GUIDED INDEPENDENT LEARNING
Adrenoceptor Activation by
Norepinephrine and Epinephrine
BLOOD PRESSURE CONCERNS C3
Responsible & Corresponding Author:
Bill Wonderlin, Ph.D.
Department of Physiology [email protected]
Written by:
Bill Wonderlin, PhD Dept. Physiology, MSU Anthony Paganini, PhD Dept. Physiology, MSU Greg Fink, PhD
Dept. Pharmacology, MSU
The physiological responses produced by the activation of adrenoceptors (a.k.a. adrenergic receptors) by norepinephrine (NE) and epinephrine (Epi) can appear complex and challenging to understand. This complexity results from a combination of several factors that influence the responses, including:
● the variable expression of different classes of adrenoceptors in different effector tissues
● the coupling of different classes of adrenoceptors to different cellular responses
● differences in the selectivity of NE and Epi for different classes of adrenoceptors
● dose-dependent selectivity of Epi for different classes of adrenoceptors
● multiple sources of synaptic and circulating NE and Epi
To make sense out of this, lets first review several conceptual building blocks and then construct some physiological responses from these building blocks.
Adrenoceptors
● There are five basic types of adrenoceptors, all of which are G-protein coupled receptors (GPCRs). The adrenoceptors fall into two categories:
○ Alpha receptors
■ 𝛂1: coupled to G𝛂q; activation stimulates the release of intracellular Ca from the sarcoplasmic reticulum and the activation of the Protein Kinase C phosphorylation cascade
● there are three subclasses of 𝛂1 receptors, which might account for some variability in the responsiveness of different tissues. We don’t need to be concerned about that now.
■ 𝛂2: coupled to G𝛂i; activation inhibits adenylyl cyclase, producing a decrease in [cAMP]
○ Beta receptors
■ All of the beta receptors are coupled to G𝛂s. Activation stimulates adenylyl cyclase, producing an increase in [cAMP] and activation of Protein Kinase A phosphorylation
■ 𝛃1, 𝛃2, 𝛃3
Functional roles of Epi and NE
● Epi functions as a circulating hormone that can broadly activate adrenoceptors throughout the body.
Epi is released from chromaffin cells in the adrenal medulla. Chromaffin cells are specialized
postganglionic sympathetic cells that release Epi directly into the bloodstream when they are stimulated by preganglionic sympathetic fibers that emerge from the lateral gray regions of T10-L1.
● NE functions as both a neurotransmitter and a circulating hormone.
○ NE is released by all sympathetic postganglionic fibers, except sympathetic postganglionic fibers innervating sweat glands that release Ach. Therefore, NE is the neurotransmitter responsible for the selective stimulation of specific sympathetically-innervated tissues. For example, in the Pupillary Light Reflex NE released onto the pupillary dilator smooth muscle selectively dilates the pupil in response to a low level of light entering the eye.
○ NE can also function as a broadly-acting hormone:
■ NE is released with Epi from the adrenal medulla chromaffin cells (an 80:20 mix of [Epi]
to [NE]).
■ During periods of intense stimulation, NE released at sympathetic nerve terminals can
“spill over” into the systemic circulation.
Selectivity of NE versus Epi for adrenoceptors
● You will often see the actions of NE associated with alpha adrenoceptors and Epi associated with beta adrenoceptors. Although there is some truth in these associations, it is an oversimplification, especially for Epi. The problem is that the selectivity of Epi, in particular, is dose dependent, with decreasing selectivity at higher doses of Epi.
● At physiologically-realistic concentrations in vivo, Epi and NE can activate the following adrenoceptors:
○ NE: 𝛂1, 𝛂2, 𝛃1, 𝛃3
○ Epi: 𝛂1, 𝛂2, 𝛃1, 𝛃2, 𝛃3
○ Therefore, the primary difference with regard to the repertoire of adrenoceptors that NE and Epi can activate is the much weaker ability of NE to activate 𝛃2 receptors.
● The relative potencies of NE versus Epi at different adrenoceptors are:
○ 𝛂1 & 𝛂2 receptors: Epi ≧ NE
○ 𝛃1 receptors: Epi ≈ NE
○ 𝛃2 receptors: Epi >> NE
○ Note that “potency” is a property of a ligand/receptor interaction expressed as the concentration of the ligand needed to produce an effect of a given intensity. Potency depends on both the affinity of the ligand for the receptor and efficacy, which is the size of the maximal response produced by a ligand-receptor complex.
Dose-dependent adrenoceptor activation by Epi and NE
● The dose-dependent activation of adrenoceptors is important when considering the effects of rising concentrations of Epi or NE in contexts such as an increasing intensity of exercise (i.e. endogenous Epi or NE) or when either agent is administered by IV injection (i.e. exogenous Epi or NE). Although the rank order of potency for Epi and NE across adrenoceptors can be found in various textbooks, the values aren’t always in complete agreement (but don’t panic). The rank orders given below are a synthesis of rank orders or discussions of relative potency given in venerable peer-reviewed
pharmacology textbooks by Goodman & Gillman, Katzung, and Miller, as well as the classic work by Furchgott.
● Relative potencies of NE and Epi for different adrenoceptors
○ NE: 𝛂1 = 𝛂2 > 𝛃1 >> 𝛃2
○ Epi: 𝛃2 > 𝛃1 > 𝛂1 = 𝛂2
● The table below (from Miller’s Anesthesia) illustrates the changes in receptor activation with increasing doses of Epi produced by IV administration (Note that at rates of administration ≧ 10ug/min, the response is dominated by the activation of 𝛂1 receptors, which is indicated in the table, but 𝛃1 and 𝛃2 receptors are also activated as well).
Putting it all together...
Let’s work through a few examples related to cardiovascular function to see how the dose-dependent effects of Epi affect the responses.
Effect of Epi on SVR. The figure below shows the effect of increasing concentrations of exogenous Epi on systemic vascular resistance (SVR). At the lowest dose of Epi, 𝛃2 receptors on arterioles supplying the vascular beds in skeletal muscle are preferentially activated. Stimulation of the 𝛃2 receptors causes these arterioles to relax and the vasodilation increases blood flow to the skeletal muscle. This produces a decrease in SVR. With increasing concentrations of Epi, there is increasing activation of 𝛂1 receptors, which are broadly distributed across arterioles. Stimulation of the 𝛂1 receptors produces a strong vasoconstriction, which
increases SVR.
(from CV Physiology)
The effects of Epi and NE administered by IV injection
The figure below compares the effects of IV administration of NE and Epi on heart (pulse) rate, blood pressure, and SVR. The differences between the two responses are remarkable! Why are they different?
● The primary response to exogenously administered NE is a large increase in SVR produced by
activation of 𝛂1 receptors on arterioles without simultaneous activation of 𝛃2 receptors. The constriction produced by stimulation of 𝛂1 receptors produces a large increase in SVR, which, in turn, produces a marked increase in the blood pressure. This increase in blood pressure stimulates baroreceptors and produces a strong parasympathetic reflex via the vagus n. that stimulates muscarinic M2 receptors on the pacemaker cells, thereby producing a decrease in heart rate. Stimulation by the vagus overrides the stimulation of 𝛃1 receptors on the pacemaker cells by exogenously administered NE.
● At an injection rate of 10 ug/min, EPI is at a plasma concentration that will activate 𝛃2 and 𝛃1 receptors, with a modest level of activation of 𝛂1 receptors. The opposing effects of stimulating 𝛃2 and 𝛂1
receptors produces only a small decrease in SVR, and the stimulation of 𝛃1 receptors increases heart rate. Overall, there is little change in MAP, although the pulse pressure is increased. The inotropic effect of 𝛃1 receptor stimulation increases contractility and, thus, increases stroke volume, which increases systolic BP without significant change in diastolic BP- thus PP increases
● The response to exogenously administered isoproterenol, a drug that selectively stimulates beta
receptors in general, demonstrates a “pure” beta receptor response (i.e., no activation of 𝛂1 receptors).
● If the administration of Epi could be repeated at a higher rate of administration (i.e., achieving a higher plasma concentration), the response would look much more like the response to NE because there would be an increasing stimulation of 𝛂1 receptors and and, thus, an increased in SVR due to net vasoconstriction
Clinical Significance
● At physiological concentrations of NE, its action is well suited to increasing blood pressure in response to challenges such as a change in posture. It can also selectively activate specific effectors innervated by sympathetic postganglionic fibers.
● At low physiological concentrations of Epi, it increases cardiac output (increased HR and SV) and directs more of the cardiac output to skeletal muscle following vasodilation of skeletal vascular beds by 𝛃2 stimulation. This action of Epi complements the vasodilator effect of local metabolic factors released from working skeletal muscle, such as increased adenosine, lactic acid and/or nitric oxide. Epi’s action is well suited to improving performance during increasing intensity of exercise.
● Epi is also administered by injection (sometimes at high concentrations) for a variety of reasons:
○ as an emergency treatment for increasing 𝛃2-mediated bronchodilation during anaphylaxis
○ to increase cardiac output in conditions of cardiovascular collapse
○ at high local concentrations to produce a targeted 𝛂1-mediated vasoconstriction. For example, Epi can be co-administered with a local anesthetic to slow the absorption (and washout) of a local anesthetic from a site of injection.
Understanding the effects of Epi and NE, including the issue of dose-dependent selectivity, is fundamental to understanding these clinical applications.
