What's an important vasoactive peptide that decreases BP?
How does it do so?
Short or long T1/2?
Atrial natriuretic peptide (ANP)
Diuretic, vasorelaxant
Short T1/2
Besides using NO donors, how else could impotence be treated?
Sildenfal (Viargra)
Which NO donor has an "ultrashort" duration of action (how long is this)?
Inhaled amyl nitrate
(3-5 minutes)
Name 5 important classes of vasoactive peptides in the body.
1. Angiotensins (I, II and III)
2. Bradykinin and related kinins
3. Vasopressin
4. Atrial natriuretic peptides and related peptides
5. Endothelins
______________ may be useful in impotence.
NO donors
Nitroglycerine ointment and nitroglycerine patches have been used.
Bosentin: MoA?
Endothelin receptor inhibitor
How is NO related to reperfusion?
lNO has been shown to protect against ischemic and reperfusion injury.
Pancreatic kallikrein can be activated by ___________.
trypsin
Describe the physiologic process that can generate endogenous nitric oxide.
*Generated from the oxidation of the guanidine group of arginine (L-arginine --> L-citrulline)
(Exposure to bacterial LPS result in the generation of NO in the macrophage.)
What are the actions of angiotensin II?
What dz can result if it's overproduced?
-
Exerts profound effects in the regulation of vascular tone, fluid and electrolyte balance.
-
It stimulates aldosterone production from the adrenal cortex.
-
At higher concentrations it produces glucocorticoid biosynthesis
Exerts profound effects in the regulation of vascular tone, fluid and electrolyte balance.
It stimulates aldosterone production from the adrenal cortex.
At higher concentrations it produces glucocorticoid biosynthesis
HTN & disorders of hemodynamics
Name (or read) some areas where prekallikreins are found. Where are they produced?
Kallikreins are glycoprotein enzymes produced in the liver as prekallikreins and are present in:
- plasma
- kidney
- pancreas
- gastrointestinal tract
- sweat glands
- salivary glands
Do the angiotensin antagonists have any effect on the actions on ACE?
No, only block receptor
What anti-inflammatory drug also has an effect on molecules generated by bradykinin? (explain, simply)
Aspirin is also known to block the algesic effects of prostaglandins generated by bradykinin.
What agents are useful during organ transplantation to preven accelerated graft atherosclerosis?
Nitric oxide acts as a cytoprotective agent and prevents cellular and platelet adhesion.
Dietary arginine supplements are helpful in the management of transplantation patients
What does angiotensinase do?
Inactivates ANG II and ANG III
What size of a peptide is ANG II?
ANG I?
*Octapeptide
Decapeptide
Desmopressin (DDAVP): MoA?
Vasopressin analogue
Desmopressin: indications?
Bleeding (restore factor VIII and vWF); control bleeding in minor surgeries.
(initially created for diabetes insipidus--vasopressin deficiency)
Explain in detail how NO affects platelets.
NO is a potent inhibitor of platelet adhesion, activation, aggregation, & regulates the release of 5-HT, growth factors, and TXA from platelets.
Platelets contain constitutive and inducible NOS's
Kinins represent one of the most potent groups of vasodilators peptides produced by the endogenous actions of enzymes known as ___________ or ___________.
kallikreins or kininogenases
Bosentin: route of administration?
PO
Pharmacologically, kinins stimulate the release of what 3 compounds?
Kinins promote water and solution passage from the blood to extracellular fluid resulting in __________.
NO, PGE2, and PGI2.
edema
How is the coagulation cascade related to kallikrein?
Factor XII (Hageman's factor) catalyzes the formation of kallikrein, which can go on to make bradykinin from HMW kininogen
Which NOS isoform is a/w chronic/acute inflammation?
NOS-3 (endothelial)
Recall: NO promotes edema + vascular permeability.
How does atherosclerosis affect NO?
What vascular effects does this lead to?
Impairs NO formation
results in vascular defects and increased cellular proliferation
Besides vasodilation, what other symptoms do kinins produce?
Kinins promote redness, local heat, swelling and pain (algesic).
What receptor subtypes can endothelins (ETs) bind?
ETA and ETB
What is the indication for ACE inhibitors? (captopril, enalapril)
HTN
Bradykinin is released by _________ kallikrein
plasma (not sure if important)
How big of a peptide is bradykinin?
What condition is it's overproduction a/w?
Nonapeptide
Hypotensive shock
How many isoforms of angiotensin are there? Which is the most active form (we care about)?
Angiotensin II
Name the (3) drugs that are known as "vasopeptide inhibitors"
What enzyme do they inhibit?
What are their physiological actions?
Omipatrilat, sampartilat, fasidotrilat
Inhibit MMPs
Enhance vasodilation, reduce vasoconstriction and increase sodium excretion
Name all of the NO inhibitors in this lecture.
N-monomethyl-L-arginine (N-MMLA)
N-nitro-L-arginine methyl ester (N-NAME)
7-nitroindazole
BBS-2
Hemoglobin
Compare and contrast the beneficial and toxic effects of nitric oxide.
• The beneficial effects include smooth muscle relaxation, vasodilation, immune regulation, anesthetic and anti-athlerosclerotic responses.
• The pathologic responses include free radical formation, nitrosation and irritant effects.
What cels possess NOS-2?
Inducible iNOS
- Macrophages, smooth m. cells
What are the indications are angiotensin receptor inhibitors? (losartin, valsartin)
HTN
_____________ and _____________ are useful in the treatment of atherosclerotic disorders.
L-arginine and nitric oxide donors
What enzymes can synthesize NO?
Identify the isoforms of the enzymes responsible for the synthesis of nitric oxide.
Nitic oxide synthase
- NOS-1, neuronal NOS, or nNOS
- NOS-2, inducible NOS, or iNOS
- NOS-3, endothelial NOS, or eNOS
Vasopeptide inhibitors inhibit what type of enzyme?
Thus, these drugs increase the levels of _________________ and decrease the formation of _________________.
Metalloproteases
natriuretic peptides, angiotensin II
Excess production of NO results in the generation of ______________, which is toxic to cells. Thus, NO inhibitors may be helpful in the treatment of sepsis related disorders.
Peroxynitrite
Name 4 inhibitors of NO.
1. L-arginine Derivatives (L-NMMA, L-NAME)
2. Inhibitors of nitric oxide synthase synthesis
3. Inhibitor of binding of arginine to NOs
4. Scavengers of NO
Which of the NOS isoforms have a calcium requirement?
NOS-1 (neuronal) and NOS-3 (endothelial) only
How many types of bradykinin receptors are there? Which is predominant?
B1 and B2
Which NO donors have an "intermediary" duration of action (how long is this)?
Oral/sustained-release NTG or isosorbide dinitrate
What's the chemical name of desmopressin?
1-diamino {D-Arg6] arginine vasopressin (dDAVP)
Name the pharmacological actions of NO.
- Smooth m relaxation
- Decreased (white) cell adhesion
- Decreased E-selectin on endothelial surface
- Inflammatory response
- Neurotransmitter
- Platelet inhibitor
- Decreased E-selectin on endothelial surface
How are angiotensin receptor inhibitors administered?
PO
Name 2 angiotensin receptor inhibitors.
Losartin, valsartin
Arginine is converted by NOS (+ NADPH and O2) to ________________ + NO.
Citrulline
*What are the effects of NO within the cell?
Activates GC --> cGMP
- Also generates several reactive nitrogen derivatives by interacting w/ O2 and superoxide radicals.
- These oxides of nitrogen are highly reactive and unstable, interact with numerous proteins, lipids, nucleic acids and metabolize.
Bosentin: indications?
Pulmonary HTN
Icatibant: MoA?
Bradykinin (B2) receptor inhibitor
What can convert HMW kininogen to bradykinin?
Plasma kallikrein
What converts angiotensinogen to ang I?
What converts ang I to ang II?
What converts ang II to ang III?
Renin
ACE
Aminopeptidase
Is L-NMMA selective or non-selective?
What about L-NAME?
(not that important)
Non-selective
Non-selective
Icatibant: indications?
Inflammatory diseases, (hypotension, myocardial hypertrophy)
How is desmoprssin administered?
IV
Name all of the vasoactive peptides, if you can (7)
-
Captopril, Enalapril
-
Losartan, Valsartan
-
Icatibant
-
Desmopressin (DDAVP)
-
Bosentan
-
Omipatrilat, sampartilat, fasidotrilat
-
Aprotinin (also thrombolytic)
Captopril, Enalapril
Losartan, Valsartan
Icatibant
Desmopressin (DDAVP)
Bosentan
Omipatrilat, sampartilat, fasidotrilat
Aprotinin (also thrombolytic)
What nerves in the PNS release NO?
Nonadrenergic, noncholinergic (NANC)
- E.g. erection
Name 2 ACE inhibitors.
Captopril, enalapril
Kininase II breaks down ______________.
Another name for this enzyme is _____________.
Kinin/bradykinin
ACE
7-nitroindazole: MoA?
Is it selective or nonselective?
(not that important)
NO inhibitor. Competitive inhibitor--binds both tetrahydrobiopteran and arginine binding sites in NOS
Partially selective for NOS-1
Septic shock:
Bacterial infection and LPS B activate _________, resulting in hypotension, shock and possible death. This effect is reversed by NO inhibitors such as the L-NMMA.
iNOS (NOS-2)
What is the MoA of N-monomethyl-L-arginine? (L-NMMA)
(not that important)
NO inhibitor
Competitive inhibitor--binds arginine binding sites in NOS
Which NO donors have a "short" duration of action (how long is this)?
SL NTG or isosorbide dinitrate
(10-30 minutes)
What is nitrous oxide used for? (N2O)
Gaseous anesthetic
What is the MoA of N-nitro-L-arginine methyl ester? (L-NAME)
(not that important)
NO inhibitor
Competitive inhibitor, binds arginine binding site in NOS
What drug is the most wide used donor of NO?
Nitrates (eg NTG)
*Describe the cellular MoA of NO on smooth m.
A. NO interacts w/heme moeity of guanylyl cyclase
B. Increased production of cGMP
C. Dephosphorylation of myosin
Potent interactions between NO donors and Viagra have been reported resulting in _____________.
hypotension
What is the physiological purpose of NO release in the bv following injury?
NO counteracts the vasoconstriction process
What's another name for vasopressin?
Explain the physiological effects of vasopressin.
Anti-diuretic hormone, ADH
- Long term control of blood pressure through its action on the kidney to increase water resorption.
- It has short term vasoconstrictor actions.
How are ACE inhibitors administered?
PO
How could decreasing NO affect BP?
Increase BP
What are 2 other names for ACE?
Peptidyl dipeptidase
* Kininase II
Would NOS-3 be elevated or decreased in IBS, arthritis, and other inflammatory diseases?
Increased (excessive vasodilation)
Hemaglobin: MoA?
NO scavenger
What is the effect of endothelin?
How many isoforms are there?
How many AAs long is it?
Vasoconstriction
3
21
Which NO donor has a "long" duration of action (how long is this)?
Transdermal NTG
(8-10 hrs)
Describe the methods of administration of NO. (kind of a dumb flashcard, just read)
-
Commercial NO systems are available which can accurately deliver inspired NO concentrations between 0.1 and 80 ppm and simultaneously measure NO and NO2 concentrations.
-
intermittent or continuous delivery
-
NO can be administered via a closely fitted mask. It is administered mostly in the management of primary pulmonary hypertension.
-
After the administration, NO should be gradually discontinued to avoid complications such as rebound
Commercial NO systems are available which can accurately deliver inspired NO concentrations between 0.1 and 80 ppm and simultaneously measure NO and NO2 concentrations.
-
intermittent or continuous delivery
NO can be administered via a closely fitted mask. It is administered mostly in the management of primary pulmonary hypertension.
-
After the administration, NO should be gradually discontinued to avoid complications such as rebound
Icatibant: route of administration?
PO
BBS-2: MoA?
Selective or non-selective?
(not that important)
NO inhibitor: Inhibits iNOS dimerization
Also weakly inhibits eNOS and nNOS
What are 2 ways by which NO is deactivated?
- Heme
- Free radicals superoxide
How does NO relate to the CNS, in terms of diseases implicated?
NO is implicated in neuromodulatory process and has impact on stroke and vascular dementia.
Besides converting ANG I to ANG II, what else does ACE do?
Therefore, what other effects can ACE-inhibitors have
Breaks down kinins
Vasodilatory (due to lack of kinin breakdown)
An elderly hypertensive hospitalized patient was treated with an ACE inhibitor, namely captopril. During hospitalization she became septic due to an infection. Soon after she went into severe hypotensive shock.
What is the likely cause of the hypotensive shock in this patient?
Pt’s ACE blocked, no ANG II produced (good). But blocking ACE blocks bradykinin breakdown, leading to excessive vasodilatory actions of bradykinin/kinins (bad).
How is NO level altered in shock?
NO levels increased, markedly
