xanthine oxidases, NADPH oxidase. -Direct damage to tissues (DNA, proteins,
lipids). -Scavenges NO. -Angiotensin II is the main mediator of oxidative stress.
LAST LECTURE
PCTH 400
Endothelial dysfunction and cardiovascular diseases.
Classic Vascular pharmacology -chronic -systemic
High blood pressure Blood pressure control
Local Vascular pharmacology -acute -targeted
Atherosclerosis Endothelial Injury Thrombus CABG
Patient burden
PTCA
Restenosis
Stent
In-sent restenosis
Drug eluting stents
Providence Heart + Lung Institute at St. Paul’s Hospital
University of British Columbia
Endothelium
Blood vessel Endothelium
SMC Nitric Oxide
Prostacyclin EDHF Superoxide
Lipid lowering drugs Platelet/SMC pharmacology
How was NO discovered
How was NO discovered
-In 1978, Furchgott discovered a substance in endothelial cells that relaxes blood vessels, calling it endothelium-derived relaxing factor (EDRF)
ACh
Endothelium
Aortic rings in cascade
Half-life of NO: ? 2 seconds -Endothelium dependent vasorelaxation -inhibited by Hemoglobin
How NO was discovered
How was NO discovered
-In 1977, Ferid Murad’s group show that nitric oxide and various nitro compounds were shown to activate the cytosolic form of guanylate cyclase and to elevate cyclic GMP levels in various tissues. Nitroglycerin was one of those nitro compounds that he had studied and speculated that it might release nitric oxide which then activated guanylate cyclase.
-In 1979, Lou Ignarro’s group showed that gaseous NO causes profound vasorelaxation and that Murad’s obervations on cGMP were induced by NO which causes relaxation using cGMP as a SMC messenger.
-inhibited by Hemoglobin
How was NO discovered
1998 Nobel Prize
-In the late 1970’s, Salvador Moncada showed that NO is released by the endothelium and that its synthesis is derived from L-arginine.
Furchgott: -died
Salvador Moncada
-L-NAME does not work in septic shock
Murad: -U Virginia -Stanford -UTexas -Abbott
Where is Salvador Moncada?
-Controversy: -2001 University of Dundee PhD Honoris Causa ‘It is widely recognised as a travesty of justice that Salvador Moncada did not share the Nobel Prize for Medicine that was awarded to Furchgott in 1998 for the discovery of nitric oxide.’
Ignarro: -Herbalife controversy
-Political manipulation of jury (Honduras) -No exception to the rule of 3 -L-Name controversy in septic shock
A phase III trial of 546C88 enrolled 797 patients with septic shock.[94] Patients received either placebo or 546C88 0-20 mg/kg/hour. The trial was stopped early by an independent data safety monitoring board after it was determined that mortality was greater in patients treated with 546C88. Twenty-eight-day mortality was 49% in placebo recipients and 59% in those who received study drug (p
