Vasoactive Peptides Flashcards
Vasoactive peptides
polypeptide hormones, transmitters that have roles in ANS and CNS
-important effects on vascular and other smooth muscles, mediators of inflammation
Vasoconstrictors
angiotensin II, vasopressin, endothelins, neuropeptide Y
Vasodilators
bradykinin and other kinins, natriuretic peptides, vasoactive intestinal peptide, substance P, neurotensin, calcitonin gene-related peptide
Biosynthesis of angiotensin
- Angiotensinogen synthesized in liver as initial substrate and ciruclates in blood stream
- Renin secreted from kidneys, and cleaves angiotensinogen–> angiotensin I (removal of last 4 AA)
- Angiotensin I has little or no bio activity but circulates in blood stream
- Angiotensin I converted to Ang II by ACE (Angiogensin converting enzyme)
Renin-angiotensin system
- driven by SNS
- long term regulation of CV fxn complementing short term NE release on peripheral vasculature
- primary mediator is ang II
Renin secretion
- Renin synthesized and stored in juxtaglomerular apparatus of nephron in kidney
- Granular cells are site of synthesis, storage, and release of renin
- Location of macula densa beside renin secreting JG cells in afferent arteriole and regulates renin secretion
Renin secretion inhibited by
1) inc NaCl flux thru chemoreceptors in macula densa
2) elevated BP thru baroreceptors in afferent arteriole wall
3) b-adrenergic blockade by inhibiting sympathetic stimulation via b1 adrenergic receptors
4) negative feedback by angiotensin II
Actions of Ang II
- Inc peripheral resistance to inc afterload
- Stimulate aldosterone secretion to inc fluid volume and plasma volume and inc preload
- direct vasoconstrictor
ACE inhibitors will act
oppositely to decrease both preload and afterload
-also protect against subsequent failure by slowing remodeling after MI
ACE inhibitors
- pril
- all are prodrugs except for captopril
- all ACE inh are equally effective in blocking conv of Ang I to Ang II
- same clinical uses and same AE
- Inhibit converting enzyme that is happening mainly in lung
- Lower BP via reduced angiotensin vasoconstriction, dec aldosterone release which will dec blood volume and CO, red destruction of bradykinin (potent vasodilator, enhance BP lowering)
AE: cough and edema because inc bradykinin located in lungs and activation of sensory nerves in lung
-Also may increase renin release because diminishing neg feedback by ang II
Toxicity of ACE inhibitors
-cough, angioedema, hyperkalemia due to inhibited aldosterone secretion esp in pts with renal insufficiency, teratogen
Angiotensin Receptor Antagonist
Mainly selective for AT1
- may cause hyperkalemia esp in pts with renal insuf
- more specific in blocking ang effects because they do not affect bradykinin metabolism (no coughing or angioneurotic edema), but lose potential added benefit of circulating bradykinin levels
- losartan
AT1r
Predominate in vascular smooth muscle in adults
AT2r
occur mainly in fetal tissues
Renin inhibitors
Aliskerin
- reduction in plasma renin activity and ang I and II and aldosterone concentrations
- red bp similar to those produced by ang II receptor antagonist
Sympatholytic drugs will also inhibit
secretion of renin
-beta blocker will act to lower renin and ang levels as well- indirect modifier because there are beta receptors that lead to renin release when acted on by catecholamines
Bradykinins and kalladin
- arteriodilators formed by enzymes called kallikreins and act on protein substrates called kininogens
- kinins released from pancreas, kidney, salivary glands, sweat
- inflammation effects promote redness, pain, swelling (leaky endothelium), heat
- produce pain
kallikreins
present in plasma and many tissues
form kinins
kininogens
present in plasma, lymph, interstitual fluid
acted on by kallikreins
B1 kinin receptor
limited tissue distribution and fxn
B2 kinin receptor
widely distributed and cause most biological effects
b2 receptor antagonist
- icatibant
- used experimentally to evaluate kinin involvement in pain, hyperalgesia, inflammation; not available for clinical use
b2 receptor agonist
may be useful for htn and CHF
what contributes to antihtn effects of ACE inhibitors
bradykinin induced vasodilation- because ACE inh reduce bradykinin destruction and elevate plasma bradykinin levels
Vasopressin
- Antidiuretic hormone (ADH)
- Synthesized in hypothalamus w/ oxytocin and secreted or released from post pit
- produces antiduiretic and vasopressor effects by acting on 3 receptors V1a, V1b, V2
- may constrict coronary blood vessels in pts with CAD
V1a receptors
in VSM cause vasoconstriction and inc bp
-receptor antagonists
V1b receptors
potentiate release of ACTH in pituitary
V2 receptors
in renal cells produce antidiuresis by inc water permeability and reabsorption in collecting tubules
desmopressin
- synthetic variant
- mostly V2 receptor action
- antidiuretic effect is more potent than vasoconstriction effect- more selective towards fluid retention side
- used to tx diabetes insipidus
Diabetes insipidus can be treated with
vasopressin and desmopressin
conivaptan
v1a and v2 (vasopressin receptor) antagonist - used to treat hyponatremia
-will lead to sodium retention
endothelins
potent vasoconstrictor substances
-locally acting
-et1, et2, et3
direct positive inotropy and chronotropy
-rapid and transient BP decrease but prolonged inc in BP
-Contract bronchial smooth muscle
-Dec glomerular filtration and sodium, water excretion
-inc secretion of renin, aldosterone, vasopressin, anp
ETA receptor
endothelin a receptor
-on smooth muscles, promotes vasoconstriction
ETB receptor
endothelial release of EDRF (endothelium derived relaxation factor- NO) and prostanoids (similar to muscarinic effect or histamine)
Bosentan
- nonselective ETA/ETB receptor antagonist
- approved for pulmonary htn
- AE: systemic hypotension, hepatotoxicity
Phosphoramidon
endothelin converting enzyme inhibitor
-non specific for endothelin converting enzyme
Substance P
- 11 amino acid tachykinin peptide
- Rapidly acting vasodilator
- contracts intestinal, bronchiolar smooth muscle
- Stimulates glandular secretion
- NT in CNS and enteric NS
- inflammatory mediator in periphery
- Makes endothelium leaky
Other tachykinins
Neurokinin A, neurokinin B
three G protein coupled neurokinin receptors are
NK1, NK2, NK3
Nonpeptide NK1 receptor antagonists
- developed as potential analgesics, under trial as antidepressants
- prevents chemotherapy induced emesis
CGRP
Calcitonin gene related peptide
- distributed widely in CNS and PNS
- most potent vasodilator yet discovered
- release of CGRP from trigeminal nerves may produce migraine
- 2 receptors: CGRP1 and CGRP2
Neuropeptide Y
- one of the most abundant neuropeptides in CNS and PNS
- frequently colocalized in noradrenergic neurons in NE
Effects of neuropeptide Y in CNS
increased feeding, hypotension, hypothermia, and resp depression
Effects of neuropeptide Y in PeripheralNS
Vasoconstriction of cerebral blood vessel, positive inotropic and chronotropic actions, hypertension
-When released NE will provide slow, long lasting vasoconstriction
Neuropeptide Y receptors
Y1- cardiovascular and peripheral effects
Y5- CNS control of food intake
Vasopeptidase inhibitors
Many vasoactive peptides are inactivated by endopeptidases
- vasopeptidase inhibitors inhibit both ACE and neutral endopeptidase- increase levels of natriuretic peptides and decrease formation of angiotensin II
- enhance vasodilation, reduce vasoconstriction, increase sodium excretion
- decrease peripheral vascular resistance and blood pressure
- produce angioedema and cough (because they inhibit ACE)
ACE inhibitor list
-prils
benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril
Ang receptor antagonist
-sartans
candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan
Neurokinin-1 receptor antagonist
Aprepitant
