Effects of direct and indirect cholinergics on cardiovascular system

Effects of direct and indirect cholinergics on cardiovascular system

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If I give intravenous acetylcholine then the effects produced on cardiovascular system are hypotension , tachycardia and increased cardiac output. Now if I give intravenous acetylcholine esterase inhibitors on another patient then the effects produced on cardiovascular system are hypertension, bradycardia and decreased cardiac output. Ach esterase inhibitors also increase acetylcholine concentration then why does the effects are exactly opposite in the above mentioned two cases.

Reference for abovementioned data : Cholinergic drugs , katzung pharmacology, 14th edition.

Is it because Ach esterase inhibitors increase Ach concentration locally in the tissues which produce more direct effects while the Ach is rapidly metabolised in the plasma so can't reach into the tissues so it produces more indirect effects via baroreflex ?


R.S. Vardanyan , V.J. Hruby , in Synthesis of Essential Drugs , 2006

Publisher Summary

Cholinomimetics or cholinergic drugs are those drugs that cause effects similar to those resulting from introduction of acetylcholine, or simulation of ganglions of the parasympathetic nervous system. These drugs imitate action of endogenously released acetylcholine. Acetylcholine is the primary neurotransmitter in the parasympathetic division of the autonomic nervous system, which mainly innervates the gastrointestinal tract, eyes, heart, respiratory tract, and secretory glands. Cholinomimetics can be classified as: Direct-acting (receptor agonists), acting on muscarinic and nicotinic, and Indirect-acting (cholinesterase inhibitors), which, in turn, can be reversible or irreversible. Direct-acting cholinomimetics are drugs that act directly by stimulating cholinergic receptors. These drugs are divided into drugs that stimulate muscarinic (M-cholinoreceptors) or nicotinic (N-cholinoreceptors) receptors. Indirect-acting cholinomimetic drugs, such as anticholinesterase drugs are inhibitors of acetylcholine metabolism and have similar effects to direct-acting cholinomimetics. Finally, this chapter discusses the classification of cholinomimetics.

Cholinergic and Anti-Cholinergic Drugs

Welcome to this video tutorial on cholinergic & anticholinergic drugs and their effects on the parasympathetic nervous system.
First we will take a look at the different divisions of the nervous system.

The nervous system is made up of the central nervous system (the brain & spinal cord) & the peripheral nervous system (neurons outside the brain & spinal cord).
peripheral nervous system is then divided into the autonomic & somatic nervous system.

The autonomic system is further broken down into the sympathetic & parasympathetic nervous system.

The sympathetic (SNS) & parasympathetic (PSNS) are opposing systems.

When the SYMPATHETIC system excites an organ, the PARASYMPATHETIC system inhibits it and when the PARASYMPATHETIC system excites an organ, the SYMPATHETIC system inhibits the action.

*Our focus in this lesson is on how cholinergic & anticholinergic agents affect the parasympathetic nervous system.

– Drugs that stimulate the parasympathetic system
– Also called parasympathomimetics – they mimic the effects of the PSNS neurotransmitter
– Cholinergic agents copy the action of acetylcholine (ACh) – a neurotransmitter released from nerve endings that bind on the receptors of cell membranes of organs, tissues & glands

Direct-acting cholinergic drugs bind to cholinergic receptors on specific effector organs, stimulating the organ in a similar way as ACh.

– They are synthetic derivatives of choline.

– Have widespread systemic effects including cardiac muscle, smooth muscle, exocrine glands, & the eye.

Indirect-acting cholinergic drugs inhibit the enzyme ‘acetylcholinesterase,’ resulting in more ACh available at the receptors.

– These drugs have the added cholinergic effect of improved skeletal muscle tone & strength.

– Indirect-acting cholinergic drugs for Alzheimer’s disease are widely distributed, including to the central nervous system, thus improving cholinergic neurotransmission in the brain.

Effects of cholinergic drugs

CNS – enhanced cognitive functions such as arousal, attention, & memory encoding – treatment for Alzheimer’s disease & dementia
Eye – pupil constriction – for surgery & treatment of glaucoma
GI – smooth muscle stimulant – for post-op abdominal distention or paralytic ileus
GU – urinary bladder stimulant – for post-op or postpartum urinary retention
Musculoskeletal (indirect acting cholinergic drugs) – improve muscle tone & strength – for myasthenia gravis

Too much cholinergic medication can result in overstimulation of the parasympathetic nervous system, causing unwanted side effects.

The acronym SLUDGE-M will help us remember the adverse effects of cholinergic drugs.

Other Adverse Effects of Cholinergic drugs

* Overdosing can cause life-threatening problems
* Antidote for cholinergics is the anticholinergic drug atropine

Specific examples of cholinergic drugs

Contraindications to using cholinergic drugs

*Cholinergic drugs can exacerbate these conditions & should be avoided.

Anticholinergic agents
– Drugs that block the action of ACh on the parasympathetic nervous system.
– These cholinergic blocking agents compete with ACh & block it at the receptors in the PSNS – so ACh is unable to bind to the receptor site & cause a cholinergic effect.
– Most anticholinergic drugs interact with muscarinic cholinergic receptors in the brain, secretory glands, heart, smooth muscle, & eye.

Effects of anticholinergic drugs on various systems:

Adverse Effects of Anticholinergics

The effect of the drug may be therapeutic, but becomes an adverse reaction if severe or if the drug is given for another purpose or if there is an overdose.
– CNS – excessive stimulation (tremor, restlessness, confusion), followed by excessive CNS depression (respiratory depression, coma)
– Tachycardia
– Constipation (result of decreased GI motility & muscle tone)
– Dry mouth (result of decreased salivation)
– Urinary retention
– Hot, dry skin (due to decreased sweating)
– Blurred vision, dilation of the pupil (pt may need sunglasses)

* The specific antidote for anticholinergic overdose is

Specific Examples of Anticholinergic Drugs

Belladonna alkaloids & derivatives:
Atropine – a naturally occurring belladonna alkaloid, given for bradyarrhythmias (it produces a stimulant effect), also given as an antidote for cholinergic poisoning.
Ipratropium (Atrovent) – causes bronchodilation, used in asthma & COPD.
Scopolamine – given for motion sickness, N/V.

Centrally acting anticholinergics used in Parkinson’s disease:
Benztropine (Cogentin) – Also used to treat dystonic reactions caused by antipsychotic drugs

Urinary antispasmodics – given for overactive bladder:
Oxybutynin (Ditropan)
Solifenacin succinate (VESIcare)

Contraindications to Using Anticholinergic Drugs
Any condition characterized by symptoms that would be aggravated by the drugs (myasthenia gravis, glaucoma, MI)

Cholinergic drugs stimulate the parasympathetic nervous system by copying the action of Ach.
Cholinergic drugs are given for Alzheimer’s disease, glaucoma, paralytic ileus, urinary retention, & myasthenia gravis.
Anticholinergic drugs block the action of ACh on the parasympathetic nervous system.

Anticholinergic drugs are given for Parkinsons’s disease, asthma, COPD, & overactive bladder

Thank you for watching this video tutorial on cholinergic & anticholinergic effects on the parasympathetic nervous system.

Cardiac glycosides with target at direct and indirect interactions with nuclear receptors

Cardiac glycosides are compounds isolated from plants and animals and have been known since ancient times. These compounds inhibit the activity of the sodium potassium pump in eukaryotic cells. Cardiac glycosides were used as drugs in heart ailments to increase myocardial contraction force and, at the same time, to lower frequency of this contraction. An increasing number of studies have indicated that the biological effects of these compounds are not limited to inhibition of sodium-potassium pump activity. Furthermore, an increasing number of data have shown that they are synthesized in tissues of mammals, where they may act as a new class of steroid hormones or other hormones by mimicry to modulate various signaling pathways and influence whole organisms. Thus, we discuss the interactions of cardiac glycosides with the nuclear receptor superfamily of transcription factors activated by low-weight molecular ligands (including hormones) that regulate many functions of cells and organisms. Cardiac glycosides of endogenous and exogenous origin by interacting with nuclear receptors can affect the processes regulated by these transcription factors, including hormonal management, immune system, body defense, and carcinogenesis. They can also be treated as initial structures for combinatorial chemistry to produce new compounds (including drugs) with the desired properties.

Keywords: Cardiac glycoside Digoxin Nuclear receptor Ouabain.

Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.

Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that have influenced the work reported in this paper.

How does the Nervous System Work?

You must know how the nervous system works to understand cholinergic and anticholinergic drugs fully.

The Nervous System has two major subdivisions:

  • Central Nervous System (CNS) – It comprises the brain and the spinal cord.
  • Peripheral Nervous System (PNS) – It is responsible for the body’s nerves, and it connects the brain and spinal cord to the organs, muscles, and other senses in the periphery of the body.

The Peripheral Nervous System consists of:

  • Somatic Nervous System (SNS) – It relays motor and sensory information back and forth to the CNS.
  • Autonomic Nervous System (ANS) – It controls the glands and internal organs.

In this topic, we will focus more on the Autonomic Nervous System that is subdivided into:

To understand more of the Parasympathetic and Sympathetic Nervous system, here is a summarized and easy-to-understand guide on their functions in the body. Just remember that these two basically have opposite functions.

Parasympathetic Sympathetic
– Constrict: Pupil & Bronchi
– Stimulates: Salivation, Digestion & Bladder
– Decreased: Heart Rate & Blood Pressure
– Study Tip: The Parasympathetic nervous system is responsible for the stimulation of “Rest and Digest” or “Feed and Breed” activities
– Dilate: Pupil and Bronchi
– Inhibit: Salivation, Digestion, Bladder
– Increased: Heart Rate & Blood Pressure
– Study Tip: It stimulates the “Fight or Flight” response of the body


The autonomic nervous system (ANS) is the component of the peripheral nervous system that controls cardiac muscle contraction, visceral activities, and glandular functions of the body. Specifically the ANS can regulate heart rate, blood pressure, rate of respiration, body temperature, sweating, gastrointestinal motility and secretion, as well as other visceral activities that maintain homeostasis[1-4]. The ANS functions continuously without conscious effort. The ANS, however, is controlled by centers located in the spinal cord, brain stem, and hypothalamus.

The ANS has two interacting systems: the sympathetic and parasympathetic systems. As illustrated in Figure ​ Figure1, 1 , sympathetic and parasympathetic neurons exert antagonistic effects on the heart. The sympathetic system prepares the body for energy expenditure, emergency or stressful situations, i.e., fight or flight. Conversely, the parasympathetic system is most active under restful conditions. The parasympathetic counteracts the sympathetic system after a stressful event and restores the body to a restful state. The sympathetic nervous system releases norepinephrine (NE) while the parasympathetic nervous system releases acetylcholine (ACh). Sympathetic stimulation increases heart rate and myocardial contractility. During exercise, emotional excitement, or under various pathological conditions (e.g., heart failure)[5], the sympathetic nervous system is activated. The stimulation of the sympathetic nervous system causes pupil dilatation, bronchiole dilatation, blood vessel constriction, sweat secretion, inhibits peristalsis, increases renin secretion by the kidneys, as well as can induce reproductive organ contraction and secretion. In contrast, parasympathetic stimulation decreases heart rate and constricts the pupils. It also increases secretion of the eye glands, increases peristalsis, increases secretion of salivary and pancreatic glands, and constricts bronchioles. Most organs receive innervations from both systems, which usually exert opposing actions. However, this is not always the case. Some systems do not have a response to parasympathetic stimulation. For example, most blood vessels lack parasympathetic innervations and their diameter is regulated by sympathetic nervous system input, so that they have a constant state of sympathetic tone. It is a decrease in sympathetic stimulation or tone that allows vasodilatation. During rest, sleep, or emotional tranquility, the parasympathetic nervous system predominates and controls the heart rate at a resting rate of 60-75 bpm. At any given time, the effect of the ANS on the heart is the net balance between the opposing actions of the sympathetic and parasympathetic systems.

Autonomic nervous system regulation of the heart function. The autonomic nervous system affects the rate and force of heart contractions. CNS: Central nervous system RA: Right atria LA: Left atria RV: Right ventricle LV: Left ventricle SA: Sino-atrial node AV: Atrioventricular node NE: Norepinephrine ACh: Acetylcholine.

Unlike the somatic nervous system, where a single neuron originating in the spinal cord typically connects the central nervous system and a skeletal muscle via a neuromuscular junction, both sympathetic and parasympathetic pathways are composed of a two-neuron chain: a preganglionic neuron and a postganglionic neuron. The neurotransmitter between the preganglionic and postganglionic neurons is acetylcholine, the same as that in neuromuscular junctions. Messages from these systems are conveyed as electrical impulses that travel along axons and cross synaptic clefts (using chemical neurotransmitter).

In the sympathetic system (thoracolumbar division), these nerves originate from the thoracolumbar region of the spinal cord (T1-L2) and radiate out towards the target organs. In contrast, the nerves of the parasympathetic system originate within the midbrain, pons and medulla oblongata of the brain stem and part of these fibers originate in the sacral region (S2-S4 sacral spinal nerves) of the spinal cord. While sympathetic nerves utilize a short preganglionic neuron followed by a relatively long postganglionic neuron, parasympathetic nerves (e.g., the vagus nerve, which carries about 75 percent of all parasympathetic fibers) have a much longer preganglionic neuron, followed by a short postganglionic neuron.

Cardiac sympathetic nervous system

The sympathetic nervous system is the component of the ANS that is responsible for controlling the human body’s reaction to situations of stress or emergency (otherwise known as the 𠇏ight-or-flight” response), while the parasympathetic nervous system is generally responsible for basal organ system function.

Cardiac sympathetic preganglionic nerves (typically all myelinated) emerge from the upper thoracic segments of the spinal cord (T1-T4). After traveling a short distance, preganglionic fibers leave the spinal nerves through branches called white rami and enter sympathetic ganglia. The cardiac sympathetic neurons form the sympathetic chain ganglia located along the side of the viscera column (i.e., paravertebral ganglia). These ganglia comprise the sympatheric trunks with their connecting fibers. The postganglionic fibers, extend to the viscera, such as the heart. In general, sympathetic preganglionic neurons are shorter than sympathetic postganglionic neurons (Figure ​ (Figure1 1 ).

Sympathetic neurotransmitters: Neurotransmitters are chemical substances released into the synaptic cleft from nerve terminals in response to action potentials. They transmit signals from a neuron to a target cell across a synapse, e.g., acetylcholine for neuromuscular junctions. While the preganglionic neurons of both the sympathetic and parasympathetic system secret acetylcholine (ACh) which is why they are referred to as cholinergic, the majority of the postganglionic endings of the sympathetic nervous system release NE, which resembles epinephrine (i.e., adrenalin). Thus, these sympathetic postganglionic fibers are commonly called adrenergic fibers.

Sympathetic receptors: There are two types of adrenergic receptors: β and α. In the cardiovascular system there are β1, β2, α1, and α2 adrenergic receptors (Table ​ (Table1 1 ).

Table 1

Sympathetic and parasympathetic receptors and their functions in the heart and vessels


β1 adrenergic receptors are expressed in the heart (in the SA node, AV node, and on atrial and ventricular cardiomyocytes). The activation of β1 receptors increases heart rate (via the SA node), increases contractility as result of increased intracellular calcium concentrations and increased calcium release by the sarcoplasmic reticulum (SR), and increased AV node conduction velocity. Additionally, activation of this receptor also induces renin release by the kidneys to help maintain blood pressure, plasma sodium levels and blood volume.

β2 adrenergic receptors are mainly expressed in vascular smooth muscle, skeletal muscle, and in the coronary circulation. Their activation elicits vasodilatation, which, in turn increases blood perfusion to target organs (especially the liver, heart, and skeletal muscle). These receptors are not innervated and thus are primarily stimulated by circulating epinephrine. There are also some low expressions of β2 receptors in cardiomyocytes.

α1 adrenergic receptors are expressed in vascular smooth muscle proximal to sympathetic nerve terminals. Their activation elicits vasoconstriction. There are also some low expressions of α1 receptors in cardiomyocytes.

α2 adrenergic receptors are expressed in vascular smooth muscle distal from sympathetic nerve terminals. Their activation also elicits vasoconstriction.

Sympathetic nervous system control and heart function: Stimulation by the sympathetic nervous system results in the following effects on the heart (Table ​ (Table1): 1 ): Positive chronotropic effect (increase in heart rate): The sinoatrial (SA) node is the predominate pacemaker of the heart. It is located within the upper posterior wall of the right atrium, and is responsible for maintaining a sinus rhythm of between 60 and 100 beats per minute. This rate is constantly being affected by innervations from both the sympathetic and parasympathetic nervous systems. Stimulation by the sympathetic system nerves results in an increase of heart rate, as occurs during the 𠇏ight-or-flight” response.

Positive inotropic effect (increase of contractility): Myocardial contractility represents the ability of the heart to produce force during contraction. It is determined by the incremental degrees of binding between myosin (thick) and actin (thin) filaments, which in turn depends on the concentration of calcium ions (Ca 2+ ) in the cytosol of the cardiomyocyte. Stimulation by the sympathetic nervous system causes an elevation in intracellular (Ca 2+ ) and thus an increase in contraction of both the atria and ventricles.

Positive dromotropic effect (enhancement of conduction): Stimulation by the sympathetic nervous system also enhances the conductivity of the electrical signal. For example, it increases AV conduction velocity.

Parasympathetic nervous system

As previously mentioned, the parasympathetic nervous system is responsible for the unconscious regulation of the body’s systems, most notably, salivation, lacrimation, urination, digestion, and defecation (acronym SLUDD). Importantly, the parasympathetic nervous system plays an antagonistic role in regulating heart function.

The parasympathetic system has preganglionic neurons (craniosacral division) that arise from neurons in the mid-brain, pons and medulla oblongata. The cell bodies of parasympathetic preganglionic neurons are located in the homologous motor nuclei of the cranial nerves. Parasympathetic preganglionic fibers associated with parts of the head are carried by the oculomotor, facial, and glossopharygeal nerves. The fibers that innervate organs of the thorax and upper abdomen are parts of the vagus nerve which as previously mentioned carries approximately 75% of all parasympathetic nerve fibers passing to the heart, the lungs, the stomach, and many other visceral organs. Preganglionic fibers arising from the sacral region of the spinal cord make up parts of S2-S4 sacral spinal nerves and carry impulses to viscera in the pelvic cavity. The short postganglionic neurons reside near effector organs, e.g., lacrimal gland, salivary glands, heart, trachea, lung, liver, gallbladder, spleen, pancreas, intestines, kidney, and urinary bladder, etc. Unlike the sympathetic system, most parasympathetic preganglionic fibers reach the target organs and form the peripheral ganglia in the wall of the organ. The preganglionic fibers synapse within the ganglion, and then short postganglionic fibers leave the ganglia to the target organ. Thus, in the parasympathetic system, preganglionic neurons are generally longer than postganglionic neurons (Figure ​ (Figure1 1 ).

Parasympathetic neurotransmitters: Acetylcholine is the predominant neurotransmitter from the parasympathetic nervous system, in both the preganglionic and postganglionic neurons. Although excitatory in skeletal muscle by binding to nicotinic receptors and inducing the opening of ligand gated sodium channels, acetylcholine inhibits the contraction of cardiomyocytes by activating muscarinic receptors (M2). These parasympathetic postganglionic fibers are commonly called cholinergic fibers because they secrete acetylcholine at their nerve endings.

Acetylcholine is synthesized by choline acetlytransferase in cholinergic neurons by combining choline and acetyl-COA molecules. Once assembled in synaptic vesicles near the end of the axon, the entry of calcium causes the vesicles to fuse with the membrane of the neuron and to release acetylcholine into the synaptic cleft (the space between the neuron and post-synaptic membrane or effector cell). Acetylcholine diffuses across the synaptic cleft and binds to receptors on the post-synaptic membrane increasing the permeability to sodium causing depolarization of the membrane and propagation of the impulse. This chemical transmission is much slower than the electrical 𠇊ll or none” transmission of the action potential seen in the intrinsic nervous system of the heart. To regulate the function of these neurons (and thus, the muscles they control), acetylcholinesterase is present in the synaptic cleft. It serves to hydrolyze the acetylcholine molecule by breaking it down into choline and acetate, which are then both taken back up by the neuron, to be again synthesized into acetylcholine.

Parasympathetic receptors: The parasympathetic postganglionic fibers are cholinergic. Acetylcholine can bind to two types of cholinergic receptors called nicotinic receptors and muscarinic receptors. Muscarinic receptors are located in the membranes of effector cells at the end of postganglionic parasympathetic nerves and at the ends of cholinergic sympathetic fibers. Responses from these receptors are excitatory and relatively slow. The nicotinic receptors are located at synapses between pre- and post-ganglionic neurons of the sympathetic and parasympathetic pathways. Nicotinic receptors in contrast to muscarinic receptors produce rapid, excitatory responses. Neuromuscular junctions found in skeletal muscle fibers are nicotinic.

In relation to the cardiovascular system the parasympathetic nervous system has two different kinds of muscarinic receptors: the M2 and M3 receptors (Table ​ (Table1 1 ).

The M2 receptors are expressed in the heart abundant in nodal and atrial tissue, but sparse in the ventricles. The binding of acetylcholine to M2 receptors serves to slow heart rate till it reaches normal sinus rhythm. This is achieved by slowing the rate of depolarization, as well as by reducing the conduction velocity through the atrioventricular node. Additionally, the activation of M2 receptors reduces the contractility of atrial cardiomyocytes, thus reducing, in part, the overall cardiac output of the heart as a result of reduced atrial kick, smaller stroke volume, and slower heart rate. Cardiac output is determined by heart rate and stroke volume (CO = HR x SV).

The M3 receptors are mainly expressed in vascular endothelium. The predominate effect of M3 receptor activation is dilatation of the vessels, by stimulating nitric oxide production by vascular endothelial cells[6]. M3 receptors impact afterload and vascular resistance which can again alter cardiac output and blood pressure.

Parasympathetic nervous system control and heart function: As mentioned earlier, parasympathetic activity produces effects that are, in general, opposite to those of sympathetic activation. However, in contrast to sympathetic activity, the parasympathetic nervous system has little effect on myocardial contractility.

Negative chronotropic effect (decrease in heart rate): The vagus nerve directly innervates the sinoatrial node when activated, it serves to lower the heart rate, thus exhibiting a negative chronotropic effect.

Negative inotropic effect (decrease in myocardial contractility): Currently, it is a matter of debate whether parasympathetic stimulation can exhibit negative inotropic effects, as the vagus nerve does not directly innervate cardiomyocytes other than that of the sinoatrial and atrioventricular nodes, however, recent in vivo studies may suggest otherwise, at least in the atrium.

Negative dromotropic effect (decrease conduction velocity): Stimulation of the parasympathetic system serves to inhibit AV node conduction velocity.

Cellular signal transduction

Most sympathetic and parasympathetic receptors are known to be G protein-coupled receptors (GPCRs). In the heart, the G-protein-cAMP-PKA signaling pathway mediates the catecholaminergic control on heart rate and contractility.

Signaling pathway of sympathetic stimulation: The sympathetic stimulation-induced effects in the heart result from activation of β1-adrenoceptors, which are GPCRs (Figure ​ (Figure2). 2 ). The sympathetic neurotransmitter NE (as well as other catecholamines) bind to β1 receptors and activate stimulatory G proteins (Gs) by causing a conformational change within the Gs, so that the disassociated αs subunit can then bind to and activate adenylyl cyclase (AC). The activation of this enzyme then catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP). This second messenger may then activate a myriad of other pathways, ion channels, transcription factors, or enzymes. With regards to the cardiovascular system, the most important enzyme that cAMP activates is protein kinase A (PKA). PKA, which in turn, phosphorylates multiple target proteins, such as L-type Ca channels (LTCC), the SR Ca handling protein phospholamban, and contractile machinery such as troponin C, I and T. Additionally, cAMP binds directly to ion channels responsible for the funny current (If), thus increasing the heart rate[7].

Signal transduction systems for β-adrenergic receptor and muscarinic-receptor stimulations in a cardiac myocyte. NE: Norepinephrine 㬡: Beta1-adrenergic receptor Gs: Stimulatory G-protein: Ach: Acetylcholine m2: Type-2 muscarinic receptors Gi: Inhibitory G-protein AC: Adenylate cyclase PKA: Protein kinase A ICa,L: L-type Ca channel RyR2: Ryanodine receptor 2 SERCA: Sarcoplasmic reticulum Ca 2+ -ATPase2a PLB: Phospholamban.

Signaling pathway of parasympathetic stimulation: The parasympathetic stimulation-induced effects in the heart result from activation of muscarinic (M2) receptors, which are also GPCRs by acetylcholine (Figure ​ (Figure2). 2 ). The parasympathetic neurotransmitter ACh binds to M2 receptors thereby activating inhibitory G proteins (Gi) by causing a conformational change within the Gi subunit, so that the disassociated αi subunit can then bind to and inhibits AC. Since M2 receptors are negatively coupled to AC and thus reduce cAMP formation, M2 receptors act to inhibit PKA activity and exert an opposite effect on ion channels, Ca 2+ handling proteins, and contractile machinery, compared to sympathetic stimulation.

Autorhythmic cells: Regulation of pacemaking current and heart rate: The funny current (If) is thought to be the pace making current in the SA node. It is a non-selective cation channel that can inwardly conduct both sodium and potassium ions. As the membrane potential becomes increasingly hyperpolarized during phase 3 and 4 of the action potential, If increases inward potassium and sodium currents, which causes the phase 4 diastolic depolarization. If channels are activated by direct binding of cAMP[7].

In addition to the funny current, one of the other driving mechanisms behind the automaticity of the pacemaking cells within the SA node is the calcium clock[8]. As the SR fills with calcium, the probability of spontaneous calcium release increases in contrast, when the SR calcium stores are depleted, the probability of spontaneous calcium release is reduced. Increased Ca 2+ entry also increases automaticity because of the effect of [Ca 2+ ]i on the transient inward current carried by the sodium-calcium exchange current (INCX). When these pacemaking mechanisms depolarize the resting membrane potential and reach the threshold voltage, which induces the opening of L-type Ca channel (LTCC), an action potential is fired.

On the other hand, M2 receptor stimulation opens muscarinic potassium channels (KACh)[9]. These channels are opened by M2 receptors binding to ACh and produce a hyperpolarizing current that opposes the inward pacemaker current. Therefore, the parasympathetic stimulation increases outward K + permeability, slowing the heart rate and reducing automaticity.

Cardiomyocytes: Regulation of cellular Ca 2+ handling and cardiac contraction: Excitation-contraction coupling in cardiomyocytes is dependent on calcium-induced calcium release, whereby an action potential initiates an increase in cellular calcium through opening of the LTCC on the cellular membrane. This creates a positive feedback loop by activating the ryanodine receptors of the SR causing the release of an even greater amount of calcium. This calcium then binds to troponin C, moving the tropomyosin complex off the actin active site, so that the myosin head can bind to the actin filament. Hydrolysis of ATP then causes the myosin head to pull the actin filament toward the center of the sarcomere. Free intracellular calcium is then resequestered into the SR via the SR ATPase pump (SERCA), or is pumped from the cell via the sodium-calcium exchanger on the cellular membrane. Finally, the troponin complex returns the actin filament to its binding sites to tropomyosin.

Sympathetic stimulation leads to the elevation of cAMP levels and the activation of PKA, which phosphorylates the α1 subunits of the LTCCs. This increases the opening probability of LTCCs and the inward Ca 2+ current, and thus enhances the force of cardiac contraction. In addition, PKA phosphorylates phospholamban, thus relieving its inhibition of SERCA, which in turn facilitates Ca 2+ uptake by the SR and increases the amount of Ca 2+ (i.e., SR Ca 2+ content) available for release by the action potential. Furthermore, activation of β1-adrenoceptors also increases the Ca 2+ sensitivity of the contractile machinery, mediated by phosphorylation of troponin C. Taken together, the net result of sympathetic stimulation is to elevate cardiac function and steepen both contraction and relaxation.

Since M2 receptors are negatively coupled to AC and thus reduce cAMP formation, they act to decrease the open probability of LTCCs and reduce Ca 2+ current. In opposition to sympathetic stimulation, parasympathetic stimulation reduces the activity of Ca 2+ handling proteins in cardiomyocytes.

Autonomic regulation of vascular function: In contrast to the heart, most vessels (arteries and veins) only receive sympathetic innervation, while capillaries receive no innervation. These sympathetic nerve fibers tonically release norepinephrine, which activates α1-adrenergic and β2-adrenergic receptors on blood vessels thereby providing basal vascular tone. Since there is greater α1-adrenergic than β2-adrenergic receptor distribution in the arteries, activation of sympathetic nerves causes vasoconstriction and increases the systemic vascular resistance primarily via α1 receptor activation. On the other hand, modified sympathetic nerve endings in the adrenal medulla release circulating epinephrine, which also binds to α1 and β2-adrenergic receptors in vessels. However, β-adrenergic receptors show greater affinity for epinephrine than for norepinephrine. Therefore, circulating epinephrine at low concentrations activates only β1-adrenergic (mainly in the heart) and β2-adrenergic (mainly in vessels) receptors, which increase cardiac output and cause vasodilation, respectively. It should be noted that vessels at different locations may react differently to sympathetic stimulation. For example, during the 𠇏ight or flight” response the sympathetic nervous system causes vasodilation in skeletal muscle, but vasoconstriction in the skin.

Cardiovascular reflexes and the regulation of blood pressure

In the human body, the ANS is organized as functional reflex arcs (Figure ​ (Figure3). 3 ). Sensory signals from receptors distributed in certain parts of the body are relayed via afferent autonomic pathways to the central nervous system (i.e., spinal cord, brain stem, or hypothalamus), the impulses are then integrated and transmitted via efferent pathways to the visceral organs to control their activities. The following reflexes play major roles in regulating cardiovascular functions.

Schematic of cardiovascular reflexes and their influences on heart and vessels functions. NTS: Nucleus tractussolitarii Symp: Sympathetic CNS: Central nervous system RAAS: Renin-angiotensin-aldosterone system.

Baroreceptor reflex: Baroreceptors located within the aortic arch and the carotid sinuses detect increases in blood pressure. These mechanoreceptors are activated when distended, and subsequently send action potentials to the rostral ventrolateral medulla (RVLM located in the medulla oblongata of the brainstem) which further propagates signals, through the autonomic nervous system, adjusting total peripheral resistance through vasodilatation (sympathetic inhibition), and reducing cardiac output through negative inotropic and chronotropic regulation of the heart (parasympathetic activation). Conversely, baroreceptors within the venae cavae and pulmonary veins are activated when blood pressure drops. This feedback results in the release of antidiuretic hormone from cell bodies in the hypothalamus into the bloodstream from the nerve endings in the posterior lobe of the pituitary gland. The renin-angiotensin-aldosterone system is also activated. The subsequent increase in blood plasma volume then results in increased blood pressure. The final baroreceptor reflex involves the stretch receptors located within the atria like the mechanoreceptors in the aortic arch and carotid sinuses, the receptors are activated when distended (as the atria become filled with blood), however, unlike the other mechanoreceptors, upon activation, the receptors in the atria increase the heart rate through increased sympathetic activation (first to the medulla, then subsequently to the SA node), thus increasing cardiac output and alleviating the increased blood volume-caused pressure in the atria[10].

Chemoreceptor reflex: Peripheral chemoreceptors located in the carotid and aortic bodies monitor oxygen and carbon dioxide content as well as the pH of the blood. Central chemoreceptors are located on the ventrolateral medullary surface in the central nervous system and are sensitive to the surrounding pH and CO2 levels. During hypovolemia or severe blood loss, blood oxygen content drops and/or pH is decreased (more acidic), and levels of carbon dioxide are likely increased, action potentials are sent along the glossopharyngeal or vagus nerves (the former for the carotid receptors, the latter for the aortic) to the medullary center, where parasympathetic stimulation is decreased, resulting in an increase in heart rate (and thus an increase in gas exchange as well as respiration). Additionally, sympathetic stimulation is increased, resulting in further increases to heart rate, as well as stroke volume, which in turn results in an even greater restoration of cardiac output.

Cardiovascular autonomic dysfunction and heart rate variability: It has been known that sympathetic stress/dominance occurs during heart failure or after myocardial infarction, and may trigger lethal arrhythmias. This sympathovagal imbalance is reflected by reduced heart rate variability (HRV). HRV is determined from ECG and has currently been used clinically as both a diagnostic as well as a prognostic factor for assessing cardiovascular autonomic dysfunction including cardiac autonomic neuropathy. Please refer a recent review article for specific HRV indicators and their interpretations[11].


Cholinergic drugs that act like the neurotransmitter ACh are called direct-acting cholinergics . The parasympathetic branch of the autonomic nervous system partly controls the process of micturition (voiding of urine) by constricting the detrusor muscle and relaxing the bladder sphincter (see Fig. 26.1). Micturition is both a voluntary and an involuntary act. Urinary retention (not caused by a mechanical obstruction, such as a stone in the bladder) results when micturition is impaired. Treatment of urinary retention with direct-acting cholinergic drugs causes contraction of the bladder smooth muscles and passage of urine.

Myasthenia gravis is a disease that involves rapid fatigue of skeletal muscles because of the lack of ACh released at the nerve endings of parasympathetic nerves. Cholinergic drugs that prolong the activity of ACh by inhibiting the release of AChE are called indirect-acting cholinergics or anticholinesterase muscle stimulants . Drugs used to treat this disorder act indirectly to inhibit the activity of AChE and promote muscle contraction.

Treatment of glaucoma with an indirect-acting cholinergic drug produces miosis (constriction of the iris). Although used for many years, these drugs are rarely used today due to frequency of dosing and side effects experienced. See the Summary Drug Table: Cholinergic Drugs for a more complete listing of these drugs.

Major uses of the cholinergic drugs are in the treatment of the following:

Mechanism of venous and arterial responses

Reports on the mechanism of any acute venodilatory effect brought about by intravenous frusemide are somewhat inconsistent. Again patients with chronic heart failure, acute heart failure secondary to myocardial infarction and sodium-depleted healthy volunteers have all been studied. Yet from these different groups, enough consistent observations have arisen to allow us to determine some of the events which follow the injection of frusemide.

Plasma renin activity has been consistently noted to rise in the minutes following the administration of frusemide [14], irrespective of whether venodilatation [4, 5, 15,] or arterial constriction [12] predominates. Prostaglandins are thought to be responsible for promoting the acute release of renin into the circulation [16]. Inhibition of prostaglandin synthesis by cyclooxygenase inhibition diminishes the level of plasma renin activity after frusemide [17, 18]. Plasma renin activity but not the venodilator effect increases with dose [7]. This seems to suggest, that the ability of frusemide to stimulate renin release is not instrumental in its venodilator action. However bumetanide, which does not appear to cause venodilatation, also does not cause an acute rise in plasma renin activity following intravenous administration [6]. Unfortunately no other studies have addressed the lack of association between renin release and venous relaxation, but it may simply be due to a finite degree of dilatation in the veins being achieved before the limit of renin release is reached.

Following the acute release of renin it has been assumed that angiotensin II is formed. Indeed pre–treatment of patients with an ACE inhibitor causes the venodilatation in response to frusemide in salt depleted subjects to diminish [19]. In patients with chronic heart failure, the arterial constricting effect is similarly reduced [20].

Angiotensin II is an arterial [21] and venous vasoconstrictor [21, 22] which induces contraction in internal mammary arteries greater than that in saphenous vein segments at the same concentration [23]. This effect is probably mediated through the AT1 receptor [24�]. Activation of the AT2 receptor is thought to counter many of the effects of the AT1 receptor and therefore may cause dilatation in response to angiotensin II [27�]. When the endothelium is removed from a vein segment, the constrictor response to angiotensin II is increased [21]. Human venous endothelial cells can produce prostaglandins, in vitro, in response to angiotensin II stimulation [30]. This implies that in vivo, the endothelial cell responds to the direct effect of angiotensin II, possibly via the AT2 receptor, by producing prostaglandins as a compensatory response to angiotensin II induced contraction mediated by the AT1 receptor. Prostaglandins, produced by the endothelium would be the obvious candidates through which frusemide induces venodilatation in capacitance vessels. This would also concur with the findings that pre–treatment with cyclooxygenase inhibitors diminishes the acute effects of frusemide [8, 15].

In view of the above, it is probable that frusemide causes prostaglandin mediated release of renin. It has been assumed that angiotensin II is formed as a result. Angiotensin II may cause contraction of the venous and arterial smooth muscle via the AT1 receptor. This effect would, seem to be outweighed in veins, but not arteries, through the relaxation of the smooth muscle in response to dilatory prostaglandins formed by the endothelium as a result of angiotensin II binding to the AT2 receptor. Therefore, in patients with acute heart failure secondary to myocardial infarction and salt depleted volunteers, venodilatation is primarily observed with arterial constriction being less evident. Hence, with venous dilatation rather arterial constriction being dominant, symptomatic relief occurs (before the onset of diuresis).

Yet in patients with chronic heart failure, the venous relaxant effect does not seem to take place, or at least seems to be outweighed by arterial constriction. There is no reason to suppose that this is due to any sort of tolerance. The additional angiotensin II produced by frusemide administration, and resultant arterial constriction, is compensated by venodilatation in patients with acute heart failure secondary to myocardial infarction. However, in patients with chronic heart failure veins may be already compensating for the higher levels of circulating angiotensin II [25]. Further angiotensin II may lead only to deleterious arterial constriction, unopposed by a venous response. Either the veins may be unable to effect any further dilatation, or, they are unable dilate enough to outweigh the effects of arterial vasoconstriction and produce a beneficial haemodynamic response.

The different outcome between salt deplete subjects and chronic heart failure patients is harder to explain. Possibly, chronically high angiotensin II concentrations could alter angiotensin II receptor density and the seemingly delicate balance between angiotensin II mediated contraction of arteries and compensatory dilatation in veins. Chronic structural changes may occur in the veins of patients with chronic heart failure and this could alter their responsiveness to frusemide.

Direct venodilatation

Most evidence would point to an indirect method of venodilatation for frusemide. Some investigators have found frusemide to be a direct in vivo dilator of veins [8], whilst others have not [11]. Pickkers et al. [8] found frusemide to have a direct dilatory effect on dorsal hand veins of normal volunteers and that this effect was independent of nitric oxide by inhibiting nitric oxide synthase with N-monomethyl- l -arginine (L-NMMA). The concentration of frusemide at the point in the vein where venodilatation was measured, was far less than the supra-therapeutic concentrations used by Ellory & Stewart [31] to inhibit the Na + /K + /2 CL-ion channels in human red blood cells. Thus Pickkers et al. [8] concluded that inhibition of these channels was not the mechanism by which frusemide was working. The direct effect of frusemide was inhibited by cyclooxygenase inhibition and was therefore deemed to be prostaglandin dependent. This finding concurs with that of investigators who advocate an indirect mechanism of action. Furthermore, in 1998, Stanke and colleagues [23] reported that frusemide in therapeutic concentrations can inhibit the response to angiotensin II of internal mammary artery and saphenous vein segments in vitro. Therefore, it can be speculated that frusemide might have very weak angiotensin receptor blocking properties.

The acute haemodynamic response to frusemide would seem to depend upon a balance between indirect and direct effects, with indirect mechanisms predominating. The balance between these mechanisms would appear to depend on the type of patient studied. The acute haemodynamic response in different patient groups would therefore appear to be dependent on how these mechanisms equilibrate.

II. Endocrine Signals and the Cardiovascular System

The cardiovascular system responds to multiple endocrine signals, and there are strong parallels between the mechanisms of endocrine and other types of signals that influence the function of the cardiovascular system (nutritional signals, nerve inputs, etc.). Endocrine signals that influence the cardiovascular system can be divided largely into two types according to whether they are mediated by nuclear receptors (including cholesterol and fatty acid metabolites, steroids, and thyroid hormones) or cell surface receptors that work by initiating second messenger signaling cascades (including peptide hormones, cytokines, and neurotransmitters). We discuss below the roles of nuclear and cell surface receptors separately. However, in reality, the actions of both types of signal overlap extensively and are significantly integrated.

Gum disease and the connection to heart disease

For me, it's been one of the more surprising observations in recent years: study after study has shown that people who have poor oral health (such as gum disease or tooth loss) have higher rates of cardiovascular problems such as heart attack or stroke than people with good oral health.

Why would cardiovascular disease and poor oral health be connected?

A number of theories have been proposed, including:

  • The bacteria that infect the gums and cause gingivitis and periodontitis also travel to blood vessels elsewhere in the body where they cause blood vessel inflammation and damage tiny blood clots, heart attack and stroke may follow. Supporting this idea is the finding of remnants of oral bacteria within atherosclerotic blood vessels far from the mouth. Then again, antibiotic treatment has not proven effective at reducing cardiovascular risk.
  • Rather than bacteria causing the problem, it's the body's immune response – inflammation - that sets off a cascade of vascular damage throughout the body, including the heart and brain.
  • There may be no direct connection between gum disease and cardiovascular disease the reason they may occur together is that there is a 3 rd factor (such as smoking) that's a risk factor for both conditions. Other potential "confounders" include poor access to healthcare and lack of exercise – perhaps people without health insurance or who don't take good care of their overall health are more likely to have poor oral health and heart disease.

A study published in 2018 is among the largest to look at this question. Researchers analyzed data from nearly a million people who experienced more than 65,000 cardiovascular events (including heart attack) and found that:

  • After accounting for age, there was a moderate correlation between tooth loss (a measure of poor oral health) and coronary heart disease.
  • When smoking status was considered, the connection between tooth loss and cardiovascular disease largely disappeared

This study suggests that poor oral health does not directly cause cardiovascular disease. But if that's true, how do we explain other studies that found a connection even after accounting for smoking and other cardiovascular risk factors?

It's rare that a single study definitively answers a question that has been pondered by researchers for decades. So, we'll probably need additional studies to sort this out.

But wait, there's more!

The connection between poor oral health and overall health may not be limited to cardiovascular disease. Studies have linked periodontal disease (especially if due to infection with a bacterium called porphyromonas gingivalis) and rheumatoid arthritis. In addition, a 2018 study found a link between this same bacterium and risk of pancreatic cancer. However, as in the case of the connection with heart disease, an "association" is not the same as causation we'll need additional research to figure out the importance of these observations.

The bottom line

Whether the link is direct, indirect or coincidence, a healthy mouth and a regimen to keep it that way (including not smoking, and getting regular dental care) can help you keep your teeth. That's reason enough to do what you can to make oral health a priority. Perhaps it will turn out to have other benefits though much of that remains speculative.

Stand by for more studies on the link between oral health and overall health. Until then, keep brushing, flossing and seeing your dentist.

— Robert H. Shmerling, MD

Robert H. Shmerling, MD, is associate professor of medicine at Harvard Medical School and Clinical Chief of Rheumatology at Beth Israel Deaconess Medical Center in Boston where he teaches in the Internal Medicine Residency Program. He is also the program director of the Rheumatology Fellowship. He has been a practicing rheumatologist for over 25 years.

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Watch the video: Άμεσες και έμμεσες επιπτώσεις στην κυπριακή οικονομία από το Ρωσικό εμπάργκο (November 2022).