4.2 MedChem ONLY Text from PPT

______ is a short-lived, endogenously produced molecule that acts as a signaling agent in the body.

Nitric oxide (NO)

Lifestyle and Physiologic Risk factors that lead ↓ Nitric Oxide (NO) Bioavailability

1. Poor diet

2. Family history of cardiovascular disease

3. Tobacco smoking

4. Diabetes

5. Gender

6. Hyperlipidemia or atherosclerosis

7. Age

8. Sedentary lifestyle

9. High blood pressure

Mechanisms That Reduce NO Production or Activity

1. Reduced eNOS (endothelial nitric oxide synthase) activity

2. Reduced eNOS expression

3. eNOS uncoupling

4. Arginase upregulation

5. Endogenous NOS inhibitors

6. Oxidative stress

Which are the 3 isoforms of NO Synthase (NOS)?

1. neuronal NOS (nNOS)

2. endothelial NOS (eNOS )

3. inducible NOS (iNOS) found in macrophages

____, _____ and ____ are cofactors of all isozymes of NOS

- BH4 (tetrahydrobiopterin)

- BH2 (7,8-dihydrobiopterin)

- Haem

RELAXATION MECHANISM: NO diffuses into smooth muscle cells where it binds to the _______ and activates ________ to produce ________

- haem center

- soluble guanylate cyclase (sGC)

- cyclic guanosine monophosphate (cGMP)

RELAXATION MECHANISM: cGMP activates _________

Protein Kinase G (PKG)

RELAXATION MECHANISM: ________ phosphorylates several targets in regulating the intracellular Ca2+ concentration, resulting in relaxation.

Protein kinase G (PKG)

Nitroglycerin [glyceryl trinitrate (GTN)]

Isosorbide

Isosorbide Mononitrate (ISMN)

Isosorbide Dinitrate (ISDN)

Organic nitrates are ________, characterized by a sequence of _____________.

- polyol esters of nitric acid

- carbon- oxygen-nitrogen (—C—O—NO2)

All organic nitrates are _________

prodrugs

______ was the first organic nitrate

Nitroglycerin (a.k.a. glyceryl trinitrate)

T. Lauder Brunton administered _______ by inhalation and noted that anginal pain was relieved within 30-60 s.

amyl nitrite

amyl nitrite

MOA Organic Nitrates: In smooth muscle, the net result is ______________ and thus promotes relaxation.

- reduced phosphorylation of myosin light chain

- reduced Ca2+ concentration in the cytosol

MOA Organic Nitrates: NO reduces myocardial O2 demand by decreasing _____________

both preload and afterload

MOA Organic Nitrates: NO dilates coronary arteries, thereby _____________

increasing coronary blood flow

MOA Organic Nitrates: NO limits _________

platelet aggregation/adhesion

For High potency Nitrates 3 potential ways lead to the production of NO, which are?

1) Direct formation in response to interaction with the ALDH2

2) Formation of NOx species

3) Formation of nitrite which may be reduced by the xanthine oxidase (XO) in the cytoplasm to form NO

Which are the HIGH potency Nitrates?

GTN, PETN

Low-potency nitrates can be activated by ______ enzyme(s) in the endoplasmic reticulum (ER), directly yielding nitric oxide.

Cytochrome P450

Which are the LOW potency Nitrates?

- ISDN

- ISMN

- GDN

- PEDN (high dose)

Allow nitrate free interval of _______ to avoid nitrate tolerance

10-14 hours

Within 1 day of continuous low-dose GTN therapy, __________ reduces therapeutic efficacy (pseudotolerance).

neurohormonal counter-regulation

After_______, endothelial and smooth muscle dysfunction develops (vascular tolerance and cross-tolerance)

3 days

In nitrate tolerance, the end result of the mechanism is __________

increased inactivation of cGMP by PDE.

Do not take PDE-5 inhibitor within at least ______ of taking nitrate due to severe and potentially fatal ________

24h, hypotension

Cellular concentration of cGMP can be reduced by ___________

phosphodiesterases (PDE), particularly PDE5.

How can NO's efficiency be increased?

- Block other pathways (PDE-5 inhibitor)

- Add exogenous NO (nitric oxide)

PDE5

Which are some commonly used PDE-5 inhibitor drugs?

- Avanafil

- Sildenafil

- Vardenafil

- Tadalafil

_________ are rich of inorganic nitrate.

Vegetables

_________, such as nitroglycerin, have been available for more than 150 years and acted as vasodilators via NO release, though tolerance may occur.

Organic nitrates

________ and ______ may act as substrates for NO formation, and clinical trials are currently ongoing using nitrate and nitrite salts for several cardiovascular indications.

Inorganic nitrate and nitrite

_______ from diet can enhance NO bioactivity.

Polyphenols

________ can also lead to relaxation

PDE-5 inhibitors