Medical Pharmacology: Autonomic nervous System (Adrenergic)

Adrenergic Receptor Subtypes continued: Three subtypes of β-adrenergic receptors have been described: β₁, β₂, and β₃.⁹
- Activation of these receptors by agonist ligands cause activation of the stimulatory G protein, G_s, (as noted earlier, certain G proteins are inhibitory). G_s increases adenylyl cyclase catalytic activity which results in elevation of intracellular cAMP.
- Higher levels of cAMP in turn promote phosphorylation of various proteins; the phosphorylation step changes protein function and thus is an important regulatory step.
- cAMP is the primary second messenger system for the β-adrenergic receptor system and activation of the receptor system can cause, via cAMP, numerous tissue-specific effects.

One example is activation of glycogen phosphorylase in the liver secondary to β-adrenergic receptor induced [cAMP] elevation ([ ] refers to molar concentration).

In the kidney, β₁-adrenergic receptor stimulation results in increased renin release; whereas, β₁-cardiac adrenergic receptor stimulation increases both contractility and heart rate (positive inotropism and positive chronotropism respectively).

The positive chronotropic effect occurs because of the change in the slope of phase 4 spontaneous depolarization at sinoatrial nodal pacemaker cells.
The positive inotropic effect of adrenergic agonists occurs due to increased phosphorylation of Ca²⁺ ion channels.
- In addition to enhanced sarcolemmal Ca²⁺-channel phosphorylation, β₁-adrenergic activation also phosphorylates an important regulatory protein of the cardiac muscle Ca²⁺ calcium channel, phospholamban.⁴⁰
- Phospholamban, when acted on by protein kinase A, an effects stimulated by cAMP secondary to β₁-adrenergic receptor activation, becomes phosphorylated and then exhibits a reduced ability to inhibit a sarcoplasmic reticulum calcium pump (SERCA2).
- Therefore, the phosphorylated phospholamban increases activity of this Ca²⁺ pump, consequence of which is to both reduce free Ca²⁺ (this favors cardiac muscle relaxation in diastole) and increase the amount of Ca²⁺ calcium released from sarcolemmal stores with the next action potential.⁴⁰
  - This latter action results in the positive inotropic effect observed following phospholamban phosphorylation. (More detailed studies of the phospholamban phosphorylation pattern indicate three protein kinase-dependent phosphorylation sites:
    - (1) cAMP-dependent protein kinase just described phosphorylates a serine amino acid residue,
    - (2) a Ca²⁺/calmodulin-dependent protein kinase catalyzes a phosphorylation reaction at a threonine amino acid residue and
    - (3) protein kinase C catalyzes phosphorylation of a distinct serine amino acid residue. These phosphorylation reactions all appear to stimulate initial rates of sarcoplasmic reticulum Ca²⁺-transport.⁴⁰
  - Dephosphorylation of phospholamban is catalyzed by a cardiac sarcoplasmic reticulum-associated type 1 protein phosphatase, which is also controlled by cAMP-dependent phosphorylation of its inhibitor protein.⁴⁰
  - Phospholamban Pentamer⁴¹
  - With respect to possible clinical correlation, heart failure (CHF, congestive heart failure) is a disease associated with abnormal intracellular Ca²⁺-"handling."
    - Specifically, cardiac relaxation and rapid reduction of cytosolic [Ca²⁺] by SERCA2 appear impaired with a resulting increase in diastolic [Ca²⁺].
    - Such an increase, by reducing cardiac sarcoplasmic reticulum stores, reduces Ca²⁺ availability for subsequent cardiac contractions.
    - Possible clinical therapeutic approaches might involve altering phospholamban or SERCA2 protein expression levels or disruption of the phospholamban-SERCA2 complex.⁴⁰

The combination of β₁-adrenergic receptor mediated increases in both heart rate and contractility (positive inotropism) results in an increase in cardiac output.

Changes in conduction velocity at the atrioventricular (AV) node are also mediated by β₁ receptors: ⁹

(1) Activation of these receptors increases conduction velocity by increasing Ca²⁺-channel conductance. Depolarization of AV nodal cells is especially sensitive to Ca²⁺ because in this specialized cardiac tissue Ca²⁺ as opposed to Na+ provides the primary inward, depolarizing current.

(2) Therefore, by contrast, blockers or antagonists that act at β₁-receptors decrease conduction through the AV node.

Short-acting β-receptor antagonists, such as esmolol, ( β₁-receptor selective) may be helpful in rapid, short-term management of high ventricular following rates in the setting of supraventricular arrhythmias (e.g. atrial fibrillation).

Lead II (2) ECG tracing of supraventricular tachycardia (heart rate about 150/min) in a 40 year old male⁴⁵

**Esmolol (Brevibloc): β₁-adrenergic receptor Antagonist**

The recognition that β₁-receptors promote increases in both heart rate and myocardial contractility presents opportunities for pharmacological management of several cardiovascular disorders, including hypertension and angina.⁹
- A reduction in blood pressure would be expected with β-adrenergic receptor antagonism because heart rate and force of contraction decrease.
- Angina is a clinical symptom associated with an imbalance between myocardial oxygen requirements and oxygen availability.
- If oxygen availability is limited by suboptimal coronary perfusion secondary, for example, to coronary atherosclerosis, one option is to decrease myocardial oxygen demand, by decreasing myocardial contractility.
Myocardial oxygen extraction is about 70% at rest (dog model).^{42, 42a}
- Therefore, increased myocardial oxygen consumption must be accompanied by an increase in coronary blood flow, since there is limited additional oxygen extraction possible.

The relationship between coronary blood flow and myocardial oxygen consumption is approximately linear.⁴²

The Relationship of Coronary Flow to Oxygen Usage (Dog Model)⁴³
Anatomical overview: large epicardial branches of the left and right coronary arteries undergo additional branching.
- Epicardial (surface) Coronary Vessels⁴⁴
The smaller branches enter the myocardium and right angles and then divide into many more arteries and arterioles.
- The smaller structures support a very dense capillary network, with approximately one capillary for each cardiac fiber.⁴²

Transmural (across the myocardial wall) blood flow distribution in accordance with moment to moment oxygen supply versus local demand change is supported by control of subendocardial and subepicardial vessel tone.⁴²

Vasoactive substances released by coronary vascular endothelium provide circulatory regulation.

For example, a number of factors including pulsatile flow and hypoxia stimulate release of the coronary vasodilator prostacyclin.

**Prostacyclin (Epoprosterol), an eicosanoid**

Hypoxia and shear stress are two factors that increase production and release of nitric oxide (N-O) by increasing catalytic activity of nitric oxide synthase (NOS). By this mechanism, coronary vasodilatation occur secondary to N-O-dependent cGMP (cyclic GMP) mechanisms.⁴²
Endothelium also elaborates vasoconstrictors such as the endothelins, thromboxane A2, and angiotensin in response to several exogenous and endogenous factors.⁴²
- Thromboxane A2
Pathophysiological changes associated with coronary vascular disease can induce abnormalities between these vasodilator and vasoconstrictor effects. For example, a reduction in N-O release with a concurrent increase in endothelin synthesis.
- Endothelins in addition to being vasoconstrictive also promote platelet adhesion which may increase thrombosis risk and cause smooth muscle proliferation.⁴²

References
Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.199-242 Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, p. 260 Carotic Baroreceptors: CRRx: Mediine ReEnvisioned http://www.cvrx.com/patients/index.php?id=41 Westfall, TC and Westfall DP Adrenergic Agonists and Antagonists in Goodman and Gilman's The Pharmacological Basis of Therapeutics, eleventh editions, (Brunton LL, Lazo JS and Parker KL, eds), McGraw-Hill Medical Publishing Division, New York, 237-295, 2006. Catecholamine Biosynthesis: The Interactive Library; Edinformatics.com: http://www.edinformatics.com/interactive_molecules/info/adrenaline.htm . Standaert DG and Young AB Treatment of Central Nervous System Degenerative Disorders In Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp536-537. Adrenergic Neuronal Diagram adapted from http://www.drugabuse.gov/pubs/teaching/Teaching4/Teaching.html Guanetidine (Ismelin™, brand name not available in the U.S.) pharmacology: Clinical Pharmacology, RxList: The Internet Drug Index, http://www.rxlist.com/ismelin-drug.htm . Williams FM and Turner TJ Adrenergic Pharmacology in Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition (Golan DE, Tashijan Jr AH, Armstrong EJ and Armstrong AW, eds) Wolters Kluwer-Lippincott Williams & Wilkins, Philadelphia, 129-144, 2008. Moss J and Glick D Autonomic Function in Anesthetic Pharmacology: Physiological Principles and Clinical Practice: A Companion to Miller's Anesthesia (Evers AS and Maze M, eds) Churchill Livingstone, Philadelphia, Chapter 14, 209-226, 2004. Presynaptic Proteins, Synaptic Vesicle Docking and Membrane Fusion, http://neuromuscular.wustl.edu/pathol/snare.htm#cachan, Neuromuscular Disease Center, Washington University, St. Louis, MO USA (http://neuromuscular.wustl.edu/index.html) Sudhof TC The Synaptic Vesicle Cycle, Annual Review of Neuroscience, July 200, Vol. 27, pp 509-547. Phenochomocytoma picture (http://health-pictures.com/pheochromocytoma.htm); Geneva Foundation of Medical Education and Research, Pheochromocytoma, http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=1&cat2=113&cat3=22&cat4=2&stype=n . Brown H, Goldberg PA, Selter JG, Cabin HS, Marieb NJ, Udelsman R and Setaro JF Hemorrhagic Pheochromocytoma Associated with Systemic Corticosteroid Therapy and Presenting as Myocardial Infarction with Severe Hypertension. Clinical Case Seminar, J Clin Endocrinol Metab 2005 90: 563-569. (http://jcem.endojournals.org/cgi/content/full/90/1/563). "Clevidine (Cleviprex) for IV Treatment of Severe Hypertension", Table 1. Some Parenteral Drugs for Hypertensive Emergencies. The Medical Letter^® on Drugs and Therapeutics, Volume 50 (Issue 1295) September 22, 2008. Katzung, BG Introduction to Autonomic Pharmacology (Section II: Autonomic Drugs) in: Basic and Clinical Pharmacology (10th edition), (Katzung BG, ed) McGraw-Hill Medical , New York, pp. 75-92, 2007. Sympathetic Nerve Pathway: Neuroeffector Junction ("Simplified diagram of a sympathetic neuroeffector junction displaying genes which may be involved"); PharmGKb modified slightly to highlight uptake1, uptake-2, uptake 1 block, and location of intravesicular norephinephrine synthesis. (Pharmacogenomics Knowledge Base). http://www.pharmgkb.org/search/pathway/neurotransmitter/neuroeffector.jsp . T.E. Klein, J.T. Chang, M.K. Cho, K.L. Easton, R. Fergerson, M. Hewett, Z. Lin, Y. Liu, S. Liu, D.E. Oliver, D.L. Rubin, F. Shafa, J.M. Stuart and R.B. Altman, "Integrating Genotype and Phenotype Information: An Overview of the PharmGKB Project" (220k PDF), The Pharmacogenomics Journal (2001) 1, 167-170. Tellioglu T, Robertson D (November 2001). "Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications". Expert Rev Mol Med 2001: 1–10. Kekuda R, Prasad PD, Wu X, Wang H, Fei YJ, Leibach FH, Ganapathy V (Aug 1998). "Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta". J Biol Chem 273 (26): 15971–9. Amphoux A, Vialou V, Drescher E, Brüss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bönisch H, Gautron S. (Jun 2006). "Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain.". Neuropharmacology 50 (8): 941–952. Bourne HR and von Zastrow M "Drug Receptors and Pharmacodyamics" Chapter 2 in Basic and Clinical Pharmacology (10th edition), (Katzung BG, ed) McGraw-Hill Medical , New York, pp. 17-27, 2007. Muller M Lecture Material Online: Lecture 6: "Cellular Communication" http://www.uic.edu/classes/bios/bios100/summer2003/lect06.htm. Bowman T and Jove R STAT Proteins and Cancer: From the Molecular Oncology Program at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida http://www.moffitt.org/moffittapps/ccj/v6n6/dept6h.htm . Tong L, Warren TC, King J, Betageri R, Rose J, Jakes S (March 1996). "Crystal structures of the human p56lck SH2 domain in complex with two short phosphotyrosyl peptides at 1.0 A and 1.8 A resolution". J. Mol. Biol. 256 (3): 601–10. Sadowski I, Stone JC, Pawson T (December 1986). "A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps". Mol. Cell. Biol. 6 (12): 4396–4408. Russell RB, Breed J, Barton GJ (June 1992). "Conservation analysis and structure prediction of the SH2 family of phosphotyrosine binding domains". FEBS Lett. 304 (1): 15–20. von Zastrow M and Bourne HR "Drug Receptors and Pharmacodynamics" Chapter 2 in Basic and Clinical Pharmacology (11th edition), (Katzung BG, Masters, SB and Trevor AJ, eds) McGraw-Hill Medical , New York, on-line version (Access Medicine) 2009. Powledge TM (2004) Nicotine as Therapy. PLoS Biol 2(11): e404. doi:10.1371/journal.pbio.0020404 (http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020404) Green T, Heinemann SF and Gusella JF Molecular Neurobiology and Genetics: Investigation of Neuron Function and Dysfunction (Review) Neuron, Vol. 20, 427-444, March, 1998 (Cell Press (c), 1998). Unwin N Nicotinic acetylcholine receptor at 9 Å resolution. J. Mol. Biol. 229, 1101-1124. Eyford, T Adenylyl cyclase http://proteopedia.org/wiki/index.php/Adenylyl_cyclase . 31 a. Hurley JH. Structure, mechanism, and regulation of mammalian adenylyl cyclase. J Biol Chem. 1999 Mar 19;274(12):7599-602. 31 b, Zhang G, Liu Y, Ruoho AE, Hurley JH. Structure of the adenylyl cyclase catalytic core. Nature. 1997 Mar 20;386(6622):247-53. Goodsell DS illustrator, The Scrips Research Institute, public domain work, http://en.wikipedia.org/wiki/Adenylate_cyclase . Ranganathan R, Ross E (1997). "PDZ domain proteins: scaffolds for signaling complexes.". Curr Biol 7 (12): R770–3 PDZ domain http://en.wikipedia.org/wiki/PDZ_domain Biaggioni I and Robertson D Adrenoceptor Agonists & Sympathomimetic Drugs (Chapter 9) in in Basic and Clinical Pharmacology (11th edition), (Katzung BG, Masters, SB and Trevor AJ, eds) McGraw-Hill Medical , New York, on-line version (Access Medicine) 2009. Korte E "PIP2 cleavage by PLC to release IP3 and DAG", public domain, http://en.wikipedia.org/wiki/File:PIP2_cleavage_to_IP3_and_DAG.jpg . McVary KT A review of combination therapy in patients with benign prostatic hyperplasia, Clinical Therapeutics 2007 29 (3): 387-398. Caine M The present role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. J Urol. 1986; 136: 1-4. Shapiro E Hartanto V and Lepor H. The response to alpha blockade in benign prostatic hyperplasia is related to the percent area density of prostate smooth muscle. Prostate. 1992; 21: 297-307. Brittsan AG and Kranias EG Review: Phosphlakmban and Cardiac Contractile Function. J. Mol Cell Cardiol 32. 2131-2139. Lomize A Phospholamban Pentamer, protein image from OPM database, public domain media (http://en.wikipedia.org/wiki/File:1zll_opm.gif) Foex P and Highan H. Myocardial Performance: Physiological Principles and Clinical Practice: A Companion to Miller's Anesthesia (Evers AS and Maze M, eds) Churchill Livingstone, Philadelphia, Chapter 14, 284-2285, 2004. 42(a) Weiss HR Effect of coronary artery occlusion on regional arterial and venous O2 saturation, O2 extraction, blood flow and O2 consumption in the dog heart. Circulation Research 47(3) 400-407, September 1980. Khouri EM Gregg DE and Rayford CR Effect of exercise on cardiac output, left coronary flow and myocardial metabolism in the unanesthetized dog. Circulation Research 17(5) 327-437, November 1965. Epicardial Vessels: Gray's Anatomy, 20th U.S. edition of Gray's Anatomy of the Human Body, originally publishedin 1918, public domain. Supraventricular tachycardia, public domain image, http://en.wikipedia.org/wiki/File:SVT_Lead_II-2.JPG