Epinephrine stimulates the Beta Adrenergic Receptor on the cell membrane, which causes the G-regulatory proteins to activate the Adenylate Cyclase (AC, an enzyme). This enzyme then takes ATP (energy from foods) and catalyzes it to cAMP which gets broken down in AMP which gets broken down to ADO (adenosine). The increased levels of cAMP are what cause the physiological effects of epinephrine (which is tissue specific).

Epi--> BAR --> G Pr- --> Adenylate cyclase -->ATP --> cAMP -->AMP --> ADO

Norepinephrine has a local response that yields a similar result on the target tissue as EPI does it causes stimulation of the BAR and causes an increase in cAMP levels.

NorEpi---> BAR --> G Pr- --> Adenylate cyclase --> ATP --> cAMP -->AMP --> ADO

Adenosine (ADO) is a product of the ATP metabolism when the BAR is stimulated by EPI/NorEpi. When there is too much stimulation, adenosine moves to the outside of the cell and stimulates the adenosine receptors on its membrane. This stimulation of the adenosine receptor causes a change to where the G-regulatory proteins shift focus on the adenosine receptor. Since these proteins are no longer stimulating the Adenylate Cyclase, the cell does not catalyze ATP to cAMP. Therefore, adenosine “blocks” the effects of EPI/NE. Adenosine has a very short half-life (about 10 sec.) so it only can act locally.

Epi/NorEpi---> BAR --> /// Adenosine///G Pr-

Acetylcholine (ACH) is released systemically by the parasympathetic nervous system (PNS) when the body wants to stop the stimulation of the BAR by EPI/NorEpi (sympathetic stimulation). It achieves this by a similar method as adenosine. Acetylcholine stimulates an ACH receptor on the same cell membrane and causes the G-regulatory proteins to focus on it. Thereby, the Adenylate Cyclase is not stimulated and ATP is not catalyzed to cAMP.

Epi/NorEpi---> BAR --> /// ACH///G Pr-

Epinephrine, Norepinephrine, Adenosine, Acetylcholine

Which of the 4 neurotransmitters listed above have local effects and which have more general effects?

Epinephrine has a general effect because the adrenal medulla is its only producer so it has to spread to have effect. Its release is stimulated by sympathetic nervous system (SNS- Fight or Flight).

Norepinephrine is made locally at the site and only has local effects. It does not have systemic effects because what is not metabolized, used in stimulation, or what the cell does not reuptake becomes too diluted to have effect on the rest of the body.

Adenosine has only a local effect because it has such a short half life (less than 10 seconds).

Acetylcholine has systemic effects; its release is stimulated by the parasympathetic nervous system.

What effect does norepinephrine have on intracellular cAMP production?

How does norepinephrine produce these effects?

Norepinephrine increases cAMP production. It achieves this by stimulating the Beta Adrenergic Receptor on the cell membrane, which causes the G-regulatory proteins to activate the Adenylate Cyclase (AC, an enzyme). This enzyme then takes ATP (energy from foods) and catalyzes it to cAMP which gets broken down in AMP which gets broken down to ADO (adenosine). The increased levels of cAMP are what cause the physiological effects of norepinephrine.

Something to think about -- When you were in the unit administering inotropes like EPI, NEPI or milrninone (Primacor), the main effect you were achieving was produced as intracellular levels of cyclic AMP increased. In a few weeks we will see how raising cAMP increases myocardial contractility and HR

What is cAMP broken down to?

 What more readily traverses cellular membranes, adenosine or adenosine phosphate?

Why?

cAMP -->AMP (adenosine monophosphate) --> ADO(adenosine)

Adenosine more readily traverses cell membranes because it is lipid soluble. The phosphate molecule causes the adenosine phosphate to be more polarized and thus water soluble. Lipid soluble substances pass through the bilipid cell membrane easily.

Epinephrine that is synthesized in the adrenal glands attaches and activates beta adrenergic receptors in cardiac muscle. The BAR is attached to G proteins that activate Adenylate Cyclase within the cell membrane. This then changes ATP to cAMP, and after another catalyzed reaction it is changed to AMP and then another catalyst changes that to Adenosine. Since Adenosine is highly lipid soluble it can readily diffuse through the lipid bilayer cell membrane into circulating blood system.

NEPI and other catecholamines can also stimulate BAR.

ADO comes from AMP which comes from cyclic AMP which comes from ATP.

Think cyclic AMp.

If cAMP goes up, sympathetic response is increased (eg, HR/contractility will increase).

If cAMP goes down, sympathetic response goes down.

NEPI and EPI will increase cAMP; ADO and ACh will decrease cAMP. NEPI and EPI increase cAMP by increasing adenylate cyclase activity via g-proteins which link BAR to AC. ADO decreases cAMP by decreasing AC activity via inhibitory g-proteins which link ADO receptors to AC. Like adenosine, ACh decreases cAMP by decreasing AC activity via inhibitory g-proteins which link ACh receptors to AC.

Here is a clue. Think about the heart. Your heart is beating at a certain rate. If your kidneys or carotid baroreceptors decide that your blood pressure is too low, they can cause sympathetic tone to be increased and HR and cardiac contractility will increase. This effect is mediated through the sympathetic fibers that innervate the heart (via NEPI). On the other hand, if your carotid baroreceptors sense that blood pressure is too high, they can cause parasympathetic tone to be increased. In this case, the vagus nerve will start firing more, releasing more acetylcholine (ACh). The ACh will stimulate ACh receptors that will then lead to decreasing levels of intracellular cAMP (this is mediated by the inhibitory g-proteins and the enzyme adenylate cyclase). Heart rate and contractility will then decrease.

In addition, the heart itself has local ways to oppose sympathetic stimulation. During cardiac ischemia the heart may consume large amounts of ATP. If this happens, ADO is produced. ADO can leave the inside of the heart cell and stimulate ADO receptors on the cell surface. The net result is that less ATP will be consumed (this is also mediated by the inhibitory g-proteins and the enzyme adenylate cyclase).

Sympathetic and parasympathetic stimulation oppose each other; in the case of the heart, sympathetic stimulation causes cAMP levels to increase and parasympathetic stimulation causes cAMP levels to decrease.

During an MI, the extreme pain and hemodynamic abnormalities (loss of contractility, decreased blood flow to the ischemic area of the heart, hypotension, etc) cause a massive surge of catecholamines from the autonomic nervous system. This is believed to cause the symptoms of nausea, vomiting, and bradycardia.

Catecholamines, such as epinephrine, norepinephrine, and dopamine, are released as a function of the sympathetic nervous system which also causes decreased gastric motility (which may cause nausea) and increased esophageal peristalsis (which may cause vomiting).

Milrinone and amrinone are positive inotropic drugs, meaning that they increase cardiac contractility. These drugs produce thier pharmacologic effect by blocking the action of phosphodiesterase, which is a substance that is responsible for the breakdown of cAMP into AMP (adenosine monophosphate). Intracellular cAMP levels increase as less cAMP is broken down. JM

EPI, NEPI and other catecholamines activate BAR, BAR linked to G(+) regulatory protein in the cell wall activates the enzyme AC, AC catalyzes the conversion of ATP to cAMP. - JM

Which one of the following statements concerning the parasympathetic nervous system is correct:

a. The PNS uses NEPI as a neurotransmitter.

b. The PNS often discharges as a single functional system.

c. The PNS is involved in accomodation of near vision, movement of food, and urination.

d. The postganglionic fibers of the parasympathetic division are long compared to those of the sympathetic nervous system.

e. The PNS controls the secretion of the adrenal medulla.

The PNS is maintains essential bodily functions, such as vision, movement of food, and urination.

It uses acetylcholine as a neurotransmitter, and it discharges as discrete fibers that are activated seperately.

The postganglionic fibers of the PNS are short compared to those on the SNS Division, and the adrenal medulla is under SNS not PNS control.  

Which one of the following is characteristic of parasympathetic stimulation?

a. Decrease in intestinal motility

b. inhibition of bronchial secretions

c. contraction of sphincter muscle in the iris of the eye (miosis).

d. Increase in heart rate.