1. 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) +
Renin
±PG
NH2-Asp-Arg-Val…Pro-Phe-COOH
Angiotensin I
Non-ACE
(eg. Chymase
in heart)
ACE
Endopeptidase
Angiotensin II
NH2-Asp-Arg-Val…Pro-Phe-COOH
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. 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

3. 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

4. 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 (?)

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

7. ACE Inhibitors and Left Ventricular Hypertrophy

8. ACE Inhibitors and Left Ventricular Hypertrophy

9. ACE Inhibitors after Myocardial Infarction

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

11. 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

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

13. ACE Inhibitors – Effect on Progression of Non-Diabetic
Nephropathy

14. 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

15. Angiotensin II Type 1 Receptor Blockers
Losartan
Valsartan
Candesartan

16. 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
(?)

17. 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?)

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

19. 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:

20. Hypertensive Patients with Nephropathy

21. ↑ 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