DISCOVERY OF ANGIOTENSIN CONVERTING ENZYME IN THE LUNG

Kevin KF Ng, MD, PhD, FRACPFormer Associate Professor of Pharmacology

University of SingaporeFormer Associate Professor of Medicine

University of Miami, Florida

Presented at Department of Medicine, Tan Tock Seng Hospital, Republic of Singapore: Jan 22, 2016

Discovery of the lung angiotensin converting enzyme 1967

History of the renin-angiotensin system.

Vane’s blood bathed organ superfusion technique.

Estimation of half-lives in circulating blood.

Disappearance of angiotensin II in vascular beds.

Estimation of conversion of angiotensin I to angiotensin II in circulating blood.

Disappearance of angiotensin I in vascular beds

Evidence that angiotensin I is converted to angiotensin II in the lungs.

The lung as an endocrine organ.

Subsequent research on endothelium of capillaries of the pulmonary vascular bed.

Recent advances in basic science and clinical research.

Timeline on Discovery of Pulmonary Angiotensin Converting Enzyme 1890-1967

Assay of Hormones in Blood

Isolated Bioassay Organs

Reactions of isolated organs to physiological concentrations of substances (1-5 ng/ml) likely to be found in blood

The dynamics of the renin-angiotensin system 1966

Vane’s blood-bathed organ technique: superfusion & incubation circuit

Half-life of angiotensin II in circulating blood (sec)

Disappearance of a substance in one circulation through vascular bed

Disappearance of angiotensin II in vascular beds

% conversion of angiotensin I to angiotensin II in circulating blood

% conversion of angiotensin I to angiotensin II in blood and vascular beds

5 sec90 sec

Disappearance of Angiotensin I and Angiotensin II in vascular beds

Evidence that angiotensin I is converted to angiotensin II in lungs

1. Intravenous angiotensin I.2. IV Exogenous Renin infusion.3. Endogenous Renin release

from Golblatt kidney.4. Lung perfusate from isoalated

lungs.

A New Concept of Renin-angiotensin System in 1967

The endothelium and ectoprotein angiotensin converting enzyme

Vasoactive substances metabolized by the endothelium

http://ceaccp.oxfordjournals.org/content/early/2013/01/10/bjaceaccp.mks060.full.pdf+html

Vasoactive substances synthesized by the endothelium of lungs

Pulmonary extraction, metabolism or both of drugs used in anesthesia

Respiratory and Non-respiratory functions of the lung

Respiratory function: Gas exchange of Carbon Dioxide for Oxygen

Non-respiratory functions: Activation, Inactivation, Free passage of vasoactive substances

Paracrine functions : Nitric oxide (NO), Prostacylcin (PGI), Platlete acting factor, Endothelin.

Impact of the discovery of Lung Angiotensin Converting Enzyme (ACE) since 1967.

Unique function of the pulmonary angiotensin converting enzyme (ACE) in converting the inactive angiotensin I to the active angiotensin II.

Selective filter of vasoactive substances in the circulation.

The endocrine function of the lung in the release of active pharmacological substances.

Development of angiotensin converting enzyme inhibitor (ACE inhibitor) in the treatment of hypertension, congestive heart failure and diabetic kidney disease since 1981.

Recognition of the role of plasma ACE in pathological states e.g. sarcoidosis.

Recent research in ACE-2.

Number of counts on PubMed related to ACE, ACEI, ARB since 1967

References

KKF Ng: “The dynamics of the renin-angiotensin system”.Ph. D. Thesis, University of London, 1968.

RL Hodge, KKF Ng and JR Vane: Disappearance of angiotensin from the circulation of the dog.Nature (1967),215,138-141.

KKF Ng and JR Vane: Conversion of angiotensin to angiotensin II.Nature (1967), 216,762-766.

KKF Ng and Vane: Fate of angiotensin I in the circulation.Nature (1968), 218,144-150.

KKF Ng and Vane: Some properties of angiotensin converting enzyme in the lung.Nature (1970) 225, 1142-1144