PCTH 400. Drugs that improve endothelial function. Atherosclerosis LAST LECTURE

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1 PCTH 400 LAST LECTURE Drugs that improve endothelial function. Pascal N. Bernatchez, Assistant Professor icapture Research Centre Dept. Anesthesiology, Pharmacology & Therapeutics University of British Columbia Classic Vascular -chronic -systemic Local Vascular -acute -targeted High blood pressure Blood pressure control Endothelial Injury Thrombus CABG PTCA Stent Drug eluting stents Patient burden Restenosis In-sent restenosis Lipid lowering drugs Platelet/SMC Providence Heart + Lung Institute at St. Paul s Hospital University of British Columbia Endothelial dysfunction causes hypertension and vice-versa Which one comes first? Hypertension EC dysfunction Arteriosclerosis Macrophage accumulation Formation of necrotic core Formation of fibrous cap R.Ross, N.Engl.J.Med., 1999

2 Arteriosclerosis Endothelium Endothelium SMC -Hardening of arteries -Consequence of atherosclerosis + calcification -Hypertension -Endothelial dysfunction -MI -Aortic aneurysm -Stroke -Improve the bioavailability/release/ mimic of endothelial mediators -Decrease oxidative stress -Increase/potentiate the downstream effect Nitric Oxide Prostacyclin EDHF Superoxide Endothelial dysfunction causes hypertension and vice-versa Which one comes first? Diuretics? Hypertension EC dysfunction Arteriosclerosis

Carvedilol Pharmacology of NO -First β-blocker to get FDA approval for heart failure -Improves LV function, used in hypertension and heart failure -Anti-oxidant activities: Long term months (no acute

Several metabolites of carvedilol (which have been found in human plasma) exhibit a much greater antioxidant activity than carvedilol itself (up to 50 times more activity) What is the most profitable

3 Carvedilol Pharmacology of NO -First β-blocker to get FDA approval for heart failure -Improves LV function, used in hypertension and heart failure -Anti-oxidant activities: Long term months (no acute activities). Several metabolites of carvedilol (which have been found in human plasma) exhibit a much greater antioxidant activity than carvedilol itself (up to 50 times more activity) What is the most profitable drug of all time? Effects of Carvedilol Versus Metoprolol on Endothelial Function and Oxidative Stress in Patients With Type 2 Diabetes Mellitus *, AmJHypertension Viagra Structure of Viagra -Sildenafil (UK-92,480) was synthesized by Pfizer in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (ischaemic cardiovascular disease). -Year? Viagra cgmp

to increased inflow of blood and erection.

4 Mechanism of action Has anyone heard of? -Mechanism: 1- parasympathetic nervous system causes NO release in the corpus cavernosum and leads to increased inflow of blood and erection. 2- selective inhibitor of cgmp specific phosphodiesterase type 5 which is responsible for degradation of cgmp in the corpus cavernosum. -Has anyone heard of? -Used to treat pulmonary hypertension cgmp Mechanism of action?

Fir;. 1 William Murrell(1853-1912). Photograph provided by the National Library of Medicine, Bethesda, Maryland. useful in treating patients with angina?

A pioneer of cardiovascular, Brunton was the first to propose vasodilator as a treatment for angina. He advocated amyl nitrate for the treatment of complaint in 1867.

Brunton knew that some patients with angina seemed to improve with phlebotomy, and he thought that amyl nitrite might cians confirmed his observations and my1 nitrate became a standard remedy for

Although Brunton studied nitro- glycerin before Murrell experimented with it, he did not administer it to humans because it gave him such a severe head- ache he thought patients would not tolerate

Fye: William Murrell 427 by his early experience with the drug. He began administering nitroglycerin to patients with angina in the summer of 1878.

5 Fir;. 1 William Murrell( ). Photograph provided by the National Library of Medicine, Bethesda, Maryland. useful in treating patients with angina? His interest in organic nitrates can be traced to the observations of the Scottish physi- cian and pharmacologist T. Lauder Brunton? A pioneer of cardiovascular, Brunton was the first to propose vasodilator as a treatment for angina. He advocated amyl nitrate for the treatment of complaint in Earlier experi- ments had led medical scientists to classify this substance as a vasodilator that acted on the vasomotor nerves. Brunton knew that some patients with angina seemed to improve with phlebotomy, and he thought that amyl nitrite might cians confirmed his observations and my1 nitrate became a standard remedy for angina. Although Brunton studied nitro- glycerin before Murrell experimented with it, he did not administer it to humans because it gave him such a severe head- ache he thought patients would not tolerate Murrell was not deterred. He thought nitroglycerin might be useful, in angina because the two drugs seemed to have the same effect on the circulation. Murrell s theory was supported W. B. Fye: William Murrell 427 by his early experience with the drug. He began administering nitroglycerin to patients with angina in the summer of His first patient was a 64-year-old heavy smoker with symptoms consistent with angina. After ingesting a 1 % solutions of nitroglycerin three times a day for a week, the patient reported that the anginal attacks occurred less frequently and were less severe. Murrell did not depend solely on his patient s subjective impressions. He used the sphygmograph, an instrument recently invented for graphically recording the pulse, to document the drug s effects on the heart rate and pulse wave form. The special role of nitroglycerin in the treatment of angina pectoris was acknowledged rapidly. British physician William Green claimed in 1882, I am not overstating [nitroglycerin s] merits when I say it deserves to rank only second to digitalis in the treatment of disease of the heart. 9 The liquid nitroglycerin preparation Murrell prescribed was inconvenient, however. Within a year the drug was available in tablet form in a variety of strengths. Anticipating the logical concern about the explo- sive potential of nitroglycerin, British chemist William Martindale explained that it was stable and perfectly inexplo- sive-it cannot be detonated. O In addition to his classic work on nitroglycerin, which was reprinted in book form in 1882, Murrell published mono- graphs on several other subjects including the treatment of bronchitis, the medical value of massage, and toxicology. He diedin References 1. Fye WB: Nitroglycerin: A homeopathic remedy. Circulation 73, (1986) 2. Smith E, Hart FLl: William Murrell, physician and practical therapist. Br Med 53, (1971) 3. Murrell W: Nitro-glycerine as a remedy for angina pectoris. Lancet I, 8CL8l,113-ll5, , (1879) 4. Fye WB: Vasodilator therapy for angina pectoris: The intersection of homeopathy and scientific medicine. J Hist Med Allied Sci 45, (1990) 5. Murrell W Nitm-glycerine. (1879) 8 I 6. Fye WB: T. Lauder Brunton and amyl nitrite: A Victorian vastdila- tor. Circulation 74, ( 1986) 7. Brunton TL: On the use of nitrite of amyl in anginapectoris. Lancet 2,97-98 (1 867) 8. Brunton TL, Tait ES: Preliminary notes on the physiological action of nitroglycerin [ In Collected Papers on Circuhtion and Respiration. Fir.st Series. Macmillan & Co., London (1907) 22CL Green WG: Notes on the use of nitro-glycerine in the treatment of heart disease. Ther Guz 6, ( 1882) Martindale W Nitroglycerin in pharmacy. Practitioner 24,35-39 (1880)37 and Viagra Nitroglycerin Viagra Nitroglycerin Angiotensin II Angina (mostly stable or unstable?) Severe hypertension Myocardial infarction Do not use with viagra or revatio Workers? accomplish the same result without causing anemia. Soon after Brunton published his findings in the Lancet, other physi- Murrell He had unwittingly touched the moist cork stopper of a vial of nitroglycerin to his tongue while seeing outpatients.this caused a severe, pounding headache, tachycardia and a dramatic increase in the force of his heart beat.

Angiotensin II Angiotensin II and Oxidative stress -AngII has a direct

an indirect negative effect on endothelial function: -Oxidative stress

-AngII has a indirect effect on blood pressure: -oxidative stress

6 Angiotensin II Angiotensin II and Oxidative stress -AngII has a direct negative effect on endothelial function: -Decreases enos levels -AngII has an indirect negative effect on endothelial function: -Oxidative stress AT1vsAT2 -AngII has a direct effect on blood pressure: -SMC Constriction -AngII has a indirect effect on blood pressure: -oxidative stress Angiotensin II and Oxidative stress Angiotensin II ACEi Increase NO function indirectly and directly

Nitric Oxide Synthase Coupling Charalambos Antoniades, MD, PhD; Constantinos Bakogiannis, MD; Paul Leeson, PhD; Tomasz J. Guzik, PhD; Mei-Hua Zhang, PhD; Dimitris Tousoulis, MD, PhD; Alexios S.

7 AngII inhibitors and direct effect on endothelial function Angiotensin II -Inhibit HMGCoA Reductase -Extremely controversial (why?) -Upcoming Lecture Statins Vascular Medicine Rapid, Direct Effects of Statin Treatment on Arterial Redox State and Nitric Oxide Bioavailability in Human via Tetrahydrobiopterin-Mediated Endothelial Nitric Oxide Synthase Coupling Charalambos Antoniades, MD, PhD; Constantinos Bakogiannis, MD; Paul Leeson, PhD; Tomasz J. Guzik, PhD; Mei-Hua Zhang, PhD; Dimitris Tousoulis, MD, PhD; Alexios S. Antonopoulos, MD; Michael Demosthenous, MD; Kyriakoula Marinou, MD, PhD; Ashley Hale; Andreas Paschalis, MD; Costas Psarros, BSc; Costas Triantafyllou, MD; Jennifer Bendall, PhD; Barbara Casadei, MD, DPhil; Christodoulos Stefanadis, MD, PhD; Keith M. Channon, MD, FRCP Background Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease. Methods and Results We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O 2 ) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O 2 generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O 2 generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-L-arginine methyl ester inhibitable O 2 in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O 2. These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition. Conclusions This study demonstrates for the first time in humans the direct effects of statin treatment on the vascular wall, supporting the notion that this effect is independent of low-density lipoprotein lowering. Atorvastatin directly improves vascular NO bioavailability and reduces vascular O 2 through tetrahydrobiopterin-mediated endothelial NO synthase coupling. These findings provide new insights into the mechanisms mediating the beneficial vascular effects of statins in humans. Clinical Trial Registration URL: Unique identifier: NCT (Circulation. 2011;124: ) Key Words: statins tetrahydrobiopterin oxidative stress superoxide nitric oxide synthase tatins are now considered a fundamental component of Sthe treatment of patients with atherosclerotic vascular disease. 1 Reducing low-density lipoprotein (LDL) cholesterol by statins reduces cardiovascular risk in both primary 1 and secondary 2 prevention and is associated with improvements in other markers of vascular disease risk, including inflammation and endothelial function. 3,4 Clinical Perspective on p 345 In addition to LDL lowering, statins have been demonstrated to exert a number of pleiotropic effects. 5 7 Reduction of LDL by statin therapy appears to confer a greater reduction of cardiovascular risk than LDL lowering by other modalities, 8 and clinical trials demonstrate that statin treatment improves This study demonstrates for the first time in humans the direct effects of statin treatment on the vascular wall, supporting the notion that this effect is independent of low-density lipoprotein lowering. Atorvastatin directly improves vascular NO bioavailability and reduces vascular O(2)( -) July 2011 Received August 20, 2010; accepted May From the Department of Cardiovascular Medicine, University of Oxford, NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK (C.A., P.L., M.-H.Z., A.H., J.B., B.C., K.M.C.); First Department of Cardiology, University of Athens, Hippokration Hospital, Athens, Greece (C.A., C.B., D.T., A.S.A., M.D., K.M., A.P., C.P., C.S.); Department of Medicine, Jagiellonian University, Krakow, Poland (T.J.G., A.P.); and Department of Cardiac Surgery, Hippokration Hospital, Athens, Greece (C.T., A.P.). The online-only Data Supplement is available with this article at Correspondence to Keith M. Channon, MD, FRCP, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital OX3 9DU, Oxford, UK. keith.channon@cardiov.ox.ac.uk 2011 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

8 Food supplement Polyphenols -Vitamin C: Increase enos activity and decrease NADPH oxidase activity. Increases enos cofactor activity -Vitamin E: Best anti-oxidant, but elusive activity -All have been shown to reverse endothelial dysfunction in coronary of patients -Poor clinical outcomes -Polyphenols: -French paradox, Mediterranean diet % lower CVD than North America -apples, blackberries, blueberries, cantaloupe, cherries, cranberries, grapes, pears, plums, raspberries, strawberries, vegetables, red wine, chocolate, green tea, olive oil -resveratrol -2 glasses a day (men) -1 glass a day (women) -Reduce oxidative stress -Reduces LDL oxidation -Increases HDL -Resveratrol supplements LAST LECTURE Classic Vascular -chronic -systemic Local Vascular -acute -targeted High blood pressure Blood pressure control Endothelial Injury Thrombus CABG PTCA Stent Patient burden Restenosis In-sent restenosis Lipid lowering drugs Platelet/SMC Drug eluting stents Providence Heart + Lung Institute at St. Paul s Hospital University of British Columbia

PCTH 400. Endothelial dysfunction and cardiovascular diseases. Blood vessel LAST LECTURE. Endothelium. High blood pressure

PCTH 400. Endothelial dysfunction and cardiovascular diseases. Blood vessel LAST LECTURE. Endothelium. High blood pressure PCTH 400 LAST LECTURE Endothelial dysfunction and cardiovascular diseases. Classic Vascular pharmacology -chronic -systemic Local Vascular pharmacology -acute -targeted High blood pressure Blood pressure