Natriuretic Peptides, Bradykinin, Histamin Flashcards
What are natriuretic peptides degraded by
Neprilysin (neutral endopeptidase, NEP)
What are the 3 natriuretic peptides present in mammals and where are they found
ANP: mainly atria
BNP: ‘brain’-type but mainly ventricle
CNP: CNS? fibroblasts? Endothelium?
ANP enzyme
Corin
BNP enzyme
Furin
ANP release (mainly) from ….. due to …..
Atria
Myocyte stretch (blood volume, atrial fibrilation)
Rise in Na ion
Angiotensin 2, noradrenaline
ANP synthesis and release
BNP released from …. With …..
Left ventricle
With increased pressure/stretch/dysfunction
Receptors for ANP,BNP,CNP
ANP,BNP,CNP - NPR-C
ANP,BNP - NPR-A
CNP - NPR-B
Describe the action of natriuretic peptides
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
What happens when homeostasis disturbed (incr BP and BV )
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
BNP levels correlate with ….
Systolic function and heart failure severity
Natriuretic peptides as BIOMARKERS
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
BNP as screening tool
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??
Therapeutic applications (natriuretic peptides)
• 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
Describe bradykinin synthesis
• 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
Describe bradykinin metabolism
• 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]
Describe bradykinin receptors
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
Describe the actions of bradykinin
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)
Describe histamine synthesis and storage
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)
Describe the release of histamine
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
Describe histamine receptors
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
Describe the actions of histamine
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
What is the flare response
Is an axon reflex
Sensory nerve stimulation causes release of vasodilator neuropeptides including CGRP from adjacent branches of same nerve
Other actions of histamine (not allergy)
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)
Clinical applications of H3 antagonists
Cognitive impairment in Alzheimer’s disease, ADHD and schizophrenia
Describe calcitonin Gene-related peptide
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
describe adrenomedullin
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
Receptors for CGRP and adrenomedullin
Calcitonin receptor-like receptor CRLR
+ receptor activity modifying protein (RAMP)
Describe adrenomedullin and heart failure
• 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?
