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THE PHARMACOLOGY OF ADRENERGIC RECEPTORS
Learning
Objectives,
I
Lecture
1. Integrate pharmacodynamic principles to aid in the understanding of adrenergic receptors and the actions of drugs on these receptors. 2. Understand the criteria upon which alpha and beta receptors are defined. 3. Understand the second messenger systems utilized by alpha and beta receptors and how activation of these receptors leads to a change in physiologic function. 4. Understand the effects of alpha and beta receptor activation on the heart and blood vessels. 5. Understand the effects of isoproterenol, epinephrine and norepinephrine on the cardiovascular system. 6. Understand the rationale for the use of epinephrine in dental practice.
• Key drugs • Isoproterenol - Isuprel Epinephrine - Adrenalin Norepinephrine- Levophed
The adrenergic receptors which subserve the responses of the sympathetic nervous system have been divided into two discrete subtypes: alpha adrenergic receptors (alpha receptors) and beta adrenergic receptors (beta receptors). The classification of these receptors, and indeed receptors in general, is based on the interaction of agonists and antagonists with the receptors.
PUTATIVE STRUCTURE OF ADRENERGIC RECEPTORS
• Beta Receptors • Beta receptors have been further
subdivided into beta1 and beta2 receptors. It should be pointed out that beta3 and beta4 receptors have recently been isolated, cloned and characterized. The beta3 receptor may be involved in regulating the metabolism of fatty acids. This receptor could be the site of antiobesity drugs in the future. The functions of the beta4 receptor remains to be discovered. For the purposes of this material we will focus on the beta1 and beta2 receptors only.
• Beta Receptor Systems • Most tissues express multiple
receptors. However, the dominant beta receptor in the normal heart is the beta1 receptor while the beta2 receptor is the dominant regulatory receptor in vascular and nonvascular smooth muscle. Tissue Receptor subtypes Heart Adipose tissue
beta 1 beta 1 and 3?
Vascular smooth muscle
beta 2
Airway smooth muscle
beta 2
Mechanism of Beta Receptor Activation in Cardiac Muscle
1. Agonist binds to the myocardial beta1-receptor. The receptor is a typical G-protein coupled receptor with 7 membrane spanning regions
2. G-protein complexed with GDP
3. The receptor promotes exchange of GTP for GDP and release of Gα complexed with GTP.
4. Gα activates adenylate cyclase.
5.Intracellular cAMP increases and activates cAMP dependent protein kinase (PKA).
6-10 PKA phosphorylates cellular effectors leading to a positive inotropic response.
11. Prolonged stimulation can lead to receptor down-regulation via PKA and other protein kinases which induced phosphorylation of the receptor. The other protein kinases which are involved in phosphorylation of the receptor are referred to as G-protein coupled receptor kinases or GRKs. These phosphorylation steps lead to internalization of the receptor.
• Effect of Beta Receptor
Activation on the Heart:
• Activation of the beta1 receptor
leads to increases in contractile force and heart rate. Excess stimulation by catecholamines can induce significant increases in heart rate and arrhythmias. Arrhythmias are a major concern with drugs such as E, NE and ISO that can activate the beta1 receptor.
• Effect of Beta Receptor Activation on Smooth Muscle:
The beta2 receptor associated with smooth muscle also utilizes the cAMP signaling system. However, the results of receptor activation are different. Stimulation of the beta2 receptor leads to smooth muscle relaxation. This is because in the pathways leading to activation of myofibrillar proteins and contraction are different in smooth muscle when compared to cardiac muscle. Therefore, steps 1-5 in the diagram would be the same. However, the cellular proteins phosphorylated by PKA are different in smooth muscle when compared to cardiac muscle.
ALPHA RECEPTORS SYSTEMS: • The receptor mediating the vasconstrictor actions of
•
•
catecholamines is referred to as an alpha receptor. The concentration of isoproterenol necessary to activate alpha receptors is so large that isoproterenol can be thought of as a pure beta receptor agonist. Alpha receptors have been further subdivided into alpha1 and alpha2 receptors. Epinephrine and norepinephrine are equipotent at both alpha1 and alpha2 receptors. Three subtypes of the alpha1-receptor, the alpha1A, the alpha1B, and the alpha1D, and 3 subtypes of the alpha2-receptor, the alpha2A, the alpha2B, and the alpha2C have been isolated, cloned and characterized. However, we will refer to only the alpha1 and alpha2 receptors.
Postsynaptic Alpha1 And Alpha2 Receptors: • Alpha1 and alpha2 receptors exist postsynaptically. Activation of these receptors in vascular smooth muscle leads to Ca2+ influx and release of Ca2+ from intracellular stores. The increased intracellular Ca2+ activates vasoconstriction. 1. Agonist binds to the vascular smooth muscle alpha1-receptor. The receptor is a typical G-protein coupled receptor with 7 membrane spanning regions.
2. G-protein complexed with GDP. 3. The receptor promotes exchange of GTP for GDP and release of Gα complexed with GTP.
4. The G-protein activates phospholipase C leading to an increase of the intracellular second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG).
5. IP3 binds to specific sites on the SR and stimulates the release of intracellular Ca2+.
6. Ca2+ influx is activated. 7. Like the beta-receptors, alpha receptors can also be desensitized and down regulated via phosphorylation of the receptor. However, the alpha receptors, both alpha1 and alpha2 are much more resistant to desensitization and down regulation than are the beta receptors.
Effect of Catecholamines on Vascular Smooth Muscle:
• Associated with vascular smooth
muscle are a large number of alpha1 receptors relative to beta2 receptors. However, epinephrine has a higher affinity for the beta2 receptors when compared to the alpha1 receptors. Therefore, the effect of epinephrine is dependent on which type of receptor is occupied. Recall that receptor occupancy is dependent on the concentration of a drug and its equilibrium dissociation constant. At low doses, epinephrine can selectively stimulate beta2 receptors, thus producing muscle relaxation and a decrease in peripheral resistance. At high doses, epinephrine produces contraction of vascular smooth muscle and an associated increase in peripheral resistance.
• Effect of Catecholamines on Vascular
Smooth Muscle: (Continued) Norepinephrine has little affinity for beta2 receptors. Therefore, it will stimulate only alpha1 receptors, producing an increase in peripheral vascular resistance. In contrast, isoproterenol will only produce vasodilation due to activation of the beta2 receptors.
Effects On The Cardiovascular System Recall that: • Blood pressure = Cardiac output X total peripheral vascular resistance (TPR) • Cardiac output = Stroke volume X heart rate • Therefore: Blood pressure = (stroke volume X heart rate) X Total peripheral vascular resistance • For the drugs listed below, indicate how the drugs would affect (increase, decrease, no changes) the indicated hemodynamic parameters. It is important, both from a basic science as well as a clinical perspective, that you understand the actions of these agents on the cardiovascular system.
Be sure to make an attempt at answering the question BEFORE you click on the answer.
Completed Table Isoproterenol Norepinephrine Low Doses of Epi High Doses of Epi
Heart Rate
Contractile Force
TPR
Blood Pressure
Heart Rate
Contractile Force
TPR
Blood Pressure
Isoproterenol
Increases due to Increases due to activation of Decreases due to activation of cardiac output x total activation of beta1 beta 1 receptors on myocardial beta 2 receptors peripheral vascular receptors in SA and cells. resistance AV nodes
Norepinephrine
Decrease due to reflex increase in vagal tone on SA and AV nodes
Increases due to effects on Increases due to activation of Increases due to beta1-ARs on myocardial cells alpha1-ARs on vascular effects on total smooth muscle cells peripheral vascular resistance
Low Doses of Epi
Increases due to beta1-ARs on SA and AV nodal tissues
Increases due to activation of Decreases due to preferential beta1-ARs on myocardial cells activation of beta2-ARs, at these doses there would be little activation of alpha1-ARs
High Doses of Epi
Similar to the effects Increases due to beta1-ARs onIncreases due to activation of of norepinepherine myocardial cells alpha1-ARs on vascular smooth muscle cells. Notice how at this dose the predominate effect is via the alpha1-ARs not the beta2-AR mediated decrease in total peripheral vascular resistance.
Similar to isoproterenol; the net effect will be the activity seen on cardiac output and total peripheral vascular resistance
Increases due to activation of alpha1ARs on vascular smooth muscle cells
Learning
Objectives,
I
Lecture
1. Integrate pharmacodynamic principles to aid in the understanding of adrenergic receptors and the actions of drugs on these receptors. 2. Understand the criteria upon which alpha and beta receptors are defined. 3. Understand the second messenger systems utilized by alpha and beta receptors and how activation of these receptors leads to a change in physiologic function. 4. Understand the effects of alpha and beta receptor activation on the heart and blood vessels. 5. Understand the effects of isoproterenol, epinephrine and norepinephrine on the cardiovascular system. 6. Understand the rationale for the use of epinephrine in dental practice.
• Key drugs • Isoproterenol - Isuprel Epinephrine - Adrenalin Norepinephrine- Levophed
The adrenergic receptors which subserve the responses of the sympathetic nervous system have been divided into two discrete subtypes: alpha adrenergic receptors (alpha receptors) and beta adrenergic receptors (beta receptors). The classification of these receptors, and indeed receptors in general, is based on the interaction of agonists and antagonists with the receptors.
PUTATIVE STRUCTURE OF ADRENERGIC RECEPTORS
• Beta Receptors • Beta receptors have been further
subdivided into beta1 and beta2 receptors. It should be pointed out that beta3 and beta4 receptors have recently been isolated, cloned and characterized. The beta3 receptor may be involved in regulating the metabolism of fatty acids. This receptor could be the site of antiobesity drugs in the future. The functions of the beta4 receptor remains to be discovered. For the purposes of this material we will focus on the beta1 and beta2 receptors only.
• Beta Receptor Systems • Most tissues express multiple
receptors. However, the dominant beta receptor in the normal heart is the beta1 receptor while the beta2 receptor is the dominant regulatory receptor in vascular and nonvascular smooth muscle. Tissue Receptor subtypes Heart Adipose tissue
beta 1 beta 1 and 3?
Vascular smooth muscle
beta 2
Airway smooth muscle
beta 2
Mechanism of Beta Receptor Activation in Cardiac Muscle
1. Agonist binds to the myocardial beta1-receptor. The receptor is a typical G-protein coupled receptor with 7 membrane spanning regions
2. G-protein complexed with GDP
3. The receptor promotes exchange of GTP for GDP and release of Gα complexed with GTP.
4. Gα activates adenylate cyclase.
5.Intracellular cAMP increases and activates cAMP dependent protein kinase (PKA).
6-10 PKA phosphorylates cellular effectors leading to a positive inotropic response.
11. Prolonged stimulation can lead to receptor down-regulation via PKA and other protein kinases which induced phosphorylation of the receptor. The other protein kinases which are involved in phosphorylation of the receptor are referred to as G-protein coupled receptor kinases or GRKs. These phosphorylation steps lead to internalization of the receptor.
• Effect of Beta Receptor
Activation on the Heart:
• Activation of the beta1 receptor
leads to increases in contractile force and heart rate. Excess stimulation by catecholamines can induce significant increases in heart rate and arrhythmias. Arrhythmias are a major concern with drugs such as E, NE and ISO that can activate the beta1 receptor.
• Effect of Beta Receptor Activation on Smooth Muscle:
The beta2 receptor associated with smooth muscle also utilizes the cAMP signaling system. However, the results of receptor activation are different. Stimulation of the beta2 receptor leads to smooth muscle relaxation. This is because in the pathways leading to activation of myofibrillar proteins and contraction are different in smooth muscle when compared to cardiac muscle. Therefore, steps 1-5 in the diagram would be the same. However, the cellular proteins phosphorylated by PKA are different in smooth muscle when compared to cardiac muscle.
ALPHA RECEPTORS SYSTEMS: • The receptor mediating the vasconstrictor actions of
•
•
catecholamines is referred to as an alpha receptor. The concentration of isoproterenol necessary to activate alpha receptors is so large that isoproterenol can be thought of as a pure beta receptor agonist. Alpha receptors have been further subdivided into alpha1 and alpha2 receptors. Epinephrine and norepinephrine are equipotent at both alpha1 and alpha2 receptors. Three subtypes of the alpha1-receptor, the alpha1A, the alpha1B, and the alpha1D, and 3 subtypes of the alpha2-receptor, the alpha2A, the alpha2B, and the alpha2C have been isolated, cloned and characterized. However, we will refer to only the alpha1 and alpha2 receptors.
Postsynaptic Alpha1 And Alpha2 Receptors: • Alpha1 and alpha2 receptors exist postsynaptically. Activation of these receptors in vascular smooth muscle leads to Ca2+ influx and release of Ca2+ from intracellular stores. The increased intracellular Ca2+ activates vasoconstriction. 1. Agonist binds to the vascular smooth muscle alpha1-receptor. The receptor is a typical G-protein coupled receptor with 7 membrane spanning regions.
2. G-protein complexed with GDP. 3. The receptor promotes exchange of GTP for GDP and release of Gα complexed with GTP.
4. The G-protein activates phospholipase C leading to an increase of the intracellular second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG).
5. IP3 binds to specific sites on the SR and stimulates the release of intracellular Ca2+.
6. Ca2+ influx is activated. 7. Like the beta-receptors, alpha receptors can also be desensitized and down regulated via phosphorylation of the receptor. However, the alpha receptors, both alpha1 and alpha2 are much more resistant to desensitization and down regulation than are the beta receptors.
Effect of Catecholamines on Vascular Smooth Muscle:
• Associated with vascular smooth
muscle are a large number of alpha1 receptors relative to beta2 receptors. However, epinephrine has a higher affinity for the beta2 receptors when compared to the alpha1 receptors. Therefore, the effect of epinephrine is dependent on which type of receptor is occupied. Recall that receptor occupancy is dependent on the concentration of a drug and its equilibrium dissociation constant. At low doses, epinephrine can selectively stimulate beta2 receptors, thus producing muscle relaxation and a decrease in peripheral resistance. At high doses, epinephrine produces contraction of vascular smooth muscle and an associated increase in peripheral resistance.
• Effect of Catecholamines on Vascular
Smooth Muscle: (Continued) Norepinephrine has little affinity for beta2 receptors. Therefore, it will stimulate only alpha1 receptors, producing an increase in peripheral vascular resistance. In contrast, isoproterenol will only produce vasodilation due to activation of the beta2 receptors.
Effects On The Cardiovascular System Recall that: • Blood pressure = Cardiac output X total peripheral vascular resistance (TPR) • Cardiac output = Stroke volume X heart rate • Therefore: Blood pressure = (stroke volume X heart rate) X Total peripheral vascular resistance • For the drugs listed below, indicate how the drugs would affect (increase, decrease, no changes) the indicated hemodynamic parameters. It is important, both from a basic science as well as a clinical perspective, that you understand the actions of these agents on the cardiovascular system.
Be sure to make an attempt at answering the question BEFORE you click on the answer.
Completed Table Isoproterenol Norepinephrine Low Doses of Epi High Doses of Epi
Heart Rate
Contractile Force
TPR
Blood Pressure
Heart Rate
Contractile Force
TPR
Blood Pressure
Isoproterenol
Increases due to Increases due to activation of Decreases due to activation of cardiac output x total activation of beta1 beta 1 receptors on myocardial beta 2 receptors peripheral vascular receptors in SA and cells. resistance AV nodes
Norepinephrine
Decrease due to reflex increase in vagal tone on SA and AV nodes
Increases due to effects on Increases due to activation of Increases due to beta1-ARs on myocardial cells alpha1-ARs on vascular effects on total smooth muscle cells peripheral vascular resistance
Low Doses of Epi
Increases due to beta1-ARs on SA and AV nodal tissues
Increases due to activation of Decreases due to preferential beta1-ARs on myocardial cells activation of beta2-ARs, at these doses there would be little activation of alpha1-ARs
High Doses of Epi
Similar to the effects Increases due to beta1-ARs onIncreases due to activation of of norepinepherine myocardial cells alpha1-ARs on vascular smooth muscle cells. Notice how at this dose the predominate effect is via the alpha1-ARs not the beta2-AR mediated decrease in total peripheral vascular resistance.
Similar to isoproterenol; the net effect will be the activity seen on cardiac output and total peripheral vascular resistance
Increases due to activation of alpha1ARs on vascular smooth muscle cells
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