Pulmonary angiotensin converting enzyme (ACE), First ACE inhibitor (Capoten), therapeutic uses of ACE inhibitors since 1981

1. ACE INHIBITORS (1967-1981-2021)
FROM
BASIC SCIENCE
TO
THERAPEUTIC AGENTS
By
Kevin KF Ng, MD, PhD
Former Associate Professor of Medicine
Division of Clinical Pharmacology
University of Miami, Miami, FL.,USA
Email: kevinng68@gmail.com
A Slide Presentation for HealthCare Providers June 2021

2. Presentation Outline
▪ History of the renin-angiotensin system
▪ Blood-bathed organ technique
▪ Studies with angiotensin II
▪ Studies with angiotensin I
▪ Angiotensin converting enzyme (ACE) in the lung
▪ Inhibition of Angiotensin converting enzyme (ACE)
▪ List of the Angiotensin converting enzyme inhibitors
▪ Meta-analysis of effects of ACE inhibitors in
▪ Hypertension,
▪ Congestive hear failure,
▪ Diabetic kidney disease
▪ Summary

3. Royal College of Surgeons England
University of London
JH Burn, FRS advised Kevin KF Ng to work under JR Vane in 1966
https://www.bing.com/images
Department of Pharmacology

4. Components of the 2-enzyme renin-angiotensin system
1956-1966
©DRKEVINKFNG
Angiotensin converting enzyme (ACE)

5. Assay of vasoactive chemicals in Blood
©DRKEVINKFNG

6. Discovery of angiotensin converting enzyme (ACE) in the lung
1967
©DRKEVINKFNG

8. Chronology of the synthesis of ACE (angiotensin
converting enzyme) inhibitor
©DRKEVINKFNG

9. EXPERIMENTAL METHOD
Blood-bathed organ technique

10. Assay of Vasoactive chemicals in Blood
©DRKEVINKFNG

11. Isolated Bioassay Organs
©DRKEVINKFNG
High sensitivity to 5-HT High sensitivity to Ang II High sensitivity to epinephrine

12. Superfusion technique and parallel assay
https://www.nature.com/articles/215138a0

13. Responses of isolated organs to physiological concentrations of
vasoactive substances.
https://www.nobelprize.org/uploads/2018/06/vane-lecture.pdf

14. Study of the Dynamics of the renin-angiotensin system with
Vane’s blood-bathed organ technique (1967)
©DRKEVINKFNG

15. ANGIOTENSIN II STUDIES
8 amino acid peptide

16. Half-life of angiotensin II in circulating blood (sec)
Nature .1967 Jul 8;215(5097):138-41

17. Disappearance of angiotensin II in vascular beds
https://www.nature.com/articles/215138a0

18. ANGIOTENSIN I STUDIES
10 amino acid peptide

19. Chemical structure of angiotensin l and angiotensin ll
©DRKEVINKFNG

20. % conversion of angiotensin I to angiotensin II in circulating blood
https://www.nature.com/articles/218144a0
90 sec

21. Relative potency of angiotensin I to angiotensin II in venous and arterial blood
©DRKEVINKFNG

22. Lack of activation of angiotensin I during passage through the
Peripheral vascular beds
©DRKEVINKFNG

23. Conversion of angiotensin I to angiotensin II in
venous blood and after passage through the lungs
©DRKEVINKFNG

24. Evidence that angiotensin I is activated during passage through
pulmonary circulation in isolated guinea pig lung
https://www.nobelprize.org/uploads/2018/06/vane-lecture.pdf

25. Fate of Angiotensin I and Angiotensin II in vascular beds
Adapted from Nature, Volume 218, Issue 5137, pp. 144-150 (1968).

26. Different responses of peptides bathed in venous and arterial blood:
Bradykinin is inactivated > 90% across the lungs
©DRKEVINKFNG

27. Could the enzyme that inactivates bradykinin be the same
enzyme that converts angiotensin I to angiotensin II?
enzyme
©DRKEVINNGKFNG
same enzyme?

28. ● INHIBITION OF ACE BY BPF (BRADYKININ POTENTIATING FACTOR)
● ISOLATION OF ACE INHIBITOR IN BPF
● SYNTHESIS OF CAPTOPRIL (CAPOTEN)
● CLINICAL EFFECACY OF ACE INHIBITORS

29. Effect of Bradykinin Potentiating Factor (BPF) on Pressor
Responses to angiotensin I and angiotensin II
https://www.nature.com/articles/2251142b0

30. Isolation of ACE inhibitor in BPF (Bradykinin potentiating factor)
leads to synthesis of captopril (Capoten) 1981
Bradykinin
Potentiating Factor
(a mixture of peptides)
Pentapepide
pGa-Lys-Trp-Ala-Pro
Capoten
(captopril)
1981
©DRKEVINNGKFNG

31. List of ACE inhibitors synthesized since 1981
©DRKEVINNGKFNG

32. Multiple indications for ACE inhibitors (2020)
▪ Hypertension
▪ Heart Failure
▪ Asymptomatic Left Ventricular Dysfunction
▪ Post Myocardial Infarction
▪ Diabetes
▪ Nephrotic Syndrome or Proteinuria
▪ Chronic Kidney Disease
▪ Glomerular Disease
▪ Post-transplant Glomerulonephritis
https://www.ncbi.nlm.nih.gov/books/NBK431051/

33. Contraindications of ACE inhibitors
▪ Allergy to ACE inhibitor
▪ Cough
▪ Angioedema
▪ Bilateral renal artery stenosis
▪ Second and third trimesters of pregnancy
https://pubmed.ncbi.nlm.nih.gov/16858164/#:~:text=Angiotensin%2Dconverting
%20enzyme%20inhibitors%20(ACEIs,to%20inhibition%20of%20angiotensin%20II
.

34. Antihypertensive Efficacy of ACE inhibitors as Measured by
Office Blood Pressure (2018)
https://www.sciencedirect.com/science/article/pii/S0735109718304315

35. Antihypertensive Efficacy of ACE inhibitors as Measured by
Ambulatory Blood Pressure Monitoring (2018)
https://www.sciencedirect.com/science/article/pii/S0735109718304315#fig3

36. Effects of ACE inhibitor on diabetic kidney disease (DKD) and non-DKD:
Urine protein (Uprot) and arterial blood pressure (MAP)
https://kidneyfoundation.cachefly.net/professionals/KDOQI/guideline_diabetes/guide3.htm

37. ACE Inhibitors Potently Reduce Vascular Inflammation
in the Abdominal Aortic Aneurysm (2014)
Non-treated controls (white bars)
Ramipril-treated patients (grey bars)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256371/
Anti-inflammatory

38. ACE inhibitor treatment improves survival of
new fatal or nonfatal cardiovascular events (2003) .
ACE-I (-)
DOI: 10.1161/01.STR.0000099124.84425.BB
.
.
.
.
ACE survival

39. EVALUATION OF EFFICACY OF ACE INHIBITORS:
META-ANALYSIS
SIDE EFFECTS

40. Meta-analysis in medical research: Hierarchy of evidence
https://europepmc.org/article/pmc/pmc3049418

41. An example of meta-analysis on weight loss study
https://www.researchgate.net/figure/Meta-analysis-of-weight-loss-at-12-months_fig2_266683332

42. Effect of ACE Inhibitors and ARBs on Hypertension: (2018)
https://www.sciencedirect.com/science/article/pii/S0735109718304315
Hypertension

43. Thirty Years of Evidence on the Efficacy of Drug Treatments for
Chronic Heart Failure With Reduced Ejection Fraction
A Network Meta-Analysis (2017)
ACEI indicates angiotensin-converting enzyme inhibitor;
ARB, angiotensin-II receptor blocker;
ARNI, angiotensin receptor-neprilysin inhibitor;
BB, beta blocker; and
MRA, mineralocorticoid receptor antagonist.
https://www.ahajournals.org/doi/full/10.1161/CIRCHEARTFAILURE.116.003529
ACEI_CHF

44. Risk ratios (and 95% confident intervals) of ESRD or death in
a meta-analysis of 11 trials of 1594 patients with nondiabetic
renal disease randomized to ACE inhibitor therapy or placebo (2004)
https://www.kidney-international.org/article/S0085-2538(15)50407-9/fulltext
Renal disease

45. Effect of Angiotensin-Converting Enzyme Inhibitors on All-Cause Mortality,
Cardiovascular Deaths, and Cardiovascular Events in
Patients With Diabetes Mellitus:
A meta analysis (2014)
Adapted from JAMA Intern Med. 2014;174(5):773-785
ACEI-CV

46. Most Common Adverse Effects of ACE inhibitors
▪ Dry Cough (10% to 20%)
▪ Dizziness (12% to 19%)
▪ Hypotension (7% to 11%)
▪ Increased BUN and Cr (2% to 11%)
▪ Syncope (5% to 7%)
▪ Hyperkalemia (2% to 6%)
https://www.ncbi.nlm.nih.gov/books/NBK430896/

47. QUALITY OF LIFE STUDY WITH ACE INHIBITORS

48. Patient satisfaction with antihypertensive therapy:
% patients switched to ACE inhibitor (2005)
https://www.nature.com/articles/1001899

49. Primary reasons for switching antihypertensive medications (2005)
https://www.nature.com/articles/1001899

50. Summary
▪ The pulmonary circulation plays an active role in the metabolism of
peptides:
▪ The inactive angiotensin I is converted to the active angiotensin II
▪ Bradykinin is almost completely inactivated during its passage through the lungs.
▪ Bradykinin potentiating factor (BPF) showed that the enzyme that
converted angiotensin I to angiotensin II is the same enzyme that
inactivated bradykinin.
▪ Analysis of the BPF revealed that the converting enzyme inhibitory
compound was a pentapeptide which led to the synthesis of captopril
(Capoten) and more than 10 other ACE inhibitors.
▪ ACE inhibitors have been used successfully in the treatment of
hypertension, congestive heart failure and diabetic kidney disease.

51. Acknowledgements
Grateful thanks to my family, my mentors JH Burn, JR Vane and colleagues who
helped me in the study of the “Dynamics of the renin-angiotensin system”
▪ Joshua H. Burn, FRS, Emeritus Professor at Oxford University
▪ Sir JR Vane, Nobel Laureate 1982
▪ Robert L. Hodge, MD
▪ Sergio H. Ferreira, MD
▪ Rod J. Flower, FRS
Sir JR Vane Robert L. Hodge Sergio H. Ferreira Rod J. Flower
Joshua H. Burn

52. ANY QUESTION?
Other slide presentations available at:
https://www.slideshare.net/ssusera9ba27/presentations