PC2: Histamine & Bradykinin

What is the MOA of H2 receptor antagonists?

Competitively antagonize histamine H2 (Gs) receptors and thus inhibit gastric secretion

What is a specific Bradykinin antagonist?

HOE-140

Bradykinin concentrations are __________ in patients with high BP

decreased

Describe allergies to H1 receptor antagonists

Allergies to H1 blockers can develop; atopic dermatitis is a common result

What are specific bradykinin receptors?

B1 and B2

Where is B1 expressed?

B1 expression is induced during allergy, tissue damage; activation mediates chronic pain

Which is constitutive, B1 or B2?

B2

Where is B2 expressed?

B2 is constitutively expressed in most tissues; activation mediates acute pain

Describe histamine and asthma

Individuals with bronchial asthma are sensitive to small amounts of histamine (causes bronchoconstriction)

What type of drug is aprotinin?

Kinin synthesis inhibitor/proteinase inhibitor that blocks kallidin synthesis

How is histamine made?

L-histadine decarboxylase converts histadine (from circulation) to histamine by decarboxylation

What is released along with histamine from mast cells? (3)

Leukotriene D4, platelet-activating factor, kinins

What are the biological effects of H2 receptor antagonists?

Mainly inhibit basal (not stimulated) acid secretion - e.g. not going to inhibit gastric secretion from spicy food e.g. - just blocking basal acid secretion

Aallergy-induced bronchoconstriction is mediated by what histamine receptor?

Mediated by H1 receptors (Gq)

Describe CNS effects of 2nd generation antihistamines

Newer agents (second generation) do not cross the blood brain barrier, so don't cause adverse CNS effects

First generation H1 receptor antagonists normally cause many side effects because they inhibit _______ in the CNS

Often inhibit cholinergic receptors (also may have some D2 receptor activity)

Describe the effect of Bradykinin antagonists on ACE inhibitors

Bradykinin antagonists decrease the effectiveness of ACE inhibitors

What is the effect of Bradykinin on ARBs?

Bradykinins may also increase the effectiveness of angiotensin 1 receptor antagonists but this has not been entirely proven

What type of receptors are bradykinin receptors?

GPCRs

What are receptors for IgE on mast cells?

GPCRs that couple to Gq, lead to intracellular calcium release

H3 couples to __________

Gi/₀

B1 couples to ________

Gq (stimulates release of intracellular Ca++ stores)

H1 couples to __________

Gq/₁₁

H2 couples to __________

Gs

Increased capillary permeability caused by histamine is mediated by which histamine receptor(s)?

H1

Histamine contraction of non-vascular smooth muscles is mediated by _______

H1 (Gq)

What is the main CNS histamine receptor?

H1 (Gq)

Describe Dilation of resistance vessels via H1 receptors

H1 (Gq) activation stimulates the release of NO from endothelial cells, causing vasodilation (rapid) - stimulation of nitric oxide synthetase, cGMP, etc.

Constriction of larger blood vessels is mediated by which histamine receptor(s)?

H1 (Gq) receptors on smooth muscle

Dilation of resistance vessels by histamine is mediated by which receptor(s)?

H1 and H2

_________ receptor activation stimulates acid secretion from the parietal cells in the gut

H2

Histamine relaxation of non-vascular smooth muscles is mediated by _______

H2 (Gs)

Histamine release is a major factor in allergy-induced broncho___________

constriction

Histamine usually causes _____________ of non-vascular smooth muscles

contraction

Where is histamine made in the gut?

enterochromaffin-like cells

Where are H1 receptors found?

found in the CNS, endothelial cells (increases production of nitric oxide here), and smooth muscle

Where are H2 receptors found?

found in the CNS, mast cells, gastric parietal cells, and the heart

Where are H4 receptors found?

found in the blood, on eosoniphils, neutrophils, and in the gut

Where are H3 receptors found?

found presynaptically in the CNS (often an autoreceptor), and in the myenteric plexus

When released in epidermis, histamine causes _______

itching

How does the structure of kallidin differ from bradykinin?

kallidin has an added lysine residue at the N-terminal position (also know as lysyl-bradykinin)

What types of molecules are Bradykinin and kallidin?

kinins

What stimulates release of histamine from ECL cells?

stimulation on ECLs by gastrin

What is histamines role in the brain?

Regulates wakefulness (stimulates), appetite (inhibits), and other functions

What are histamine effects of small blood vessels and what receptor(s) mediate this?

Relaxation of small blood vessels (H1 and H2 effect)

How does histamine shock occur?

When histamine is given or released in large amounts; accompanied by a fall in BP 1. Small blood vessels dilate, trapping blood 2. Vessels have increased permeability, so plasma escapes from the circulation (swelling occurs)

Increased force of contraction of the heart plus increased heart rate is mediated by which histamine receptor(s)?

both mainly H2 mediated

Why is excessive histamine release dangerous?

can cause anaphylactic reactions

What are adverse effects of H1 receptor antagonists? (3)

1. Sedation (older agents, can be useful) 2. Loss of appetite, nausea, vomiting, etc (GI effect) 3. Dryness of the mouth, nose (older agents, possibly anti-cholinergic effect)

What are the two metabolic pathways of histamine? (histamine metabolism)

1. Ring methylation to form N-methylhistamine (by histamine-N-methytransferase) 2. Oxidative deamination (by diamine oxidase)

What are bradykinin and kallidin functions at the kidney? (2) SUPER IMPORTANT

1. Act in a paracrine manner to regulate urine volume and composition 2. Increase renal blood flow, inhibit Na+ reabsorption

What are the effects of bradykinin and kallidin? (2)

1. Act locally to produce pain, vasodilation, vascular permeability 2. Stimulate prostaglandins, NO, other inflammation mediators

IgE activates release of histamine, leukotriene, and cytokines from mast cells. What is the late response?

1. Airway inflammation 2. Airflow obstruction 3. Airway hyperresponsiveness

Describe bradykinin receptors role in pain (2)

1. B2 receptors (constitutive) mediate acute pain 2. B1 receptors (induced) are involved in chronic pain sensation

What are bradykinin's cardiovascular effects? (3)

1. Bradykinin stimulates vasodilation 2. Appear to have a minor BP regulatory role in 'normal' individuals, but increased role in hypertensive states 3. Hypothesized to be cardioprotective, and help against ischemia and reperfusion injury

Describe the effect of Bradykinins on ACE inhibitors

1. Bradykinins contribute to the effectiveness of ACE inhibitors 2. MOA(s) are not well understood

IgE activates release of histamine, leukotriene, and cytokines from mast cells. What is the early response?

1. Bronchospasm 2. Edema 3. Airflow obstruction

What are the effects of H1 receptor antagonists? (4)

1. Cause dilation of smooth muscle 2. Block increase in capillary permeability/edema formation 3. Suppress itching of the skin 4. Older agents can either stimulate or depress the CNS (typically depress)

What are Bradykinin and Kallidin Functions in inflammatory diseases? (3)

1. Cause widening of junctions between endothelial cells, allowing for plasma accumulation 2. Kinins synthesis/release increased in rhinitis 3. May be involved in gout

What are histamine effects on smooth muscles?

1. Contraction of bronchial smooth muscles (direct H1 effect) 2. Relaxation of small blood vessels (H1 and H2 effect)

What are cardiovascular effects of histamine? (5)

1. Dilation of resistance vessels (i.e. the small arteries, arterioles, metarterioles that provide peripheral resistance to blood flow) 2. Histamine causes increased capillary permeability 3. Constriction of larger blood vessels 4. Increase force of contraction of both atrial and ventricular muscle plus increased HR 5. "Histamine shock" occurs when histamine is given or released in large amounts; accompanied by a fall in BP

How do Bradykinin and Kallidin cause pain? (2)

1. Excite sensory neurons 2. Cause release of neuropeptides associated with pain (substance P, neurokinin A, etc..)

B2 couples to ________

1. Gq (stimulates release of intracellular Ca++ stores) 2. B2 also couples to Gi in some cells

What are the consequences of increased capillary permeability used by histamine? (5)

1. Histamine causes endothelial cells to contract and separate leads to: 2. Basement membrane is exposed; is permeable to plasma proteins and fluids, leads to: 3. Plasma and fluid move to extracellular spaces 4. Lymph flow is increased 5. Edema formation occurs

What are the extravascular smooth muscle effects of histamine?

1. Histamine usually causes contraction of non-vascular smooth muscles 2. May cause relaxation

What stimulates release of histamine from mast cells?

1. Immune system antibodies (IgEs) 2. Drugs, peptides, venoms, and other agents also trigger histamine release

What are Bradykinin and Kallidin Functions in respiratory disease? (2)

1. Involved in rhinitis, asthma 2. Inhalation of kinins causes bronchospasm in individuals with asthma

Relatively large amounts of histamine can be found in which 5 areas?

1. Mast cells 2. Skin 3. Bronchial tree mucosa 4. Intestinal mucosa (gastric acid) 5. CNS (excitatory)

Describe dilation of smooth muscle caused by H1 receptor antagonists (2)

1. Particularly bronchial smooth muscle (inhibit contraction) 2. Inhibit vasoconstrictor actions of histamine in vasculature (large vessels)

How do Bradykinin and Kallidin relate to the sensation of pain? (2)

1. Powerful algesics (Painful; related to or causing pain.) 2. Cause burning sensation/pain

Describe hypersensitivity reactions to Aprotinin (2)

1. Symptoms can include anaphylactic reactions 2. Occurs more often in patients previously given the drug

Describe the effect of ACE inhibitors on bradykinin

ACE inhibitors slow the degradation of bradykinins, adding to the action of bradykinin increasing the effectiveness of ACE inhibitors (increase vasodilation)

What is a CNS therapeutic benefit of first generation H1 receptor antagonists?

Can decrease motion sickness symptoms

What are histamine effects of bronchial smooth muscle and what receptor(s) mediate this?

Contraction of bronchial smooth muscles (direct H1 effect)

Describe H1 receptor antagonists in pregnancy

Cross placenta, so use caution in pregnant women

TRUE OR FALSE: Histamine is an amino acid

FALSE: Histadine, its precursor, is an amino acid

TRUE OR FALSE: Histamine only acts locally and not systemically

FALSE: Histamine can act both locally and systemically (i.e. like an endocrine hormone)

TRUE OR FALSE: Histamine receptors are ligand-gated ion channels

FALSE: They are GPCRs

Where are bradykinin and kallidin in the body?

Formed during inflammatory events (e.g. allergic reactions, tissue damage, infections) and act locally

Where is H1 found in the brain?

Found throughout brain, particularly in the hypothalamus

What are skin effects of histamine?

Histamine stimulates many nerve endings and sensory receptors 1. When released in epidermis, causes itching 2. In the dermis histamine causes pain

What are adverse effects of Aprotinin?

Hypersensitivity reactions

TRUE OR FALSE: Both B1 and B2 receptors couple to Gq

TRUE

Describe Dilation of resistance vessels via H2 receptors

Smooth muscle H2 (Gs) activation stimulates dilation more slowly; also more sustained than that stimulated by H1 activation

Describe turnover rate of histamine

Turnover rate is slow, so it takes a long time to replenish depleted stores

What is the MOA of all available H1 antagonists?

all are reversible competitive inhibitors

What is the intracellular signal that stimulates histamine release?

an increase in intracellular Ca++ levels

What is a specific kinin synthesis inhibitor?

aprotinin

Where is histamine released in the gut?

from enteric chromaffin-like cells in the gut

What does histamine do once it is released in the gut?

histamine binds H2 receptors which couple to Gs, get increases in cAMP secondary messenger signaling, cAMP stimulates proton pump leading to increased acidic environment in the stomach

In what manner does histamine act?

histamine can act in paracrine, autocrine manner

What is the dominant mediator of gastric acid secretion?

histamine release

Where are Bradykinin and kallidin receptors found?

in a wide variety of tissues

Where is histamine stored?

in secretory granules

Where is histamine made?

in the hypothalamus

Bradykinin is a _____peptide

nona

Where do H2 receptor antagonists block H2 receptors?

on the basolateral membrane of parietal cells of the stomach

When released in dermis, histamine causes _______

pain

What are the effects of aprotinin?

used to inhibit mediators of inflammation, fibrinolysis, and thrombin generation