Lecture 23: Vasoactive Mediators Flashcards
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
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
Describe synthesis of Ang II
Angiotensinogen converted by Renin to
Ang I, which is converted by ACE to
Ang II
What are rapid pressor effects of Ang II?
Vasoconstriction
(Directly from AT1
Indirectly from symp.)
What are slow pressor effects from Ang II?
Na+ retention, plasma volume expansion
(Directly from AT1 effects on kidneys;
Indirectly with inc. aldosterone production)
What are renin secretion regulators?
Sympathetic division
Renal baroreceptors
Macula densa
Hormones
Why is sympathetic division important renin secretion regulator?
Major mechanism for increased Ang II when BP falls!
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
Where is renin synthesized?
Granular cells of kidneys
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
How do hormones regulate renin secretion?
Inc. Ang II = Stimulation of AT1 receptors on granular cells = Dec. renin secretion = Dec. Ang II
What are natriuretic effects?
Inc. renal excretion of Na+
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
What effects do natriuretic peptides have?
Inc. renal extraction of Na
Vasodilation
Protective effects on CV structure
Dec. renin secretion (hormonal renin secretion regulators)
How do NPs and Ang II compare in terms of renin secretion?
Both = dec. renin secretion
What can be used as an indicator of LV dysfunction?
Increased BNP levels in plasma
How are NPs metabolized?
Peptidases =
Neprilysin (NEP)
Describe the use of BNP as a drug
Nesiritide = recombinant BNP
Used for acute HF
Vasodilation = dec. BP = dec. AL
Administered IV, limited efficacy
What are NEPi’s?
NEP inhibitors
Lead to inc. NPs = vasodilation
Better when combined for less AEs
What are NEPIs usually combined with?
NEPIs + ARBs
Sacubitril - Valsartan
= ARNI
(Angiotensin receptor - neprilysin inhibitor)
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
