Mon, April 30, adrenal receptor subtypes...

Today: Epi and Norepi.... we are basically one day behind, but we will get caught up by the end of the quarter.

Brief overview of sympathetic:
The hormones we are interested in are Ep and Norepi. if you are looking at a target cell somewhere in the body, have 2 sources that they can get Epi or Norepi from. 1) post-ganglionic neurons sympathetic neurons... realse Norepi as neurotransmitter 2) adrenal medulla (central part of the adrenal gland). AM releases both Epi and Norepi as hormones.

The sympathetic nervous system is part of the autonomic NS. The autonomic NS regulates endocrin and exocrin glands, contraction of smooth muscle, and cardiac muscle.
Autonomic neurons carry signals from the CNS out to the gland. There are 2 branches: parasympathic NS, and sympathetic NS. (you can disregard parasymp for this class). Sympathetic NS anatomy:
Post-ganglionic sympathetic fiber:

if we have a cell body of a neuron in the CNS, in the spinal cord (in this exp), an axon is sent out and is passed onto smooth or cardiac muscle, or endo/exo glands. The mid point between is a ganglion. it consists of lots of cell bodies and synapses. They are a grey whitish blob. It consists of thousands of axons synapsing on cell bodies. The one between CNS and the ganglion is called a pre0ganglionic fiber or neuron. between the ganglion and the endpoint is post-ganglionic fiber (neuron). At the axon terminal they release Norepi. And the NE reacts with the cells that are close to where it is released. It will either act right there, or go into the blood. This is one source of NE for these 4 targets.

the second source is the adrenal medulla:

The AM is really a highly modified post-symp ganglionic fiber. In the diagram for an AM:
starts with cell body in the spinal cord, and the pre-ganglionic fibers head towards the adrenal gland, and the pregang fiber has lots of axon terms, which make contact with cells, and these cells are called chromoffin cells, which are the source of the Epi/Norepi. Most of the Chromoffin cells release predominants Epi, and some release both Epi/Norepi. The cells release Epi/Norepi and the Epi/Norepi diffuse into the capillaries right next to the chromoffin cells. The part where the cells meet the caps, is all the adrenal medula. The AM is a 'sac' made of a group of cells, innervated by the pre-gang symp fibers. And when the PGSF fire they trigger the release of epi/ne.
IMportant points:
once the AM, when it rleases epi/ne, it is completely random where the epi/ne ends up.
when sympathetic neurons fire, THAT firing is highly directed.
The ratio of epi/norepi from AM, in humans, 80% epi, 20%ne. they also release some dopamine, but we aren't going to worry about that. Most of the hormone in the blood epi/ne, is epi. if it is being stim'd by epi comes from AM, norepi most likely it came from a post-gang symp fiber, even though a small amount comes from AM.

Now lets look at what the hormones look like. The diagram is on eres. tyrosine, dopa, dopamine, nor, epi.

this shows the biosynth pathways for these hormones. E, NE, and DA (dopamine) are all considered catecholamines. This refers to a certain structure of 2 hydroxyl groups off a aramatic ring, side by side (OH) then that is a catechol.

Tyrosine hydrosylase with tyrosine becaome dopa, and reacts with AA decarboxylase to become DA, and reacts with dopamine B-hydroxylase to make Nori, and cortisol triggers pheynylethanolamine-N-methyltranferase (PNMT) to make epi.

You really must know that.

The rate limiting step is the tyrosine hydroxylase step. Takes place in the chromoffin cells or in the post-gang.
Cortisol is produces in the cortex around the AM. Cortisol goes into the medula before it exits into the blood. And Cortisol stims the AM. If we look at the inputs that stimulate this pathway, regulation of Epi and NE secretion:
major regulator is the symp NS. it is always 'on' to a basal level. If the activity is activated beyond the basal level then it raises levels even more. Activation of symp NS is by flight or fight situations. other sits: during exercise, hypoglycemia, hypotension (low BP), and cold exposure. Some inputs trigger AM, and some trigger the PS/symp/NS. so leave yourselves open where it is not black or white. it is case dependant.

let's look at the receptors. 'adrenergic receptor subtypes' from eres:
Adrenergic receptors are the receptors for epi/norepil, do not call them epi-receptors.
The receptors are different in the G protein, and all have specific affinities. they have rougly similar afffinites for e/ne. since the receptors are all connected, but trigger different systems, so it is dependent upon which receptors are present in that area.

let's go on to look at the bioactivities...
the bio act. of e/ne have different catagories:
intermediary metabolism, cardiovascular system,, secretion of other hormones, arousal, metabolic rate.
Let's start with Int Met:
The effect of ep/norepi are mediated largely by beta-type adrenergic receptors. They increase the breakdown of fats and carbs into forms that can be used as fuel. The specific funtions are divided into different tissue types:
liver: (controls alot of int met): Epi/NE increase glycogenolosis (glsyogen breakdown), and increase gluconeogensis, and both of those act to increase blood glucose concentration.

muscle (skeletal): (a huge percentage of body weight): increase glycogenolosys, but the glucose that is freed up can't be released from the muscle because is it phos'd. that increases muscle glucose concetration to serve as fuel for the muscle, and enters glycolosys. it increases lactate and pyruvate production, which can leave the muscle and enter the circulation, and become substrates in the liver for making more glucose.

adapose tissue (fat):(less but still high majority):E/NE increase lipolysis (triglyceride is hydrolyzed to glycerol + fatty acids), and the glycerol is a substate for gluconeogenesis in the liver. the fatty acids can be used for fuel in cells outside the CNS, and alos be broken down into ketones to be used as fuel anyplace.

keypoints: actions on muscle and liver increase glucose concetration (and fat provides glycerol for gluconeogenesis), and fatty acids to allow for alternate fuels. (gluconeogenesis, only in liver or kidney).

Last part of this: in terms of protein met: epi/ne inhibit proteolysis. This is important later because it counteracts effects of cortisol. It is important to protect proteins to maintain structural integrity.

The big difffere3nce here between GH and epi are:
GH inhibits proteolysis, but GH stims aa uptake, but epi doesn't. epi just protects again proteolysis. epi does not act against glucose use in cells. it doesn't inhibit glucose uptake in cells, and doesn't counteract the uptake of insulin in cells like GH.

Let's move on to cardiovascular system:
effects on heart, blood vessels:
heart: mediated via beta 1 adrenergic receptors, what epi does: increases heart rate and contractility (force of contraction, larger means more blood pumped). the net result of both of these is they together increase cardiac output (volume of blood pumped by one ventricle per minute). Cardiac output is one of the things that determines how high blood pressure is.

Blood vessel adrenergic receptors:
-alpha Adrenergic recptors are in the smooth muscles that make upthe walls of blood vessels. Only alpha, then when they bind it causes the smooth muslces contract, and vessel diameter decreases (vasoconstriction)

-beta2 adr. recptors have the opposite effect: smooth muscle relaxes (vasodilation) and opens up blood vessels.

The effect on a blood vessel depends upon the concentrations of both of these. Most contain more alpha than beta adrenergic receptors. The response is vasoconstriction. the exceptions to this are: blood vessels in skeletal muscle, heart, liver, these contain more beta 2 than alpha, and so when epi/ne at high concetrations it causes vasodilation.

The interaction between going on from changing cardiac output vs changing blood vessel diameter. Heart to arteries to arterioles and returning capillaries, to veins and back to heart. (it is alphabetical) BP is measured in arteries. that pressure drives blood all the way through the cardiovascular system. it enters the arts and is at very high pressure, adn it flows down the pressure gradient. the only way for it to work properly is if arterial pressure is higher than veinous pressure, othewise it would go backwards. the body very closesly mointors and regs the pressure in arteries to keep it at the appropriate prssure. if it s too high then arteries in the brain will explode and you have a stroke and die. the two major things that determine blood pressure are: blood pressure entering arteries and blood pressure leaving the arteries. Blood in minus blood out, give you the blood pressure. you can increase the pressure in the arteries by: 1) increasing bloodflow into the arts,from the heart, (cardiac output) of 2) by decreasing the bloodflow out of the arts. what the sympathetic NS and epi/norepi do is to regulate cardiac output, and regulate bloodflow out of the arteries (decrease by vasoconstriction of blood flow out of arterioles. Vasoconstriction by raising E/NE binding to alpha-adrenergic cells.