1. The Renin-Angiotensin System (RAS) Zahid H. Khan, SRNA York College of Pennsylvania

2.  Review History of RAS  Discuss Physiology of RAS  Describe Mechanism of Action of RAS  Explain Nurse Anesthetist’s view of RAS

3.  One peptide, two continents, two names  The Argentine Research Group  Dr. Braun-Menendez  The United States Research Group  Dr. Irvine H. Page  Linguistic confusion

4.  Skeggs et al.  1956  The amino acid sequence  ANG I to ANG II  Drs. Ferreira and Silva  1965  Brazillian pit snake  ACE inhibitor

5.  The Juxtaglomerular Apparatus

7.  As Emerson said:  “Nothing is rich but the inexhaustible wealth of nature. She shows us only surfaces, but she is a million fathoms deep…”

10. LIGANDRECEPTORFUNCTIONS 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 receptorUnknown Angiotensin IVAngiotensin IV receptor Vasodilation, inflammation, improved memory, plasminogen activator inhibitor-1 release, decreased tubular sodium transport Angiotensin (1-7)Mas receptorInhibits cell growth. Antagonism of AT1 Renin and proreninRenin/prorenin receptorIncreased contractility, hypertrophy, fibrosis, apoptosis

11.  Mitogen activated protein kinases (MAPKs)  ERK  P38  JNK  Transcription factors  C-Jun/C-Fos  ATF2  Proto-oncogene:  Ras, Rac1

13.  Target areas of RAS Inhibitors

14. CharacteristicCaptoprilEnalaprilLisinoprilBenazeprilFosinoprilQuinaprilRamipril EliminationRenal Hepatic 50% Renal 50% Hepatic 37% Renal 61% Renal Onset of hypotensive action (hr) 0.25111111–2 Peak hypotensive effects (hr) 1–1.54–662–42–623–6 Duration of hypotensive effects (hr) Dose related 24 (18– 30) 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

15. DrugDosage 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

16.  Preoperative period  ACEIs OR ARBs  Medication taken before surgery?  Target organ damage?

17.  Intra-op Management  Fluid volume management  Maintenance of arterial BP  Electrolyte abnormalities

18.  RAS: A friend or foe

19.  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?”

20.  Complex and multilayered physiology  Existence of Intracellular RAS  Better comprehension = Better pharmaceutical agents  Benefits of RAS blockade

21.  Which is more effective, ACEI or ARBs?  Is dual blockade of RAS better?  ONTARGET Study

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