Lecture 23: Vasoactive Mediators Flashcards by Serinna Singh

Describe the effects of Ang II on cardiovascular system

Hypertrophy of cardiac myocytes, vascular SM

Inc. EC matrix production by cardiac fibroblasts, vascular SM = remodeling

Proliferation (hyperplasia) of vascular SM

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List the Ang II receptors, identifying the major responses mediated by each

AT1 = 
pressor effects (vasoconstriction), CV hypertrophy and remodeling

AT2 =
Vasodilation (NO mediated)
Protective effects on CV structure

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Describe synthesis of Ang II

Angiotensinogen converted by Renin to

Ang I, which is converted by ACE to

Ang II

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What are rapid pressor effects of Ang II?

Vasoconstriction
(Directly from AT1
Indirectly from symp.)

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What are slow pressor effects from Ang II?

Na+ retention, plasma volume expansion
(Directly from AT1 effects on kidneys;
Indirectly with inc. aldosterone production)

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What are renin secretion regulators?

Sympathetic division

Renal baroreceptors

Macula densa

Hormones

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Why is sympathetic division important renin secretion regulator?

Major mechanism for increased Ang II when BP falls!

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How does sympathetic division regulate renin secretion?

Dec. BP
=
Baroreceptor reflex
=
Inc. symp. Tone to kidneys
=
Stimulation of Beta1 receptors on granular cells
=
Inc. renin secretion
= 
Inc. Ang II = Inc. BP

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Where is renin synthesized?

Granular cells of kidneys

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How do renal baroreceptors regulate renin secretion?

Dec. BP
=
Dec. perfusion pressure
=
Dec. stretch of afferent arterioles in kidney
=
Dec. renin secretion
= 
Inc. Ang. II = Inc. BP

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How do hormones regulate renin secretion?

Inc. Ang II 
=
Stimulation of AT1 receptors on granular cells
=
Dec. renin secretion
= 
Dec. Ang II

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What are natriuretic effects?

Inc. renal excretion of Na+

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Where are the natriuretic peptides synthesized and what is their stimulus for release?

Synthesized in heart
ANP = atria
BNP = ventricles

Stimulus for release = stretch due to increased pressure or volume

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What effects do natriuretic peptides have?

Inc. renal extraction of Na

Vasodilation

Protective effects on CV structure

Dec. renin secretion (hormonal renin secretion regulators)

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How do NPs and Ang II compare in terms of renin secretion?

Both = dec. renin secretion

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What can be used as an indicator of LV dysfunction?

Increased BNP levels in plasma

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How are NPs metabolized?

Peptidases =

Neprilysin (NEP)

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Describe the use of BNP as a drug

Nesiritide = recombinant BNP

Used for acute HF
Vasodilation = dec. BP = dec. AL

Administered IV, limited efficacy

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What are NEPi’s?

NEP inhibitors

Lead to inc. NPs = vasodilation

Better when combined for less AEs

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What are NEPIs usually combined with?

NEPIs + ARBs

Sacubitril - Valsartan

= ARNI
(Angiotensin receptor - neprilysin inhibitor)

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Describe the synthesis of NO in endothelial cells

Synthesized from Arginine

Catalyze by eNOS

Identify two mechanisms for activation of endothelial NO synthase (eNOS)

1) shear stress on luminal surface of endothelial cell

2) increased intracellular calcium

Identify inhibitor of eNOS

L-NAME

Describe mechanism for NO mediated vasodilation and for termination of this response

Increased shear stress on endothelial cells = NO mediated flow induced vasodilation in large arteries in SKM during exercise

Describe mechanism for flow mediated vasodilation

``` Inc. MVO2 = Inc. metabolites in myocardial cells = Dilation of coronary arterioles = Inc. CBF = Inc. shear stress on ECs in surface coronary aa. = Inc. NO synthesis by ECs in surface coronary aa. = Dilation of surface coronary aa. ```

Identify at least one example of a mediator that can cause both direct vasoconstriction and NO mediated vasodilation

ACh acting at M3 receptors (Gq GPCRs = inc. [Ca]i)

Identify two important examples of nitridergic neurotransmission

Parasympathetic postganglionic fibers inner sting sphincters in GI, urinary tracts = relaxation Parasympathetic postganglionic fibers innervating blood vessels in blush areas of face, genital erectile tissue = vasodilation

What does nitridergic refer to?

Neurons that release NO as a neurotransmitter

Describe the vascular effects of the endothelins (ETs)

Vasoconstrictors (contribute to basal tone of vascular SM)

List the ET receptors, identifying the subtype that mediates most ET effects

ETa **** ETb

List the drugs that target ET receptors, identifying their major indication

Bosentan Used for PULMONARY HPT

List 3 locations of histamine in body, identifying cells that contain majority of the body's histamine

1) GI 2) CNS 3) Mast cells ****

List important examples of stimuli that trigger release of histamine from mast cells

Triple response = localized release Anaphylaxis = systemic release

Identify the major responses mediated by two most important histamine receptor subtypes

``` H1 = Vasoconstriction, bronchoconstriction, inc. GI motility Activation of eNOS, EC contraction Pain, itch Inc. secretion (rhinorrhea) ``` H2 = Inc. gastric acid secretion Vasodilation

Describe histamine vascular effects

Vasoconstrictor (veins, venules) from direct stimulation of H1 Vasodilator (from NO mediated and direct stimulation of H2) Inc. vascular permeability from EC contraction

Describe the triple response that follows local release of histamine from mast cells under skin

``` Erythema NO mediated (H1) + direct H2 vasodilation ``` Flare Stimulation of H1 sensory fibers leads to release of vasodilator neuropeptides Wheal Arteriolar dilation (NO + direct H2) Venoconstriction (H1) Contraction of ECs

Describe the synthesis of kinins and explain why the term kallikrein-kinin system (KKS) is used when discussing the kinins

Kininogens are converted to kinins by kallikreins Rate of kallikrein synthesis and/or activation = main determinant of rate of BK synthesis

What is bradykinin (BK) metabolized by?

ACE

Where is kallikrein released from?

Mast cells!

What are the vascular effects of kinins?

Vasoconstrictors (veins, venules) Vasodilators (NO mediated) Inc. vascular permeability from EC contraction

Describe effects of kinins on the respiratory system

Bronchoconstriction, cough

Identify the major indication for drugs that are used to antagonize the KKS

Hereditary angioedema (caused by high levels of kinins)

Define eicosanoid and list two major classes

Derived from membrane phospholipids, with arachidonic acid important FA precursor Prostanoids (from COX) Leukotrienes (from LOX)

What are important examples of prostanoids?

Prostanoids = TXA2 (thromboxane) PGI2 (prostacyclin)

What are vascular effects of PGI2 and TXA2? PGE2?

PGI2 = vasodilation, Dec. platelet aggregation TXA2 = vasoconstriction, Inc. platelet aggregation PGE2 = vasodilation

Where do eicosanoids produce physiological effects?

Bronchial SM GI secretions Kidneys Inflammation, pain, fever

What are physiological effects of eicosanoids?

bronchial SM PGE2, PGI2 = dilation Leukotrienes = constriction GI secretions PGE2, PGI2 = dec. acid, more mucus, bicarbonate Kidneys PGs = vasodilation = inc. renal blood flow = inc. glomerular filtration

Describe major indications of PGs and synthetic analogs that have effects on vasculature

Epoprostenol, nIloprost, Treprostinil Synthetic PGI2 for pulmonary HPT Alprostadil Synthetic PGE1 for maintenance of ducts in neonate with congenital heart disease

Identify the most important category of eicosanoid antagonists

NSAIDs block COX = dec. prostanoids

List primary adverse effects of NSAIDs

GI - abdominal pain, peptic ulcers, bleeding Kidneys = dec. renal blood flow, glomerular filtration (from less vasodilator PGs) Inc. risk of CV thrombotic events = MI, stroke (dec. PGI2 = inc. platelet agg) Prolonged bleeding (dec. synthesis of TXA2) Premature closure of ductus arteriosus in fetus