The Renin-Angiotensin System (RAS)

Zahid H. Khan, SRNAYork College of Pennsylvania

DISCUSSION AGENDA

Review History of RAS

Discuss Physiology of RAS

Describe Mechanism of Action of RAS

Explain Nurse Anesthetist’s view of RAS

SEARCH FOR THE TRUTH: 7 DECADES OF RESEARCH!

One peptide, two continents, two names

The Argentine Research Group Dr. Braun-Menendez

The United States Research Group Dr. Irvine H. Page

Linguistic confusion

ORIGIN OF THE CLASSIC VIEW

Skeggs et al. 1956 The amino acid

sequence ANG I to ANG II

Drs. Ferreira and Silva 1965 Brazillian pit snake ACE inhibitor

KEY ELEMENTS OF THE CLASSIC VIEW

The Juxtaglomerular Apparatus

KEY ELEMENTS OF THE CLASSIC VIEW

As Emerson said:

“Nothing is rich but the inexhaustible wealth of nature. She shows us only surfaces, but she is a million fathoms deep…”

EMERGENCE OF THE CURRENT VIEW

MECHANISM OF ACTION OF RAS

RECEPTORS AND FUNCTIONS OF PEPTIDES

LIGAND RECEPTOR FUNCTIONS

Angiotensin II

Angiotensin III

Angiotensin II type I receptor

(AT1)

Vasoconstriction, sympathetic stimulation, aldosterone release, ADH release, fibrosis, hypertrophy, inflammation, thrombosis

Angiotensin II Angiotensin II type II receptor

(AT2)

Vasodilation, nitric oxide release, antihypertrophic, antifibrotic, antithrombotic

? Angiotensin II type III receptor Unknown

Angiotensin IV Angiotensin IV receptor Vasodilation, inflammation, improved memory, plasminogen activator inhibitor-1 release, decreased tubular sodium transport

Angiotensin (1-7) Mas receptor Inhibits cell growth. Antagonism of AT1

Renin and prorenin Renin/prorenin receptor Increased contractility, hypertrophy, fibrosis, apoptosis

RAS: INTRACELLULAR SIGNAL TRANSDUCTION

Mitogen activated protein kinases (MAPKs) ERK P38 JNK

Transcription factors C-Jun/C-Fos ATF2

Proto-oncogene: Ras, Rac1

RAS: INTRACELLULAR SIGNAL TRANSDUCTION

CRNA’S VIEWPOINT

Target areas of RAS Inhibitors

COMPARISON OF ACE INHIBITORSCharacteristic

Captopril

Enalapril

Lisinopril

Benazepril

Fosinopril

Quinapril

Ramipril

Elimination Renal Renal Renal Renal

Hepatic 50% Renal 50%

Hepatic 37%Renal 61%

Renal

Onset of hypotensive action (hr)

0.25 1 1 1 1 1 1–2

Peak hypotensive effects (hr)

1–1.5 4–6 6 2–4 2–6 2 3–6

Duration of hypotensive effects (hr)

Dose related

24 (18–30)

24 (18–30) 24 24 24 >24

(24–60)

Dose (mg)25–150, max 450

5–40, max 40

10–40, max 80

20–80, max 80

10–40, max 80

10–80, max 80

2.5–20, max 20

COMMON ANGIOTENSIN RECEPTOR BLOCKERS

Drug Dosage

Candesartan (Atacand) 4–32 mg

Irbesartan (Avapro) 150–300 mg

Losartan (Cozaar) 50–100 mg

Telmisartan (Micardis) 40–80 mg

Valsartan (Diovan) 80–320 mg

CRNA’S VIEWPOINT Preoperative period ACEIs OR ARBs Medication taken

before surgery? Target organ

damage?

CRNA’S VIEWPOINT

Intra-op Management

Fluid volume management

Maintenance of arterial BP

Electrolyte abnormalities

CRNA’S VIEWPOINT

RAS: A friend or foe

CRNA’S VIEWPOINT

Should ACEI or ARB be held prior to surgery? “Renin-angiotensin blockade is

associated with increased mortality after vascular surgery”

“Should I continue or discontinue that medication?”

SUMMARY

Complex and multilayered physiology Existence of

Intracellular RAS Better comprehension

= Better pharmaceutical agents

Benefits of RAS blockade

DISCUSSION

Which is more effective, ACEI or ARBs?

Is dual blockade of RAS better? ONTARGET Study

REFERENCES

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Ferrario, C. M. (2010). New physiological concepts of the renin-angiotensin system from the investigation of precursors and products of angiotensin I metabolism. Hypertension, 55(Pt. 2), 445-452. doi: 10.1161/hypertensionaha.109.145839

Fyhrquist, F., & Saijonmaa, O. (2008). Renin-angiotensin system revisited. Journal of Internal Medicine, 264, 224-236. doi: 10.1111/j.1365-2796.2008.01981.x

Gradman, A. H. (2009). Evolving understanding of the renin-angiotensin-aldosterone system: Pathophysiology and targets for therapeutic intervention. American Heart Journal, 157(6, Suppl. 1), 51-56. doi: 10.1016/j.ahj.2009.04.005

Grandi, A. M., & Maresca, A. M. (2006). Blockade of the renin-angiotensin-aldosterone system: Effects on hypertensive target organ damage. Cardiovascular & Hematological Agents in Medicinal Chemistry, 4, 219-228.

Guyton, A. C., & Hall, J. E. (2006). Textbook of medical physiology (11th ed.). Philadelphia: Elsevier Saunders.

REFERENCES

Jankowski, P., Safar, M. E., & Benetos, A. (2009). Pleiotropic effects of drugs inhibiting the renin-angiotensin-aldosterone system. Current Pharmaceutical Design, 15, 571-584.

Lee, H. T, Vidovich, M., & Mujais, S. (2006). Renal Physiology. In H. C. Hemmings Jr, & P. M. Hopkins, Foundations of Anesthesia Basic Sciences for Clinical Practice (2nd ed.) (pp.

687-698). Philadelphia: Mosby Elsevier.Mallick, A., & Bodenham, A. R. (2006). Regulation of blood volume and electrolytes. In H.

C. . Hemmings Jr & P. M. Hopkins, Foundations of Anesthesia Basic Sciences for ClinicalPractice (2nd ed.) (pp. 709-722). Philadelphia: Mosby Elsevier.

Martini, F. H., Ober, W. C., Garrison, C. W., Welch, K., & Hutchings, R. T. (2006). Fundamentals of Anatomy & Physiology (7th ed.). New York: Pearson Benjamin Cummings.

Qiagen Sample & Assays Technologies. (2011). Renin Angiotensin Pathway. Retreived from Qiagen website: https://www.qiagen.com/geneglobe/pathwayview.aspx?pathwayID=388

Skrbic, R., & Igic, R. (2009). Review: Seven decades of angiotensin (1939-2009). Peptides, 30(2009), 1945-1950. doi: 10.1016/j.peptides.2009.07.003