Baroreceptor

BARORECEPTOR Baroreceptors are sensors located in the cardio-regulatory centers in the brain stem and in Hering’s nerve. They sense blood pressure and relay the information to the brain, which maintains it within normal limits. They are activated by ANY change in BP, stimulating centers in the brain (send information to the brain) which perform reflex actions restoring homeostasis. The sensory information activates autonomic reflexes, which influences the total peripheral resistance by affecting the cardiac output and vascular smooth muscle contraction. Baroreceptors are stretch receptors, so they: 1. Detect stretching in arteries during an increase in BP 2. This results in their stimulation and so the activation of the Vagus nerve (a parasympathetic nerve) 3. Parasympathetic activity then immediately decreases the heart rate which causes the BP to decrease back to normal. Baroreceptors also detect decreases in BP, activating the sympathetic nervous system causing the heart rate to go up. This mechanism is very powerful and interferes with the action of drugs that cause vasoconstriction and an increase in BP. The baroreceptors immediately detect the increase in BP and reflexively stimulate the HR to decrease. | Page1 DIRECT EFFECTS OF AUTONOMIC NERVE ACTIVITY recap of things we are familiar with, but there's no harm IN mentioning them: Organ Sympathetic Receptor Parasympathetic Receptor Mydriasis (pupil becomes wider) No effect α1 Miosis (pupil becomes narrower) Contraction (for near vision) M3 ↑ in heart rate β1 ↓in heart rate M2 Accelerate Increases β1 β1 Decreases (atria) M2 Skin, splanchnic vessels Contract α1 Skeletal muscle vessels Relax β2 Endothelium (drug effect) releases (NO) M3&M5 Relaxes β2 Contracts M3 Eye Radial muscle + Circular muscle Ciliary muscle M3 Heart Sinoatrial node SA node (pacemaker of heart) Ectopic pacemakers Contractility Blood vessels Lungs Bronchiolar smooth muscle Gastrointestinal tract Smooth muscle Walls Relaxes β2 + α2 Contracts M3 Sphincters Secretion Contracts No effect a1 Relaxes Increases M3 M3 Relaxes Contracts Relaxes Ejaculation β2 α1 β2 α Contracts Relaxes No effect Erection M3 M3 Contract α Increase M Genitourinary smooth muscle Bladder wall Sphincter Uterus, pregnant Penis, seminal vesicles M Skin Pilomotor smooth muscles Sweat glands Metabolic functions Liver Fat cells Glycogenolysis, Gluconeogenesis Lipolysis β2, α β2, α β3 Renin release β1 Kidney Kidney | Page2 Additional information about the table: Eye: Has radial muscles (dilators), circular muscles (sphincters) and ciliary muscles. Under parasympathetic stimulation, the circular muscles contract whilst the radial muscles relax, this causes the pupil to constrict and less light enters the eye. The opposite happens under sympathetic stimulation. Ciliary muscles have ligaments attached to the eye lenses and are affected parasympathetically only. When they are stimulated, they contract, pulling the ligaments, which causes the shape of lenses to change. In this case the lenses focus on near objects enabling the vision of near objects like when reading. Heart: An ectopic pacemaker is an excitable group of cells that causes a premature heart beat outside the normally functioning SA node of the heart. In a normal heartbeat rhythm, the SA node usually suppresses the ectopic pacemaker activity due to the higher impulse rate of the SA node. However, in the instance of an ectopic focus bearing an intrinsic rate superior to SA node rate, ectopic pacemaker activity may take over the natural heart rhythm. They reach the AP at a higher frequency than the SA node, causing the heart to pump at a higher rate. β1 receptors increase the activity of these ectopic pacemakers. The contractility is the contractile force of the target cardiac muscles. This is increased by β1 stimulation. The ventricles have no parasympathetic innervation, so the parasympathetic effect is only on the atria, BUT the sympathetic effect is on both the ventricles and atria. Ventricular contraction is very important because it is for ejection of the blood, so M2 receptors only decrease atrial contraction. | Page3 Blood Vessels: Skin and splanchnic (organs in the abdominal cavity) blood vessels have α1 receptors. During the fight-or-flight response they vasoconstrict resulting in decreased blood flow to these organs. This is why your skin’s color becomes white/yellow when you become scared. Extra Information (doctor didn’t explain it clearly): Skeletal muscle blood vessels have both β2 and α1 receptors, β2 stimulation causes vasodilation and α1 stimulation causes vasoconstriction. β2 receptors are less sensitive than α1 receptors which means that at lower concentrations α1 receptors are stimulated without activating β2 receptors. During the fight-orflight response, epinephrine is released into blood in high concentrations stimulating the β2 receptors which cause vasodilation of the skeletal muscle blood vessels. Almost all blood vessels (99%) don’t have parasympathetic innervation. However, they still have M3 receptors, which are found on endothelial cells adjacent to the smooth muscles of the blood vessel. When an exogenous parasympathetic drug (injected) binds to them, they release NO (nitric oxide), which causes the vessel smooth muscles to relax, resulting in vasodilation. Bronchiolar Smooth Muscle: Sympathetic stimulation of β2 receptors causes bronchodilation, hence β2 agonists are used to treat bronchial asthma. However parasympathetic stimulation of M3 receptors causes bronchoconstriction and increases bronchial secretions. These effects resemble a bronchial asthma attack. Gastrointestinal Tract: Stimulation β2 and α2 receptors of the GIT smooth muscle wall causes relaxation, whereas M3 stimulation causes contraction. The sphincter muscle has α1 receptors which are stimulated causing it to close. When the intestinal muscles are relaxed, and the sphincter is closed, nothing passes to the intestine so peristatic activity is inhibited. However, under parasympathetic stimulation the sphincter opens and the GIT smooth muscles contract, so peristatic activity is fast. The person in this case will suffer from diarrhea, colic…, etc. Secretions are only affected by the parasympathetic system. M1 receptors in the stomach reduce gastric (acid) secretions while M3 in the intestine reduce intestinal secretions. | Page4 Genitourinary Smooth Muscles: Sympathetic stimulation causes the bladder wall to relax due to β2 receptors, and the sphincter to contract (close) due to α1 receptors, this makes urination difficult. Parasympathetic stimulation on the other hand causes the opposite effect, contracting the bladder wall and relaxing the sphincter, making urination easy. The uterus is stimulated by the sympathetic system (depends on hormonal balance) but not by the parasympathetic system. Sympathetic stimulation of β2 receptors causes uterus muscle relaxation. Therefore, premature contractions of the uterus in pregnancy are treated by giving β2 agonists to relax the uterus and hence save the pregnancy. Skin: Sweat glands are innervated by cholinergic sympathetic nerves. Specifically, they have muscarinic receptors which increase sweating upon stimulation. Metabolic Function: The liver has α2 and β2 receptors (more important). Under sympathetic stimulation, these promote glycogenolysis (breaking down of glycogen) and gluconeogenesis (synthesis of glucose from non-carbohydrate carbon sources like proteins), because in fight or flight conditions, your body needs energy and blood glucose. Diabetic patients and patients with anxiety, have high blood sugar because epinephrine stimulates β2 receptors to increase gluconeogenesis and glycogenolysis. Fat cells have β3 receptors that promote lipolysis which is the breakdown of lipids to form free fatty acid that are used for energy production in the body. Kidney: Have sympathetic β1 receptors which upon stimulation cause: 1. The release of Renin which is an enzyme that acts on a large protein in blood called angiotensinogen 2. Renin breaks down angiotensinogen into angiotensin I 3. Angiotensin I is converted into angiotensin II which is a potent vasoconstrictor 4. Angiotensin II stimulates the release of the hormone aldosterone 5. Aldosterone causes the retention of sodium and water. | Page5 CHOLINOCEPTOR ACTIVATING & CHOLINESTERASE INHIBITING DRUGS There are two types of drugs that are cholinoceptor stimulants: 1-Direct acting drugs. 2-Indirect acting drugs INDIRECT ACTING DRUGS They perform their job by inhibiting Acetylcholinesterase (ACE), which is a very powerful enzyme; it hydrolyzes Acetylcholine (Ach) within milliseconds of its release. Inhibiting this enzyme increases the con. of ACh at the receptor site thus prolonging its effect (high effect). The drugs don't act directly on the receptor but they inhibit ACE therefore producing an effect similar to the activation of the cholinergic receptors directly. There are two types of indirect acting drugs: 1. Reversible: Inhibit ACE for a short period of time (mins to hours). 2. Irreversible: Very toxic, they permanently inactivate the enzyme, e.g nerve gases. Nicotinic receptors exist in two places: DIRECT ACTING DRUGS 1. Neuromuscular end plates of skeletal muscles 2. Autonomic ganglia cells a- Choline esters The most popular example is endogenous acetylcholine. ACh is not clinically useful, you can't use it as a drug because it'll be degraded the moment it's injected as it has a very short lifetime. If you want to see the effect of Ach you have to give it by infusion (administration directly into a vein). The response obtained depends on the infusion rate. | Page6 Acetylcholine’s structure can be modified to produce new drugs that function better clinically. Examples: 1. Carbachol: acetyl group is substituted with an amide group. a. Dangerous so it can’t be used for systemic actions. 2. Methacholine: methyl group is added. a. Dangerous so it can’t be used for systemic actions. b. Very dangerous as it can cause the heart to stop within seconds. c. Has an increased sensitivity for the cardiovascular system. 3. Bethanechol: a combination of the drugs above; A methyl group is added, and the acetyl group is substituted with an amide group. a. Can be used for systemic actions. b. Bethanechol's muscarinic effect is more in the GI tract and urinary tract than in the cardiovascular system (unlike Methacholine); so it has a less chance of causing bradycardia c. Best drug. * Here we’re talking about cholinoceptor activating drugs, so 99% of their effect is parasympathetic. The effect of ACE on the drugs, and the effect of the drugs on muscarinic and nicotinic receptors: Choline Ester Acetylcholine Methacholine Carbachol Benthanechol by ACE Extremely affected ++++ Slightly affected + Not affected Not affected Degree of effect Muscarinic Receptors Highly affects +++ Extremely affects ++++ Moderately affects ++ Moderately affects ++ Nicotinic Receptors Highly affects +++ No effect Highly affects +++ No effect | Page7 NOTE that the drugs that target nicotinic receptors have more like sympathomimetic effect which is not our point here. b-Alkaloids 1. Muscarine: a. Most well-known one b. Natural c. Has a stronger effect than ACh on muscarinic receptors 2. Pilocarpine (muscarinic agent): a. Direct acting b. Natural alkaloid that comes from plants. 3. Nicotine a. Only stimulates nicotinic receptors 4. Lobeline a. Very similar to nicotine (acts on nicotinic receptors) b. Natural alkaloid that comes from plants. MECHANISM OF ACTION MUSCARINIC TRANSMISSION IN THE HEART The M2 receptor is the most abundant receptor on the heart while the M3 receptor is present in the stomach and most other tissues Mechanism: Ach activates M2 receptors which release Gi proteins: A. Gi protein stimulates K+ channels to open: a. This results in an outflux of K+ ions causing hyperpolarization; the inside of the cell becomes more negative, so a greater AP is needed to produce an effect. b. In the case of the cardiac pacemaker, the voltage-dependent opening of pacemaker Na+ channels is shifted to more negative potentials making them harder to open. Thus, we get less action potentials per unit time and so less contractility and heart rate. | Page8 B. Gi protein also inhibits adenylyl cyclase AC: 1. This decreases cAMP production inside the cell 2. Which results in a decrease in phosphorylation of L-type Ca+2 channels which are responsible for the excitation-contraction coupling of the cardiac muscle. Phosphorylation of these channels increases their permeability to Ca+ and increases the contractility of their respective cardiac myocyte. 3. So less phosphorylation = less contraction of the myocytes which results in a lower heart rate and force of contraction Summary: • M2R stimulates Gi protein → Open K+ channel → Hyperpolarization → ↓HR & ↓ force of contraction. • M2R stimulates Gi protein →↓adenylyl cyclase → ↓cAMP formation→ ↓HR & ↓ force of contraction. NICOTINIC TRANSMISSION AT NEUROMUSCULAR JUNCTIONS: 1. Released Ach binds to and opens the Na+ nicotinic receptors 2. This allows Na+ to flow into the cell, producing an excitatory postsynaptic potential (EPSP). 3. The EPSP depolarizes the muscle membrane, generating an action potential, and triggering contraction. 4. After Ach dissociates, it is metabolized into choline and acetate by the extracellular Acetylcholinesterase (ACE). | Page9 EFFECTS OF DIRECT-ACTING CHOLINOCEPTOR STIMULANTS: MOST OF THESE EFFECTS ARE PARASYMPATHETIC HENCE 99% OF THE CHOLINOCEPTORS ARE PARASYMPATHETIC. Organ Eye Sphincter muscle of iris (circular muscle) Ciliary muscle Heart SA node Atria Atrioventricular node Ventricles Blood vessels Arteries + Veins Lung Bronchial muscle Bronchial glands GI tract Motility Sphincter Secretion Urinary bladder Detrusor Trigone and sphincter Glands Sweat, salivary, lacrimal, nasopharyngeal Response Contraction – stimulation of miosis • Contraction (for near vision) • Facilitation of Aqueous humor outflow into the canal of Schlemm. Decrease in rate (negative chronotropy) Decrease in contractile strength (negative inotropy) • Decrease in conduction velocity (negative dromotropy) • Increase in refractory period. Small decrease in contractile strength (because it is only sympathetic) Dilation via Nitric Oxide Contraction (Bronchoconstriction) Stimulation - increase bronchial secretion Increase Relaxation Stimulation Contraction Relaxation (voiding of urine) ↑ Secretion | Page10 Glaucoma In a normal eye, a liquid called the aqueous humor is continuously produced and drained, maintaining the shape of eye. In glaucoma (eye condition), aqueous humor builds up and increases pressure within the eye. Such increased pressure can damage the optic nerve directly or restrict blood flow, thus damaging the optic nerve indirectly. If a patient has glaucoma, we give him pilocarpine which is a parasympathetic drug that causes the opening of the canal of Schlemm thus facilitating the drainage of aqueous humor to decrease intraocular pressure. Atrioventricular node The AV node is a part of the electrical conduction system of the heart that electrically connects the atria and ventricles by conducting the normal electrical impulse from the atria to the ventricles. It has a refractory period which is the minimum interval between two ventricular impulses propagated from the atria. Parasympathetic activation here decreases the conduction velocity (The speed of impulses (AP) passing from the atrium to the ventricle) and increases the refractory period, so less impulses (AP) pass. If parasympathetic activation increase drastically, heart block occurs (no impulses can pass from the AV node). ORGAN SYSTEM EFFECTS The effect of these drugs on the system as a whole: Cardiovascular system (M2) Intravenous (IV) infusions of low doses of Ach cause: 1. 2. 3. 4. Vasodilation This causes a reduction in blood pressure (Hypotension) Which evokes the baroreceptor reflex Resulting in an increase in heart rate to restore blood pressure to normal levels | Page11 Intravenous (IV) infusions of larger doses of Ach produce: • Bradycardia (↓HR): o The direct effect of Ach on the M2 receptors overrides the Baroreceptor reflex thus reducing the heart rate • Decreases in the AV node conduction velocity • Hypotension due to vasodilation of blood vessels Decrease the contractility of atrial & ventricular cells: • The sympathetic nerve innervating the ventricles has muscarinic receptors. When these are stimulated, the release of norepinephrine is reduced, hence decreasing ventricular contractility. • On the other hand, atria have parasympathetic receptors and the effect observed is due to their direct stimulation. The direct slowing of sinoatrial rate & atrioventricular conduction is often opposed by reflex sympathetic discharge, elicited by the decrease in blood pressure. Mechanism of Muscarinic stimulation (M3 receptors) IV injection of muscarinic agonists produces marked vasodilation: 1. Muscarinic agonists bind to their receptors (M3) 2. This stimulates the release of nitric oxide (NO) from the endothelial cells. 3. NO diffuses to adjacent vascular smooth muscle activating guanylyl cyclase 4. Guanylyl cyclase increases intercellular cGMP concentration resulting in muscle relaxation | Page12 Pilocarpine: Natural alkaloid that may produce hypertension (vasoconstriction) after a brief initial hypotension (vasodilation). The longer-lasting hypertensive Effect is due to sympathetic ganglionic activation caused by activation of ganglionic M1 receptors, which elicit slow excitatory postsynaptic potentials. This effect, like the hypotensive effect, can be blocked by atropine, an antimuscarinic drug. The Initial hypotension is due to stimulation of M3 receptors on endothelial cells, followed by prolonged hypertension due to stimulation of M1 receptors on the postsynaptic sympathetic fibers innervating the BVs, inducing them to release epinephrine & norepinephrine thus increasing the BP and a total result of hypertension. Pilocarpine is used to induce chronic epilepsy in rats, to examine different treatments (M1 effect). Respiratory System: Bronchoconstriction and increase in bronchial secretion. Gastrointestinal Tract: Effects: • • • • Increases the secretory and motor activity of the gut Salivary and gastric glands are strongly stimulated Peristaltic activity is increased Most sphincters are relaxed M3 receptors work through DAG and IP3, increasing calcium ion concentration, which increases contractility in the intestine. So M3 receptors are required for the direct activation of smooth muscle contraction. β2 receptors of the sympathetic nervous system cause relaxation by stimulating cAMP production. M2 receptors cause inhibition of cAMP formation. Therefore, M2 receptors reduce cAMP formation & relaxation caused by sympathomimetic drugs. | Page13 M4 + M2 have similar effects M1 + M3 + M5 have similar effects All of them exist in brain: • • M5 + M4 mostly in the brain M1 + M2 + M3 exist peripherally. Genitourinary Tract: Stimulate the detrusor muscle and relax the trigone and sphincter muscles of the bladder, thus promoting voiding. The function of M2 and M3 receptors in the urinary bladder is the same as in intestinal smooth muscle: • M3 receptors are required for the direct activation of smooth muscle contraction • M2 receptors reduce cAMP formation & relaxation caused by sympathomimetic drugs The human uterus is not sensitive to muscarinic agonists. Miscellaneous Secretory Glands: Muscarinic agonists stimulate secretion of sweat, lacrimal, and nasopharyngeal glands. NICOTINIC EFFECTS OF NICOTINE INTAKE: Central Nervous System: The CNS contains both muscarinic and nicotinic receptors. The brain is richer in muscarinic receptors while the spinal cord contains more nicotinic receptors. Presynaptic nicotinic receptors regulate the release of several neurotransmitters (in physiological concentrations). In high concentrations nicotine induces tremor, emesis, and stimulation of the respiratory center. At even higher levels, nicotine causes convulsions & fatal coma. | Page14 Autonomic ganglia: In the CVS, the effects of nicotine are chiefly sympathomimetic. Nicotine causes: • Hypertension • Tachycardia which may alternate with a bradycardia mediated by vagal discharge (due to baroreceptors). GIT and urinary tracts: The effects are parasympathomimetic: nausea, vomiting, diarrhea, and voiding of urine. Prolonged exposure to nicotine may result in depolarizing blockade of the ganglia. Neuromuscular Junction: Nicotine stimulates nicotinic receptors producing contractile responses that vary from disorganized fasciculations to strong contraction of entire muscles. Nicotine is a stimulant in low concentrations and inhibitor (blocker) at high concentrations Under high concentrations, nicotine causes rapid development of depolarization blockade. This happens when the motor end plate is depolarized for a long period, desensitizing it by blocking the generation of new action potentials for some time. Transmission blockade persists even when the membrane has repolarized. This latter phase of block is manifested as flaccid paralysis of skeletal muscle. | Page15