Lecture 9 Nitrates and Vasodilators

Question 1

enodthelial Nitric oxide synthase (eNOS) helps convert the amino acid _____ to ____, which releases NO

Answer 1

arginine, citrulline

Question 2

NO made by eNOS diffuses into the _____ ____ _____, where it stimulates ___ ____

Answer 2

vascular smooth muscle;

guanylate cylase

Question 3

stimulation of guanylate cyclase causes production of ____ and activation of ______

Answer 3

cGMP, protein kinase G (PKG)

Question 4

PKG relaxes smooth muscle in 4 ways:

1. inhibits __ ___ channels
2. stimulates ___ ____ channels
3. decreases ____ ____ _____ ____
4. enhances ____ uptake to the _____

Answer 4

L-type calcium (CaV1.2)
2. Ca-activated K+ channels (BKca)
3 . Myosin Light chain phosphorylation
4. Ca, ER (phospholamban)

Question 5

Organic nitrates are broken down into ____ ____, causing vasodilation

they (do/do not) require functional endothelium

Answer 5

nitric oxide;
do not (directly stimulate guanalyl cyclase

Question 6

Of the nitrates, _____ has basically 0 oral bioavailability. It is given _____ in treatment of acute anginal attacks.

_____ and _____ have better oral bioavailability and longer half life and are used for _____ _____

Answer 6

glyceryl trinitrate (nitroglycerin), sublingually

isosorbide mononitrate (ISMN) and dinitrate (ISDN);
prolonged prophylaxis

Question 7

describe “monday disease”

Answer 7

workers who are exposed to nitrates at work build up tolerance during the week (so no symptoms tuesday-sunday). after not being at work on the weekend, tolerance is loss–> tachycardia and dizziness on monday

Question 8

nitroglycerin is metabolized by ____. This explains its lack of efficacy in a large percentage of the asian population. _____ is also metabolized by this same enzyme

Answer 8

Aldehyde dehydrogenase 2 (ALDH2);

alcohol

Question 9

Nitroprusside is given for acute management of ______ and heart failure. It dilates _____. It is metabolized to ____, which limits duration of treatment

Answer 9

HTN crisis;
veins and arterioles;

cyanide

Question 10

hydralazine preferentially dilates ____. It appears to interfere with release of ____ from the _____. It can cause what important side effect?

Answer 10

arterioles, calcium, ER;

lupus like syndrome

Question 11

BiDil is a combination of ____ and _____. It decreases mortality in ____ _____ with CHF

Answer 11

hydralazine, ISDN;

african americans

Question 12

_____ is a recombinant B natriuretic peptide. It binds to and activates _______ in vascular smooth muscle and endothelial cells and is used for ______

Answer 12

Natrector (nesiritide); membrane bound guanylate cyclase;

acute decompensated HF

Question 13

NO may also be involved in covalent modification of proteins by nitrosyl transfer from _____. In other words, it may inhibit ___ ____ channels

Answer 13

glutathione;

L-type calcium (CaV1.2)

Question 14

milrininone and amrinone are selective inhibitors of ____

Answer 14

phosphodiesterase (PDE) 3

Question 15

PDE3 normally causes a conversion of ____ to ____.

Answer 15

cAMP to AMP

Question 16

When PDE3 is inhibited, cAMP ______. This causes phosphorylation of ________, inactivating it and causing smooth muscle _____

Answer 16

increases;
myosin light chain kinase;
relaxation

Question 17

amrinone and milrinone have a direct positive _____ effect on myocardium and a direct _____ effect on vascular smooth muscle;

mainly used in CHF

Answer 17

inotropic;

vasodilatory

Question 18

Sildenafil, vardenafil, and tadalafil are potent inhibitors of ____ , causing an increase in _____

Answer 18

PDE 5; cGMP

Question 19

the -afils are used for _____ and ______

Answer 19

erectile dysfunction; pulmonary HTN (esp arterial type)

Question 20

the -afils can cause _____ vision due to some inhibition of ____ located in the retina

Answer 20

bluish; PDE6

Question 21

Sildenafil (viagra)/other -afils cause increased relaxation of the ____ _____ in the ____ ____

Answer 21

helicine artery; corupus cavernosum

Question 22

who should not receive -afils due to a risk of severe ____?

Answer 22

patients taking nitrates;

severe hypotension

Question 23

which of the -afils has the longest duration of action? Which has the longest time to onset?

Answer 23

cialis (tadalafil) ie the weekend pill;

levitra (vardenafil)

Question 24

effect on potassium channel: general

vasoconstrictors ____ the K channel, causing _____;

vasodilators ____ the K channel, causing ____

Answer 24

inhibit, depolarization;

increase conductance; hyperpolarization

Question 25

increased hyperpolarization makes it harder to open ___ _____ channels, causing vaso____

Answer 25

voltage-gated calcium, dilation

Question 26

name 2 K+ channel agonists. what else are they used for, besides severe hypotension?

Answer 26

minoxidil, promotes hair growth;

diazoxide; hyperinsulinemia (increased K+ current decreases insulin release)

Question 27

adenosine binds to what kind of receptor? what is the receptor coupled to?

Answer 27

GPCR;

coupled to G-protein activated inwardly rectifying K+ channel (GIRK)

Question 28

Binding of adenosine causes potassium ____ and membrane _____. It is given via IV for what?

Answer 28

efflux, hyperpolarization;

coronary stress test

Question 29

Endothelin signalling is increased in what? What does endothelin cause?

Answer 29

pulmonary arterial hypertension;

normally causes vasoconstriction and proliferation of vascular smooth muscle

Question 30

Name 3 endothelin receptor antagonists:

____, macitentan and ambrisentan

Answer 30

bosentan (most important in FA)

Question 31

bosentan can cause ______. All 3 endothelin receptor antagonists are contraindicated in _____

Answer 31

hepatotoxicity;

pregnancy

Question 32

_____ is a prostacyclin analog that is inhaled. ____ is a prostacyclin analog given IV (Short half-life). what do they cause?

Answer 32

epoprostenol, iloprost;

vasodilation

Question 33

_____ is a prostcyclin analog with the longest half life and can be given orally. All prostacyclin analogs are used for what?

Answer 33

selexipag;

pulmonary arterial HTN

Question 34

Riociguat increases ____ concentration in vascular smooth muscle. It is used for ____ and is contraindicated in ____

Answer 34

cGMP; pulmonary HTN;

pregnancy

Question 35

_____ is a substrate for P-gp, CYP1A1, 3A (highlighted in red in the notes -__-)

Answer 35

riociguat