[01.28b] Autacoids and Anti-Inflammatory Agents (Part 2) V2.1.pdf

Polypeptides acting on the vasculature

What type of molecules are vasoactive autacoids?

Naturally occurring polypeptides

What is the origin of vasoactive autacoids?

Antagonists to these vasoactive polypeptides

What is an emerging class of substances related to vasoactive autacoids?

Pharmacodynamic and pharmacokinetic properties

What knowledge is important for the therapeutic action of vasoactive substances?

Newer antagonists which target the action of these drugs

What is the significance of some vasoactive peptides, particularly regarding drug development?

Arrest the primary effect on the vasculature

What is the general goal of most drugs related to vasoactive peptides?

Adverse effects from too much of one or more peptides

In what situations are drugs necessary to manage vasoactive peptide activity?

Low pressure

What initial condition triggers renin release in the RAAS?

Angiotensin Converting Enzyme (ACE)

What enzyme is responsible for converting Angiotensin I to Angiotensin II in the lungs?

Vasoconstriction

What is a primary effect of Angiotensin II that contributes to reversing hypotension?

Cardiac remodeling

What cardiac effect is Angiotensin II important for, especially in patients with chronic hypertension?

Aldosterone

What hormone does Angiotensin II stimulate the adrenal cortex to produce?

Increasing sodium reabsorption

What is the primary end-effect of Angiotensin II via the RAAS?

Angiotensin II receptor blockers (ARBs)

What class of antagonists plays a crucial role in managing hypertension by blocking Angiotensin II receptors?

Renin inhibition

What strategy is used to control hypertension when elevated renin levels are problematic?

Aliskiren

What is a specific renin antagonist used for hypertension?

Aliskiren, ACE Inhibitors, AT Receptor Blockers

What are three types of drugs involved in renin antagonism?

Angiotensin-converting enzyme (ACE)

What enzyme do key inhibitors target to prevent Angiotensin II production?

Decrease in blood pressure (hypotension caused by dehydration or hemorrhage)

What is a main trigger for renin release?

Macula densa

Where is a decrease in blood pressure sensed to initiate renin release?

Nitric oxide (vasodilator)

What substance's secretion is low when renin is released, leading to increased cGMP?

PGE2

What substance increases cAMP secretion upon renin release?

Norepinephrine (sympathetic) stimulation and a drop in renal baroreceptors

What factors increase intracellular Ca related to renin release?

Cleaves Angiotensinogen to form Angiotensin I

What is the mechanism of action of renin?

Aldosterone

What substance is released as a result of renin's action, contributing to blood pressure restoration?

Immediate

What is the characteristic duration of renin release?

1 minute

When is the peak release of renin noted after a stimulus?

30 minutes

After how long are decreased renin levels noted?

Control the downstream events leading to hypertension

Why are renin inhibitors effective despite renin's short duration?

JG cells as preprorenin cleaved to pro-renin

Where is renin synthesized and how is it initially processed?

Liver

Where is the circulating protein Angiotensinogen synthesized?

Angiotensin I

What is formed when Angiotensinogen is cleaved?

Corticosteroids, Thyroid hormones, Angiotensin II, Oral contraceptive use

List factors that can increase Angiotensinogen levels.

Angiotensin Converting Enzyme inhibitor (ACE inhibitor)

What enzyme facilitates the quick conversion of Angiotensinogen to Angiotensin I?

Little to no biologic activity

What is the characteristic biologic activity of Angiotensin I?

ANG or AT

What are the general abbreviations for Angiotensin?

Restoring blood pressure during hypotension (volume depletion)

What is the primary physiological role of Angiotensin II in the RAAS system?

Vasoconstrictor

What is Angiotensin II's primary mechanism of action in increasing blood pressure?

Aldosterone release and subsequently triggering sodium and water retention via vasopressin

How does Angiotensin II increase sodium reabsorption and water retention?

Sympathetic activity

What directly drives vasoconstriction by Angiotensin II?

AT-1 (Angiotensin Receptor I)

What specific G-protein coupled receptor mediates the primary effects of Angiotensin II, leading to strong vasoconstriction?

Rapid onset (10-15 seconds) with a very short half-life (< 1 minute)

Describe the onset and half-life of Angiotensin II's activity.

Fetal development

When is a less active, counterregulatory pathway of Angiotensin II more prominent?

Anti-inflammatory, anti-proliferative, anti-hypertrophic, anti-fibrotic, pro-apoptotic, and vasodilatory effects

What effects does AT II receptor activity mediate?

Counterregulatory to the effects of AT I receptor binding

How does the AT II receptor pathway relate to the AT I receptor pathway?

Hypertension and hypertrophy of the vasculature and cardiac muscle cells

What can excessive Angiotensin II levels contribute to?

Aminopeptidase A and M/ACE2

What enzymes are responsible for the rapid degradation of Angiotensin II?

ACE2

What is the first pathway for Angiotensin II degradation?

AT 1-7

What are the by-products of Angiotensin II degradation via ACE2?

Vasodilation, counteract proliferation, remodeling, and natriuresis

What effects does AT 1-7 mediate through the Mas receptor?

Aminopeptidase A (APA)

What is the second pathway for Angiotensin II degradation?

AT-III and AT-IV

What are the by-products of Angiotensin II degradation via Aminopeptidase A (APA)?

Learning, memory, long-term potentiation, glucose uptake

What peripheral effects are influenced by AT-III and AT-IV binding to AT-4 receptors?

Angiotensin Converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARBs)

What are the two main classes of Angiotensin II antagonists available?

Captopril, Enalapril

Name two examples of ACE Inhibitors.

Losartan, Valsartan

Name two examples of Angiotensin Receptor Blockers (ARBs).

Antihypertensives and decreasing glomerular pressure in diabetic nephropathy and idiopathic membranous nephropathy

What are the primary therapeutic uses for ACEIs and ARBs?

Vascular endothelium

Where is endothelin typically found?

Response to vascular injury

What physiological process is endothelin typically part of?

ET-1

Which endothelin subtype is the most widespread and potent vasoconstrictor?

Kidneys and intestines

Where is ET-2 primarily present?

Endothelin-1

Which endothelin subtype is present in the brain?

Mechanical, physical, or chemical stress (acidosis, tissue injury), hormones, hypertension, cardiac hypertrophy, heart failure, atherosclerosis, coronary artery disease, myocardial infarction, asthma, pulmonary hypertension, renal diseases, several malignancies

List some common triggers for endothelin release.

ET-A and ET-B

What are the two primary receptors for endothelin?

ET-A

Which endothelin receptor is predominant for ET-1 and mediates both initial vasodilation and sustained vasoconstriction?

ET-B

Which endothelin receptor has equal affinity for ET-1 and ET-3 and may produce vasoconstriction after an initial vasodilation?

Prostaglandin I2 (PGI2) and nitric oxide (NO) pathways

What mediates the initial vasodilation caused by ET-B receptor activation?

Proliferation, fibrosis, and repair mechanisms

What are other effects mediated by ET-A and ET-B receptors?

Vasoconstriction

What is the primary effect of endothelin?

Initial vasodilation

What transient effect often precedes endothelin's primary vasoconstrictive action?

Positive inotropic and chronotropic actions on the heart

What cardiac effects does endothelin have?

Mitogenic activities leading to cardiac repair, remodeling, and hypertrophy via vascular smooth muscle cells and cardiac myocytes

What mitogenic effects does endothelin exhibit on the heart?

Mitogenic activity in glomerular mesangial cells, potentially leading to chronic kidney disease (CKD)

What effect of endothelin can impact renal health?

Renin, aldosterone, arginine vasopressin (AVP), and atrial natriuretic peptide (ANP)

What hormones/peptides does endothelin increase the secretion of?

Increase in intravascular volume

What is the overall result of endothelin increasing the secretion of certain hormones after tissue injury?

CKDs, atherosclerosis, hypertension

What disease conditions can excessive endothelin-1 contribute to?

Bosentan, Ambrisentan, Macitentan

Name three ET receptor antagonists used for pulmonary hypertension.

Phosphoramidon

What antagonist inhibits endothelin-converting enzyme to decrease endothelin formation?

Systemic hypotension, increased heart rate, facial flushing or edema, headaches, nausea, vomiting, constipation, teratogenic effects, hepatotoxicity

List some adverse effects of endothelin antagonists.

Third family of vasoconstrictors

How is Neuropeptide Y categorized among vasoconstrictors?

Pancreatic polypeptide (PP), Peptide YY (PYY), and Neuropeptide Y (NPY)

What are the three variants of Neuropeptide Y?

NPY

Which variant of the NPY family is primarily classified as a vasoconstrictor?

Hypotension, hypothermia, respiratory depression, activation of the HPA (Hypothalamic Pituitary Axis)

What conditions trigger the release of NPY?

Y1, Y2, Y4, and Y5

What are the receptors for NPY?

GPCRs with inhibitory effects on adenylyl cyclase

What type of receptors are NPY receptors, and what is their general inhibitory effect?

Y1, Y2, Y5

Which NPY receptors mediate cardiovascular activity and vasoconstrictive properties?

Y4

Which NPY receptor is associated with Pancreatic polypeptide activity?

Y5

Which NPY receptor mediates orexigenic properties?

Cardiovascular disorders (hypertension, heart failure)

In what conditions is NPY more clinically significant than under normal resting conditions?

Eating disorders, obesity, alcoholism, anxiety, depression, epilepsy, pain, cancer, and bone physiology

List other conditions in which NPY is implicated.

Neurohormone

What is Pancreatic polypeptide (PP) classified as?

Islet of Langerhans

Where is Pancreatic polypeptide (PP) secreted?

Promotes appetite suppression, inhibits gastric emptying, and increases energy expenditure

What are the effects of Pancreatic polypeptide (PP)?

Neurohormone anorexigenic

What is Peptide YY (PYY) classified as?

Enteroendocrine cells of distal gut

Where is Peptide YY (PYY) secreted?

Enteroendocrine cells in the distal gut

Where is Neuropeptide Y itself secreted?

Orexigenic molecule

What term describes Neuropeptide Y's effect on feeding behavior?

True neuropeptide and neural hormone

What two classifications describe Neuropeptide Y based on its origin and function?

Cerebral vasoconstrictor

What specific vasoconstrictor effect does Neuropeptide Y have?

Co-transmitter of norepinephrine

What role does Neuropeptide Y play in conjunction with norepinephrine?