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106 > Pharmacology - Vascular > Flashcards

Pharmacology - Vascular Flashcards

1
Q

CV System - 5

A
  1. CV system, heart muscle pumps oxygenated blood through the arteries to deliver this blood to organs, to enable delivery of oxygen with nutrients, to each cell in the body.
  2. Then the blood returns through the veins, which are more capacious.
  3. This returns back to the right side of the heart & through the lungs.
  4. Pulmonary circulation, then returns back into the left side of the heart & the circle is repeated.
  5. This is a closed system.
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2
Q

BP equaiton

A

Blood pressure = Cardiac output X Total peripheral resistance

Arteries control TPR, acting as resistance against the left heart acts.
(Cardiac afterload = force the left heart works against)

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3
Q

Cardiac output - 5

A
  1. Heart rate & stroke volume.
  2. Stroke volume dependant on contractility of heart, & blood volume.
  3. Determined or regulated by this capacitance vessels.
  4. When they contract, they deliver more blood to the heart,
  5. When they relax, they reduce the delivery & reduce stroke volume.
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4
Q

Arteries & veins sharing similar basic structure - 3

A
  1. Tunica adventitia (outer layer)
  2. Tunica media (muscle layer)
  3. Tunica intima (inner layer of endothelial cells).
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5
Q

Differences in veins, arteries & capillaries - 3

A
  1. Veins have a thinner wall, are more extendable, & can hold more blood.
  2. Arteries are more muscular, controlling blood flow by contracting & relaxing.
  3. Capillaries consist of a single layer of cells, controlling permeability & facilitating nutrient & oxygen delivery at the cellular level.
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6
Q

Nervous & Muscle Control - 4

A
  1. Blood vessels are influenced by sympathetic nerves, with minimal parasympathetic involvement.
  2. Smooth muscle cells regulate vessel diameter by contracting or relaxing.
  3. The system works together as a unit, with gap junctions connecting smooth muscle & endothelial cells, enabling communication.
  4. Communication mediated by neural signals, hormones, & local mediators released from endothelial & smooth muscle cells.
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7
Q

Regulation of Blood Vessel Diameter - 2

A
  1. Blood vessel diameter is regulated through complex interactions between nerves, smooth muscle cells, & endothelial cells.
  2. Influenced by various factors including neural & hormonal signals.
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8
Q

2 main pathways of Contraction Mechanisms:

A

1) Calcium Release: Agonist-induced (Gαq/11): IP3 mediated release of Ca²⁺ from the sarcoplasmic reticulum (SR), which increases [Ca] for contraction.

2) Calcium Influx: Depolarization-activated Ca²⁺ influx through L-type voltage-activated calcium channels (L-VACCs). Contributes to [Ca] elevation, leading to muscle contraction. Voltage independent Ca channels contribute & increase depolarization.

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9
Q

Contraction Mechanism - 3

A
  1. Elevated Ca in smooth muscle cells binds with calmodulin, forming a complex that activates myosin light chain kinase (MLCK).
  2. MLCK phosphorylates the myosin light chain, enabling interaction between actin & myosin, leading to contraction.
  3. Process balanced by myosin light chain phosphatase (MLCP), which dephosphorylates the myosin light chain, promoting relaxation.
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10
Q

GPCR Signalling (Gαq/11 Pathway) - 3

A
  1. Classic Signalling: GPCR activation triggers the release of IP3, activating IP3 receptors on the SR, releasing Ca into the cell, increasing [Ca] & induces smooth muscle contraction (pharmaco-mechanical pathway).
  2. Electromechanical Pathway:
    Ca influx occurs through voltage-gated Ca channels activated by depolarization, contributing to the Ca elevation necessary for contraction.
  3. Both pharmaco-mechanical & electromechanical pathways act in parallel & are independent, allowing separate interventions to control BP.
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11
Q

CONTRACTION of Blood Vessels: 3. Calcium sensitisation - 3

A

Mechanism:
1. Glycerol activates protein kinase C (PKC), which activates protein inhibitor 17 (CPI-17). When CPI-17 is phosphorylated, it inhibits myosin light chain phosphatase (MLCP), promoting contraction.
2. This calcium sensitization shifts the balance towards contraction without requiring an increase in [calcium].
3. Additionally, some receptors also activate RhoA, a small GTPase, leading to activation of Rho-associated kinase (ROCK). ROCK inhibits MLCP, further promoting contraction.

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12
Q

Relaxation Mechanism in Smooth Muscle Cells - 3

A

Relaxation Mechanism in Smooth Muscle Cells:
1. Activation of certain G-protein coupled receptors (GPCRs), which are linked to adenylyl cyclase or guanylyl cyclase
2. These receptors can be activated by various stimuli, including natriuretic peptides.

Other Mechanisms of Relaxation:
3. Hyperpolarization: Activation of potassium channels increases potassium efflux, making inside of the cell more negative (electronegativity), which inhibits the opening of voltage-activated calcium channels & promotes relaxation.

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13
Q

Methods of Inducing Relaxation: Removal of Stimulus

A

Removal of Stimulus: Reducing or blocking the agonist or receptor involved.

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14
Q

Methods of Inducing Relaxation: Hyperpolarization

A

Hyperpolarization: Activating potassium channels, to reduce calcium elevation & promote relaxation.

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15
Q

Methods of Inducing Relaxation: Beta-1 Receptor Activation

A

Beta-1 Receptor Activation: Through Gαs subunit stimulation, increases cAMP, activating protein kinase A (PKA), which inhibits myosin light chain kinase (MLCK) & shifts the balance toward relaxation.

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16
Q

Methods of Inducing Relaxation: Natriuretic Peptide Receptors

A

Natriuretic Peptide Receptors: These are coupled to Gαs & produce cGMP from GTP, activating protein kinase G (PKG) to promote relaxation.

17
Q

Methods of Inducing Relaxation: Nitric Oxide (NO):

A

Nitric Oxide (NO): Released from endothelial cells, NO activates soluble guanylate cyclase, increases cyclic GMP, & promotes potent vasodilation, shifting the balance towards relaxation.

18
Q

Intracellular Calcium Re-uptake:
SERCA2:

A

SERCA2: Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase pumps calcium back into the Sarcoplasmic Reticulum (SR), a key mechanism in reducing calcium levels in blood vessels.

19
Q

Endothelium-Derived Vasodilators - Nitric Oxide & Prostaglandins

A
  1. Nitric Oxide: NO is produced by endothelial cells & activates the soluble guanylate cyclase (sGC) pathway, increasing cGMP levels in smooth muscle cells, which leads to relaxation.
  2. Prostaglandins: These are other signalling molecules produced by endothelial cells and involved in vasodilation.

These vasodilators help regulate vascular tone by interacting with receptors on smooth muscle cells, promoting relaxation and improving blood flow.

20
Q

NO production & 3 types

A

NO produced by nitric oxide synthase (NOS), has three types:
Neuronal NOS
Inducible NOS
Endothelial NOS

NO, produced by these NOS types, is vital for vasodilation, reducing platelet aggregation, and other physiological processes.

21
Q

Neuronal NOS (nNOS):

A

Neuronal NOS (nNOS): Calcium-dependent, found in the CNS (e.g. neurotransmission, learning) & PNS (e.g. gastric emptying & penile erection).

22
Q

Inducible NOS (iNOS):

A

Inducible NOS (iNOS): Calcium-independent, found in immune cells (macrophages, neutrophils) where it produces NO for host defence..

23
Q

Endothelial NOS (eNOS):

A

Endothelial NOS (eNOS): Calcium-dependent, found in endothelial cells, responsible for vasodilation, regulating blood flow & reducing platelet aggregation

24
Q
A
  1. eNOS regulated by intracellular calcium & phosphorylation.
  2. When Ca levels increase, calmodulin (CaM) binds to eNOS, displacing an inhibitory loop & enhancing electron flow, activating eNOS to produce NO
  3. Phosphorylation occurs at two critical sites:
    ser1177 & Thr495
25
Q

Ser1177:

A

Ser1177: Usually unphosphorylated in resting cells but becomes phosphorylated in response to stimuli. Phosphorylation of Ser1177 enhances eNOS activity by increasing electron flow.

26
Q

Thr495

A

Thr495: Site is constitutively phosphorylated & negatively regulates eNOS activity. Phosphorylation of Thr495 decreases eNOS activity, while dephosphorylation by increases activity.

27
Q

In the endothelial cell, eNOS: - 3

A

In the endothelial cell, eNOS:
1. Activated by increases in cytosolic Ca++ (Calmodulin-dependent) &/or phosphorylation (various kinases);
2. Synthetises NO from L-arginine & O2
3. NO diffuses out of endothelial cell

28
Q

In the smooth muscle cell, NO: - 4

A

In the smooth muscle cell, NO:
1. Activates soluble Guanylyl cyclase (sGC)
2. sGC converts GTP to cGMP,
3. cGMP directly stimulates MLCP & via activation of protein kinase G (PKG);
4. cGMP is broken down by PDE5, PDE5 inhibitors used to enhance NO vasodilation

29
Q

Drugs targeting eNOS & NO signalling pathway - 5

A
  1. DDAH regulates eNOS activity by breaking down ADMA.
  2. ADMA inhibits eNOS activity, reducing NO production.
  3. Elevated ADMA serves as marker for endothelial dysfunction & CVD risk factor.
  4. Therapeutic approaches to boost NO include NO donors
  5. PDE5 inhibitors like sildenafil prevent the breakdown of cGMP, enhancing NO’s vasodilatory effects.
30
Q

Synthesis of Prostanoids - 4

A
  1. In endothelial cells, the process is calcium-dependent, with elevated calcium activating cPLA2, releasing arachidonic acid from membrane phospholipids.
  2. Arachidonic acid is then converted by COX-1 enzymes into prostaglandins, rate limiting step
  3. Prostaglandin is converted to prostaglandin using e.g. prostacyclin synthase to PGI2 in endothelial cells
  4. Or Thromboxan synthase into TXA2 in platelets
31
Q

The effects of prostaglandin E2 (PGE2) depend on the receptors it activates: 3

A

The effects of prostaglandin E2 (PGE2) depend on the receptors it activates:
1. EP2 & EP4 (Gs): Cause vasodilation & bronchodilation.
2. EP1 (Gq): Induces bronchoconstriction & GI constriction.
3. EP3 (Gi/Go): Uterine contractions, GI secretion, & vascular smooth muscle contractions.

32
Q

PGE2 & PGFa2 - 3

A
  1. both used to induce labour & for abortions.
  2. PGE2 plays a role in temperature regulation & the induction of fever.
  3. PGD2 is a vasodilator &
    potent bronchoconstrictor, which can worsen asthmas

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