by changing t he diameter of the vessel (vasodilation or vasoconstriction). Changes in blood v iscosity (its ability to flow) or in the length of the blood vessels (which incr eases with weight gain) can also alter resistance to blood flow. The following mechanisms help regulate blood pressure: The cardiovascular center provides a rapid, neural mechanism for the regulation of blood pressure by managing cardiac output or by adjusting blood vessel diamet er. Located in the medullar oblongata of the brain stem, it consists of three di stinct regions: The cardiac center stimulates cardiac output by increasing heart rate and contra ctility. These nerve impulses are transmitted over sympathetic cardiac nerves. The cardiac center inhibits cardiac output by decreasing heart rate. These nerve impulses are transmitted over parasympathetic vagus nerves. The vasomotor center regulates blood vessel diameter. Nerve impulses transmitted over sympathetic motor neurons called vasomotor nerves enervate smooth muscles in arterioles throughout the body to maintain vasomotor tone, a steady state of vasoconstriction appropriate to the region. The cardiovascular center receives information about the state of the body throu gh the following sources. Baroreceptors are sensory neurons that monitor arterial blood pressure. Major ba roreceptors are located in the carotid sinus (an enlarged area of the carotid ar tery just above its separation from the aorta), the aortic arch, and the right a trium. Chemoreceptors are sensory neurons that monitor levels of CO2, O2, and H+ (pH). These neurons alert the cardiovascular center when levels of O2 drop or levels o f CO2 and H+ rise. Chemoreceptors are found in carotid bodies and aortic bodies located near the carotid sinus and aortic arch. Higher brain regions, such as the cerebral cortex, hypothalamus, and limbic syst em, signal the cardiovascular center when conditions (stress, fight-or-flight re sponse, hot or cold temperatures) require adjustments to the blood pressure. The kidneys provide a hormonal mechanism for the regulation of blood pressure by managing blood volume. The renin-angiotensis-aldosterone system of the kidneys regulates blood volume. In response to rising blood pressure, the juxtaglomerular cells in the kidneys s ecrete renin into the blood. Renin converts the plasma protein angiotensinogen t o angiotensin I, which, in turn, is converted to angiotensisn II by the lungs. A

ngiotensin II activates two mechanisms that raise blood pressure. Angiotensis II constricts blood vessels throughout the body (raising blood press ure by increasing resistance to blood flow). Constricted blood vessels reduce th e amount of blood delivered to the kidneys, which decreases the kidneys' potenti al to excrete water (raising blood pressure by increasing blood volume). Angiotensis II stimulates the adrenal cortex to secrete aldosterone, a hormone t hat reduces urine output by increasing retention of H2O by the kidneys (increasi ng blood pressure by increasing blood volume). Various substances influence blood pressure. Some important examples follow: Epinephrine and norepinephrine, hormones secreted by the adrenal medulla, increa se blood pressure by increasing heart rate and the contractility of the heart mu scles and by causing vasoconstriction of arteries and veins. These hormones are secreted as part of the fight-or-flight response. Antidiuretic hormone (ADH), a hormone secreted by the hypothalamus, increases bl ood pressure by stimulating the kidneys to retain H2O (increasing blood pressure by increasing blood volume). Arterial natriuretic (ANP), a hormone secreted by the atria of the heart, decrea ses the blood pressure by causing vasodilation and by stimulating the kidneys to excrete more water (decreasing blood pressure by reducing blood volume). Nitric oxide (NO), secreted by endothelial cells, causes vasodilation. Nicotine in tobacco increases blood pressure by stimulating sympathetic neurons to increase vasoconstriction and by stimulating the adrenal medulla to increase secretion of epinephrine and norepinephrine. Alcohol decreases blood pressure by inhibiting the vasomotor center (causing vas odilation) and by inhibiting the release of ADH (increasing H2O output, which de creases blood volume). As you know from our discussions on membrane potential in living cells, our cell s rely on the creation of an ionic gradient for the membrane potential. If you'l l remember, an ionic gradient is basically two gradients combined - the chemical and electrical gradients "combine" together to make the ionic gradient. As firs t year medical students who haven't fully experienced physiology yet (after all, you've only been here a couple of weeks!) you may not realize this, but no self -respecting physiologist is happy unless s/he can apply an equation to something (some say this is the result of deep-seated ... oh never mind...). Luckily for us, Nernst derived an equation that allows us to determine at what point the two forces (chemical and electrical gradients) balance each other - in other words, at what point we have an ionic equilibrium. In the next paragraph we'll talk ab out the two equations (one is an easier derivative that works for us in biology) that Nernst derived and then we'll talk about what it means.

The Nernst equation As originally described by Nernst, the equilbrium potential for any ion is:

E = RT -------------------------------------------------------------------------------ln [X] extracellular --------------------------------------------------------------------------------

zF [X] intracellular

where:

E = The Nernst Equilibrium Potential

R= Ideal Gas Constant

T = Temperature (in Kelvin)

z = the charge of the ion (valence)

F = Faraday's number

ln = natural log (based on e)

[x] = concentration of the ion

Luckily for us in biology, many of the variables are constants (e.g. Temperature is assumed to be body temperature and we will assume that to be 37 C) AND we ca n substitute the log (base 10) for the natural log (e) - so this equation collap ses to something far less intimidtating:

E = z(61.5) x log [X] extracellular --------------------------------------------------------------------------------

[X] intracellular

Yes, you'll still need a calculator, but at least you know where the buttons to push are!

Nernst made certain assumptions that one must be aware of when you use this equa tion. Those assumption are: This equation can only be solved for one ion at a time (e.g. either sodium or pot assium, but not both) The membrane must be completely permeable to that ion. The ion must be at equilbrium Basically, unless these three conditions are met, the membrane potential will NO T be the same as the Nernst equilibrium potential. Note that the fact that not a ll of these conditions are met for most ions most of the time doesn't stop us fr om using the equation - it just means that the Vm will not be the same as what w e calculate! There is one more thing as well - if we want to solve for a negativ e ion (like chloride), we use the absolute value of the valence (1 rather than 1), but invert the intracellular and extracellular equations (so intracellular i s now in the numerator (top) of the equation). Because we only solve for one ion at a time, the "E" in the equation will have a subscript denoting what ion you solved for. Therefore, we will talk about the Nernst potential for sodium, etc.. .

-------------------------------------------------------------------------------Solving the Nernst Equation We are now going to take a few minutes to solve the Nernst equation for sodium s o you can see how to do it... Although there are conditions where I do myself li ke to use the Nernst equation (we'll talk about those below), it is not likely t hat you'll have to do this as a physician (Neurologists, Neurosurgeons, and card iologists - Ignore that last sentence, particularly if you decide to do a little research!). However, seeing the Nernst potentials for each ion is useful to the rest of our discussion. Take a deep breath, calm yourself, find your calculator , and let's do some math... The Nernst potential for Sodium (ENa) First - we'll collect the numbers we need:

ENa = z(61.5) x log [X] extracellular --------------------------------------------------------------------------------

[X] intracellular

where:

ENa = The Nernst potential for sodium

z = the charge of the ion (valence) = +1

[x]i = intracellular concentration = 9.2 mEq

[x]e = extracellular concentration = 130 mEq

Substituting these into our equation, we now have:

ENa = 1(61.5) x log 130 mEq --------------------------------------------------------------------------------

9.2 mEq

This then collapses to:

ENa = 61.5 x log

14.13043... Note that I have truncated the decimal, but all calculations from here were done with the full number, so you may get a slightly different answer than shown bel ow if you use this number. Calculating the log leads to:

ENa = 61.5 x

1.1501555249613

All that's left is to finish out the (by now) simple multiplication:

ENa = + 70.73 mV

So the Nernst Equilibrium potential for sodium is +70.73 mV... --------------------------------------------------------------------------------

So What?

Of course, after doing all that work, one wonders what the point of it was. Ther e are two ways to look at what the number we got (they are the same, you may jus t find one of them conceptually easier to grasp).

If we stick an electrode into our cell at a time when the membrane is completely permeable to sodium and the sodium has come to equilibrium, the membrane potenti al will be +70.73 mV. (Note: remember that only very small amounts of sodium nee d to move to change the membrane potential - the concentration doesn't actually change). At 70.73 mV, the electrical gradient acting on sodium is exactly balanced by the

chemical gradient described by the intracellular and extracellular values I gave you. If we change the membrane potential to a more polarized potential (> 70.73 mV), the electrical gradient is greater then the chemical gradient and sodium w ill move out of the cell if given the chance , while if the Vm is closer to zero (less polarized, < 70.73 mV) the chemical gradient is stronger and sodium moves into the cell (as we normally see). Click here to activate an animation that illustrates this (this animation is nar rated, so have some way of listening ready to go). (I inadvertently used a slightly different set numbers for the calculation of th e Nernst Potential - leading to a difference of about 1 mV. Don't panic! None of the important facts is altered by this. The animation program just isn't very a menable to editing after the fact! Dr.K.) -------------------------------------------------------------------------------The Nernst Potential and resting membrane potential (Vm) It is fairly common to "want" the Nernst equilbrium potential to resemble the re sting Vm of a cell - and as you can quite clearly see, ENa clearly does not! The reason for this is that, at rest, the cell does not meet the criteria for the N ernst potential for sodium - if you will recall, we said that the Nernst Potenti al is calculated based on the assumption that the cell is fully permeable to the ion in question. Thinking back to lecture, the permability of a neuron/muscle c ell at rest to sodium is virtually zero. So we do NOT meet the criteria for bein g at the Nernst potential for sodium! One of the ions that has considerable permeability at rest is potassium. If we s olve for the Nernst Potential for potassium (EK ), we see something interesting:

EK = z(61.5) x log [X] extracellular --------------------------------------------------------------------------------

[X] intracellular

where:

EK = The Nernst potential for potassium

z = the charge of the ion (valence) = +1

[x]i = intracellular concentration = 150 mEq

[x]e = extracellular concentration = 3.5 mEq

Substituting these into our equation, we now have:

EK = 1(61.5) x log 3.5 mEq --------------------------------------------------------------------------------

150 mEq

EK = 61.5 x

log

0.0233333...

Calculating the log leads to:

EK = 61.5 x

-1.6320232147...

And finally, simple multiplication gives us :

EK = - 100.3694277 mV

Because the cell membrane is much more permeable to potassium than sodium at res t, the resting membrane potential is much closer to EK than it is to ENa . The r eason that the resting membrane potential and the EK are not identical is that t he membrane is not completely permeable to potassium. One other ion that has sub stantial resting membrane permability is Chloride... Take a few minutes and figu re out the ECl. Click here to check your work!

-------------------------------------------------------------------------------When might you use the Nernst Potential Despite the fact that I told you in class you will never have to solve the Nerns t equation as a physician, there are two places you might want to: 1.To decide what happens when ion concentrations change: Although intracellular concentrations of the ions don't change commonly, the extracellular concentratio n can and does change in certain clinical situations (fairly common ones, actual ly). These changes can change the resting membrane potential and have serious ef fects on the patient (particularly on the cardiac muscle). The most reliable way of deciding what will happen to the membrane potential is to figure out what ha ppens to the Nernst Potential at the new concentrations. For example, hyperkalem ia (high extracellular potassium) is a fairly common clinical occurrence with so me nasty cardiovascular effects. To decide what happens to excitable tissue, jus t plug the "new" extracellular value into the equation (use the same intracellul ar value as before). Let's say that the new extracellular potassium level is 7 m Eq.. Plug that in and see what happens! Click here to see this example worked ou t. You do have to keep in mind the permeability issue - since excitable tissue i s permeable to potassium at rest, the cell's resting membrane potential will cha nge with changes in the extracellular potassium levels (either move closer to th reshold and become too excitable or hyperpolarize and become less excitable - ne ither one is a great option if we're talking cardiac tissue!). Just another note : keep in mind that the Nernst Potential is describing what happens to the cell in a very isolated situation - there are channels that we have talked about yet whose behavior will change and so the net effect on the cell is not entirely wha t is predicted by the Nernst Potential. 2.In research, to identify the ion that is flowing through a channel: An electro de has no problem detecting ion flow through a channel - after all, that is curr ent flow, something that an electrode is designed to detect. It can even tell us which direction the flow is going (into or out of the cell), also very useful. What the electrode can't do simultaneously is tell us what ion is moving - after all, all ions with positive charges will look the same to the electrode. Howeve r, there is enough difference in the Nernst potential for the different ions tha t we can use the Nernst potential to help us figure out which ion is moving thro ugh the channel. Let's say we have a channel that is allowing a positive ion to enter the cell - but we don't know if that ion is sodium or calcium. Well, we kn ow that the ENa is +69 mV, while ECa is much different. If we bring the cell's m embrane potential to + 70 mV and see the current flow reverse (start to leave th e cell) we have circumstantial evidence that the ion moving through this channel is sodium. In the scientific literature, you will see this referred to as the r eversal potential - we're not using the name Nernst potential because we have on ly circumstantial (not direct) evidence that the ion is sodium.

The imidazole ring of histidine allows it to act as either a proton donor or acc eptor at physiological pH. Hence, it is frequently found in the reactive center of enzymes. Equally important is the ability of histidines in hemoglobin to buff er the H+ ions from carbonic acid ionization in red blood cells All of the amino acids in proteins exhibit the same absolute steric configuratio n as L-glyceraldehyde. Therefore, they are all L-a-amino acids. D-amino acids ar

e never found in proteins, although they exist in nature. D-amino acids are ofte n found in polypetide antibiotics.

The aromatic R-groups in amino acids absorb ultraviolet light with an absorbance maximum in the range of 280nm. The ability of proteins to absorb ultraviolet li ght is predominantly due to the presence of the tryptophan which strongly absorb s ultraviolet light The a-COOH and a-NH2 groups in amino acids are capable of ionizing (as are the a cidic and basic R-groups of the amino acids). As a result of their ionizability the following ionic equilibrium reactions may be written: R-COOH < > R-COO + H+

R-NH3+ < > R-NH2 + H+ The equilibrium reactions, as written, demonstrate that amino acids contain at l east two weakly acidic groups. However, the carboxyl group is a far stronger aci d than the amino group. At physiological pH (around 7.4) the carboxyl group will be unprotonated and the amino group will be protonated. An amino acid with no i onizable R-group would be electrically neutral at this pH. This species is terme d a zwitterion. Like typical organic acids, the acidic strength of the carboxyl, amino and ioniz able R-groups in amino acids can be defined by the association constant, Ka or m ore commonly the negative logrithm of Ka, the pKa. The net charge (the algebraic sum of all the charged groups present) of any amino acid, peptide or protein, w ill depend upon the pH of the surrounding aqueous environment. As the pH of a so lution of an amino acid or protein changes so too does the net charge. This phen omenon can be observed during the titration of any amino acid or protein. When t he net charge of an amino acid or protein is zero the pH will be equivalent to t he isoelectric point: pI.

back to the top Functional Significance of Amino Acid R-Groups In solution it is the nature of the amino acid R-groups that dictate structure-f unction relationships of peptides and proteins. The hydrophobic amino acids will generally be encountered in the interior of proteins shielded from direct conta ct with water. Conversely, the hydrophilic amino acids are generally found on th e exterior of proteins as well as in the active centers of enzymatically active proteins. Indeed, it is the very nature of certain amino acid R-groups that allo w enzyme reactions to occur.

The predominant carbohydrates encountered in the body are structurally related t o the aldotriose glyceraldehyde and to the ketotriose dihydroxyacetone. All carb ohydrates contain at least one asymmetrical (chiral) carbon and are, therefore, optically active. In addition, carbohydrates can exist in either of two conforma tions, as determined by the orientation of the hydroxyl group about the asymmetr ic carbon farthest from the carbonyl. With a few exceptions, those carbohydrates that are of physiological significance exist in the D-conformation. The mirror-

image conformations, called enantiomers, are in the L-conformation. Nonose Neuraminic acid, also called sialic acid Pentose Ribose, Ribulose, Xylulose in all cases, however, the predominant monosaccharide found in polysaccharides is D-glucose.

Glycogen is the major form of stored carbohydrate in animals. This crucial molec ule is a homopolymer of glucose in a (1,4) linkage; it is also highly branched, wi th a (1,6) branch linkages occurring every 8-10 residues. Glycogen is a very compa ct structure that results from the coiling of the polymer chains. This compactne ss allows large amounts of carbon energy to be stored in a small volume, with li ttle effect on cellular osmolarity. Sucrose: prevalent in sugar cane and sugar beets, is composed of glucose and fru ctose through an a (1,2) -glycosidic bond.

Lactose: is found exclusively in the milk of mammals and consists of galactose a nd glucose in a (1,4) glycosidic bond.

Maltose: the major degradation product of starch, is composed of 2 glucose monom ers in an a (1,4) glycosidic bond. Starch is the major form of stored carbohydrate in plant cells. Its structure is identical to glycogen, except for a much lower degree of branching (about every 20 30 residues). Unbranched starch is called amylose; branched starch is called a mylopectin. As a class, the nucleotides may be considered one of the most important metaboli tes of the cell. Nucleotides are found primarily as the monomeric units comprisi ng the major nucleic acids of the cell, RNA and DNA. However, they also are requ ired for numerous other important functions within the cell. These functions inc lude: 1. serving as energy stores for future use in phosphate transfer reactions. Thes e reactions are predominantly carried out by ATP. 2. forming a portion of several important coenzymes such as NAD+, NADP+, FAD and coenzyme A. 3. serving as mediators of numerous important cellular processes such as second messengers in signal transduction events. The predominant second messenger is cy clic-AMP (cAMP), a cyclic derivative of AMP formed from ATP.

4. controlling numerous enzymatic reactions through allosteric effects on enzyme activity. 5. serving as activated intermediates in numerous biosynthetic reactions. These activated intermediates include S-adenosylmethionine (S-AdoMet or SAM) involved in methyl transfer reactions as well as the many sugar coupled nucleotides invol ved in glycogen and glycoprotein synthesis