The Renin-Angiotensin System Angiotensinogen NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH 1. ↓ Renal Perfusion Pressure 2. ↓ Na at Macula Densa cells 3. ↑ Sympathetic nerve activity (ß-1) 1 2 3 7 8 9 10 + Renin ±PG NH2-Asp-Arg-Val…Pro-Phe-COOH Angiotensin I 1 2 3 7 8 9 10 Non-ACE (eg. Chymase in heart) ACE Endopeptidase Angiotensin II NH2-Asp-Arg-Val…Pro-Phe-COOH 1 2 3 7 8 Angiotensin 1-7 Releases ADH; ↑ PG; Natriuretic; ↓ RVR; ↓ BP (brain stem inj.) ? Role in effects of ACEI Aminopeptidase Angiotensin III NH2-Arg-Val…Pro-Phe-COOH 2 3 7 8

Angiotensin II ANGIOTENSIN II - SUPPORT OF THE BLOOD PRESSURE Cardiac & Vascular Hypertrophy Vasoconstriction Direct Renal Sodium Retention ↑ Cardiac Contractility Aldosterone Secretion Angiotensin II Sympathetic Facilitation: Central Nerve terminal (ganglionic ?) ↑ Thirst ADH Release All known physiologic effects are mediated by the angiotensin II type 1 receptor

Angiotensin Converting Enzyme Inhibitors Large number of drugs available differ mainly in the following: Potency Route of elimination Duration of action Being prodrugs or active drugs Similar therapeutic indications, adverse effects and contraindications

Adverse Effects Hypotension Renal Insufficiency (if bilateral renal artery stenosis) Hyperkalemia – special group of patients (Na restricted, on K-sparing diuretic, COX inhibitors) Cough (20 %) Angioedema With captopril especially: neutropenia, nephrotic syndrome, skin rash, taste disturbances (SH group- related). Kinin-related (?)

Enalapril Lisinopril Binds to Zn ion Binds more strongly to Zn – more active Binds to active site Enalapril Lisinopril

ACE Inhibitors and Left Ventricular Hypertrophy

ACE Inhibitors and Left Ventricular Hypertrophy

ACE Inhibitors after Myocardial Infarction

ACE Inhibitors in Heart Failure Study of LV Dysfunction (SOLVD)

Patients with Severe Heart Failure Asymptomatic Patients with EF<40% ACE Inhibitors in Severe Heart Failure Survival and Ventricular Enlargement Trial (SAVE) Captopril Placebo Probability of Survival Hydralazine Mortality Rate Captopril Patients with Severe Heart Failure Placebo Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS) Probability of Sudden Death Enalapril

ACE Inhibitors – Effect on Progression of Diabetic Nephropathy Enalapril Metoprolol Metoprolol Enalapril

ACE Inhibitors – Effect on Progression of Non-Diabetic Nephropathy

Therapeutic Uses Anti-hypertensive Prevent or reverse LVH Protect against sudden death and second myocardial infarction after acute MI Improve survival and hemodynamics in patients with congestive heart failure Protect against progression of diabetic and non-diabetic nephropathy

Angiotensin II Type 1 Receptor Blockers Losartan Valsartan Candesartan

Angiotensin Receptor Blockers e.g. Losartan Block only the AT-1 subtype Comparable effects to ACE Inhibitors in almost all situations. Less decrease in GFR in volume depleted states Less side effects especially cough, angioedema, rash Block all AII effects and not dependent on particular pathway Kinins (?)

ELITE STUDY GROUP (Evaluation of Losartan in the Elderly) – P: Placebo E: Enalapril L: Losartan C: Captopril 3 month mortality (%) P E P L C L SOLVD US +Int’l Exercise ELITE (n=2569) (n=736) (n=722) Fig. 3: 3-month mortality in three different studies ELITE STUDY GROUP (Evaluation of Losartan in the Elderly) – Losartan better than captopril in patients with heart failure (chance finding?)

Losartan Superior to Captopril (? Chance Finding) ELITE STUDY GROUP Losartan Superior to Captopril (? Chance Finding) Losartan Captopril Probability of Survival Follow-up (days)

ELITE II STUDY GROUP (3,152 patients for 1.5 y) No Difference between Captopril and Losartan Probability Of Survival % Event-free Probability % Lancet. 2000;355:1582-7.

Hypertensive Patients with Nephropathy

↑ Kinins ↓ AII effects ACE Inhibitor AII Receptor Blocker Blocks AT-1R Free Blocks formation of AII incompletely Blocks Kininase II Preserve Anti- proliferative effect ↑ Kinins More complete Inhibition of AII effects ↓ AII effects & aldosterone PROTECTION