Natriuretic Peptides, Bradykinin, Histamin

Question 1

What are natriuretic peptides degraded by

Answer 1

Neprilysin (neutral endopeptidase, NEP)

Question 2

What are the 3 natriuretic peptides present in mammals and where are they found

Answer 2

ANP: mainly atria
BNP: ‘brain’-type but mainly ventricle
CNP: CNS? fibroblasts? Endothelium?

Question 3

ANP enzyme

Answer 3

Corin

Question 4

BNP enzyme

Answer 4

Furin

Question 5

ANP release (mainly) from ….. due to …..

Answer 5

Atria
Myocyte stretch (blood volume, atrial fibrilation)
Rise in Na ion
Angiotensin 2, noradrenaline
ANP synthesis and release

Question 6

BNP released from …. With …..

Answer 6

Left ventricle
With increased pressure/stretch/dysfunction

Question 7

Receptors for ANP,BNP,CNP

Answer 7

ANP,BNP,CNP - NPR-C
ANP,BNP - NPR-A
CNP - NPR-B

Question 8

Describe the action of natriuretic peptides

Answer 8

Reduce preload by enhancing GFR, natriuresis and diuresis
Reduce after load by relaxing vascular smooth muscle (including renal afferent arteriole)
Reduce release/action of vasoconstrictors - inhibit renin, aldosterone, vasopressin, adrenaline secretion
Attenuate ventricular hypertrophy, fibrosis

Question 9

What happens when homeostasis disturbed (incr BP and BV )

Answer 9

Stretch atrial walls - ANP released
Na and water loss in kidney, inhibition of antagonist hormones, suppression of thirst, dilation of blood vessels
Incr fluids loss, reduced fluid gain, reduced blood pressure
Homeostasis restored

Question 10

BNP levels correlate with ….

Answer 10

Systolic function and heart failure severity

Question 11

Natriuretic peptides as BIOMARKERS

Answer 11

BNP correlates with systolic function and heart failure severity
Useful as diagnostic/prognostic test, predict mortality, correlate with symptom status, helpful in guiding and monitoring response to therapy

Question 12

BNP as screening tool

Answer 12

A normal BNP level strongly suggest that the is not LV systolic dysfunction
Similarly to ECG, -ve predictive value is ver high
BNP may be raised by other conditions??

Question 13

Therapeutic applications (natriuretic peptides)

Answer 13

• Nesiritide (human recombinant BNP)
– short-term use in acute decompensated heart failure, does not improve survival/may worsen renal function
• Neprilysin inhibitors
– prevent metabolism of natriuretic peptides
– sacubitril combined with angiotensin receptor antagonist, valsartan, in ARNIs reduces death, hospitalisation in chronic systolic heart failure

Question 14

Describe bradykinin synthesis

Answer 14

• Factor XII, prekallikrien and kininogens leak from blood vessels during inflammation due to enhanced vascular permeability
• Factor XII activated by contact with negatively charged surfaces (collagen, basement membrane, LPS)
• Factor XII activates kallikrien
• kallikrien forms bradykinin (9aa) and lys-bradykinin (kallidin,10aa) from circulating kininogens

Question 15

Describe bradykinin metabolism

Answer 15

• Kininase I removes one amino acid to form active metabolite, des Arg9-bradykinin (8aa)
• Kininase II (ACE-1) removes two amino acids to form inactive metabolite (7aa)
• [Additional less specific peptidases in tissues and plasma]

Question 16

Describe bradykinin receptors

Answer 16

B1 receptor - responds to des-Arg9 bradykinin; induced by cytokines in damaged, inflamed tissue
B2 receptor - respond to bradykinin and kallidin; constitutively expressed; selectively antagonised by icatibant
Both are G protein coupled

Question 17

Describe the actions of bradykinin

Answer 17

Vasodilation, increased vascular permeability (mediated by NO, PG release) - implicated in allergic rhinitis, icatibant for hereditary andioedema
Pain producing at sensory neurons - potential end by prostaglandins
Pro-spasmogenic (causes slow sustained contraction of non vascular smooth muscle)
Fluid secretion (intestinal and airway epithelium)

Question 18

Describe histamine synthesis and storage

Answer 18

Basic amine formed from histidine by histidine decarboxylase
Stored in mast cells and basophils in granules with acidic protein and macroheparin
Found in histaminocytes in stomach and histaminergic neurons in brain
Abundant in tissues exposed to outside environment (skin, airway, gut)

Question 19

Describe the release of histamine

Answer 19

Calcium-dependent release from mast cells during inflammatory or allergic reactions
Complement components C3a, C5a and Ag IgE interactions trigger release
Compound 40/80 used experimentally to stimulate release
Elevated cAMP stabilises mast cells, attenuates release
Released during Type 1 (immediate) hypersensitivity reaction in previously exposed individual

Question 20

Describe histamine receptors

Answer 20

4 subtypes of GPCR mostly linked to cAMP
All implicated in inflammation but H1 antagonists such as mepyramine primarily used as antihistamines
-modest benefit ; particularly useful in allergic rhinitis, urticaria; newer agents don’t cross into brain, less sedative

Question 21

Describe the actions of histamine

Answer 21

Vasodilation, increased vascular permeability of post capillary venules - partly endothelium dependent
Reddening, ,weal and flare response, itch in skin [H1]
-vasodilation of small arterioles, pre-capillary sphincters, permeability of post-capillary venules
-flare is an axon response

Question 22

What is the flare response

Answer 22

Is an axon reflex
Sensory nerve stimulation causes release of vasodilator neuropeptides including CGRP from adjacent branches of same nerve

Question 23

Other actions of histamine (not allergy)

Answer 23

Incr heart rate, cardiac output directly [H2]
Cardioprotection [H3]
Constriction of non-vascular smooth muscle including airways of atopic asthmatics, intestine, uterus [H1] - minor role in mild atopic asthma modest benefit of antagonists
Stimulates gastric acid secretion [H2] - H2 antagonist such as cimetidine to suppress acid secretion in peptic ulcer disease
CNS neurotransmitter (wakefulness) – circadian rhythm, histamine release greater in daytime – anti-histamines are sedative (chlorphenamine)
motion sickness, middle ear disorders, vertigo – H1 antagonists as anti-emetics (some anti-muscarinic effects)

Question 24

Clinical applications of H3 antagonists

Answer 24

Cognitive impairment in Alzheimer’s disease, ADHD and schizophrenia

Question 25

Describe calcitonin Gene-related peptide

Answer 25

Made by alternative splicing of calcitonin gene
Neuropeptide released from pain-sensing afferent neurons
-released by capsaicin in chilli peppers; released not meninges circulation during migraine
Mediates vasodilation, vascular leakage and neurogenic inflammation

Question 26

describe adrenomedullin

Answer 26

Discovered in phaeochromocytoma tumours
Wider expressed in vascular endothelium
Potent vasodilator (endo dependent/independent)
Most natriuretic effect
Attenuated cardiac hypertrophy, fibrosis
Cardioprotective from oxidative stress and Ischaemia reperfusion injury

Question 27

Receptors for CGRP and adrenomedullin

Answer 27

Calcitonin receptor-like receptor CRLR
+ receptor activity modifying protein (RAMP)

Question 28

Describe adrenomedullin and heart failure

Answer 28

• present in human plasma
• levels increased in heart failure – correlate with disease severity, response to therapy
• independent indicator of adverse prognosis? – hospitalisation, transplantation, mortality
• MR-proAM45-92 superior biomarker as biologically inactive, more stable?
• insufficient data to assess utility relative to BNP?