The Nobel Prize in Physiology or Medicine 1998 Group 6 B 王元欽 B 吳明諴 B 呂宗哲 B 徐鴻麟 B 屠冠翔 B 莊千儀 "for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system"

The Introduction of Nitric oxide

NO Is Harmful to Our Body  Free radical  The combination with hemoglobin

Robert F. Furchgott The Nobel Prize in Medicine 1998

Research  Factors Influencing Contractility of Cardiac Muscle  Endothelium-dependent Relaxation

Discovery  EDRF(endothelium-derived relaxing factor)  Actually EDRF is NO (by 1986 Louis J. Ignarro)

The paradox of ACh  1953 paper contradictive (Reactions of strips of rabbit aorta to epinephrine, isoproterenol, sodium nitrite and other drugs)  Ach In vivo  relax In vitro  contract  1980 an accidental finding (EDRF) In vitro  relax

Sandwich Experiment(1980) With no endothelium: ACh  contraction with endothelium ‘sandwich’: ACh  relaxation

Ferid Murad The Nobel Prize in Physiology or Medicine 1998 Discovery of Some of the Biological Effects of Nitric Oxide and Its Role in Cell Signaling

The Biological Effect of NO

The structure of GC （ guanylyl cyclase ）  Heterodimer with α and β subunits  α 1, α 2, β 1 and β 2

NO & GC  (A) ferrous heme histidine  (B) NO binds to ferrous heme ion  (C) ferrous heme histidine

Experiment: ventilate NO into guanylyl cyclase preparations

NO activate the guanylyl cyclase

Louis J.Ignarro The Nobel Prize in Medicine 1998  A series of experiments were designed to test the unpublished hypothesis that EDRF might be NO unpublished hypothesis that EDRF might be NO

First Experiment  Purpose: determine whether EDRF released from artery and vein could activate guanylate cyclase

Procedure:arterial & venous rings GC activated GC activated acetylcholine & bradykinin GC methylene blue responses blocked

Second Experiment  Purpose:determine whether the activation of guanylate cyclase by EDRF was heme- dependent as in enzyme activation by NO

Procedure and result: intrapulmonaryarterial rings with endotheliumIntrapulmonary arterial rings without endothelium endothelium tissue baths Ach:activity of GC  NO:activity of GC  Ach:activity of GC  NO:activity of GC  Ach & NO tissue baths Ach:activity of GC  NO:activity of GC  Ach:activity of GC  NO:activity of GC  Heme-containing GC Heme-deficient GC Heme-containing GC Heme-deficient GC

 Hemoglobin (yellow) directly exposed to NO (green)  Hemoglobin (yellow) exposed to endothelial cells that were stimulated to produce EDRF (green) produce EDRF (green) Ignarro's spectral analysis

NO& cardiovascular system  NO is a signal molecule of key importance for the cardiovascular system  Known as the 'endothelium-derived relaxing factor', or 'EDRF'

Function  Turns off the contraction, results in a dilatation of the arteries  Controls the blood pressure and its distribution  Prevents the formation of thrombi

Production of NO  NO is biosynthesised from L-arginine and oxygen by various nitric oxide synthase (NOS) enzymes

Guanylyl Cyclase (GC)

The Generation of NO in Our Bodies  In synapse  In endothelium of blood vessels  In macrophages & neutrophils

NOS (Notric oxide synthetase)  nNOS(neural NOS)  eNOS(endothelial NOS)  iNOS (inducible NOS)

In Synapse

In Macrophages & Neutrophils

Viagra － against impotence  cGMP is regulated by a enzyme called PDE(Phosphodiesterase)  PDE5(type 5)will accelerate the consumption of cGMP of cavernous body of penis. As the amount of cGMP is not enough,the penis will not erect  Viagra decreases the consumption of cGMP of cavernous body of penis by inhibiting PDE5, enhancing the function of NO and making the penis erect

NANCNOEndothelial cells Guanylate cyclase cGM P PDE5 GTP GMP Penile erection stimulation cavernous body of penis Viagra X

Shock Shock  Septic shock 、 Hemorrhagic Shock  iNOS  excessive production of NO  Dilation of blood vessels Down of blood pressure Shock

Sickle Cell Anaemia  When sickle hemoglobin (HbS) gives up its oxygen to the tissues, it sticks together to form long rods inside the red blood cells, making these cells rigid and sickle-shaped.

The latest breakthrough  Discovered by Dr. C.A.Head  Result ： NO will increase the affinity between hemoglobin and oxygen of patients, but no effect on normal people NO will increase the affinity between hemoglobin and oxygen of patients, but no effect on normal people 「 It may be one of the most important medical developments during the ten years!! 」 「 It may be one of the most important medical developments during the ten years!! 」