L7 - Drug Affecting the Vascular System

Question 1

What controls blood flow through blood vessels?

Answer 1

• Blood flow is controlled by vascular smooth muscle.

Question 2

What does contraction of vascular smooth muscle lead to?

Answer 2

• It leads to vasoconstriction.

Question 3

What initiates the contraction of vascular smooth muscle?

Answer 3

• Contraction is initiated by a rise in intracellular calcium ion concentration [Ca2+]i[Ca^{2+}]_i[Ca2+]i.

Question 4

What are the three mechanisms that cause contraction in smooth muscle?

Answer 4

• Contraction can be caused by:
  1. Release of intracellular calcium from the ER or SER via IP3.
  2. Entry of calcium through ligand-gated calcium channels (ligand is ATP).
  3. Depolarization of the membrane allowing calcium entry through voltage-gated calcium channels.

Question 5

How does calcium cause smooth muscle contraction?

Answer 5

• Calcium binds to calmodulin, which activates myosin light chain kinase (MLCK). MLCK phosphorylates myosin, allowing it to interact with actin, causing contraction.

Question 6

How is smooth muscle relaxation achieved?

Answer 6

• Relaxation is achieved through:
  o cAMP activating a protein kinase (PK) that inhibits MLCK.
  o cGMP activating a PK that activates myosin phosphatase, which dephosphorylates myosin, leading to relaxation.

Question 7

What agents can cause relaxation of vascular smooth muscle?

Answer 7

• Agents that cause relaxation may:
  1. Inhibit receptors that activate PLC (which produces IP3).
  2. Inhibit calcium entry through voltage-gated calcium channels.
  3. Increase intracellular cAMP or cGMP concentrations.

Question 8

What is an example of a drug that blocks voltage-gated calcium channels?

Answer 8

• Nifedipine is an antagonist for voltage-gated calcium channels, used to treat hypertension and angina.

Question 9

How do α1-adrenoceptor antagonists affect vascular smooth muscle?

Answer 9

• α1-adrenoceptor antagonists (e.g., prazosin, terazosin, and doxazosin) block α1-adrenoceptors on vascular smooth muscle, reducing vasoconstriction and thus treating hypertension.

Question 10

What is the effect of potassium channel activators on vascular tone?

Answer 10

• Potassium channel activators (e.g., cromakalim) open membrane potassium channels, leading to hyperpolarization, which inhibits voltage-gated calcium channels and prevents contraction.

Question 11

What role do endothelial cells play in regulating vascular tone?

Answer 11

• Endothelial cells release chemical mediators that regulate vascular tone by causing either contraction or relaxation of smooth muscle.

Question 12

How do endothelial cells induce smooth muscle relaxation?

Answer 12

• Nitric oxide (NO) secreted by endothelial cells activates guanylate cyclase, producing cGMP, which leads to muscle relaxation. Prostaglandin I2 (PGI2) activates adenylate cyclase, producing cAMP, which also causes relaxation by inhibiting MLCK.

Question 13

How do endothelial cells induce smooth muscle contraction?

Answer 13

• Angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II binds to the AT1 receptor on smooth muscle, activating PLC, which produces IP3, leading to an increase in intracellular calcium and muscle contraction.

Question 14

What is the mechanism of action of ACE inhibitors?

Answer 14

• ACE inhibitors (e.g., captopril) bind to the active site of ACE, preventing angiotensin I from being converted to angiotensin II. This reduces vasoconstriction and is used to treat hypertension and cardiac failure.

Question 15

What is Losartan and how does it work?

Answer 15

• Losartan is an antagonist of the AT1 receptor, blocking the effects of angiotensin II, reducing IP3 production, and leading to muscle relaxation.

Question 16

What are the categories of vasodilator drugs?

Answer 16

• The categories of vasodilator drugs include:
  1. ACE inhibitors (e.g., captopril).
  2. Nitrates (e.g., glyceryl trinitrate) that increase cGMP.
  3. Calcium channel antagonists (e.g., nifedipine).
  4. α1-adrenoceptor antagonists (e.g., prazosin).
  5. Potassium channel activators (e.g., cromakalim).
  6. Angiotensin II subtype 1 (AT1) receptor antagonists (e.g., losartan).
  7. β2-adrenoceptor agonists that increase cAMP (e.g., adenosine).

Question 17

What two receptors, when activated, lead to vasodilation?

Answer 17

• Receptors that lead to vasodilation when activated include β2-adrenoceptors and muscarinic acetylcholine receptors (M3 subtype).

Question 18

What two receptors, when inhibited, lead to vasodilation?

Answer 18

• Receptors that lead to vasodilation when inhibited include α1-adrenoceptors and AT1 receptors.

Question 19

What ion channel leads to vasodilation when activated?

Answer 19

• Potassium channels lead to vasodilation when activated by causing hyperpolarization.

Question 20

What ion channel leads to vasodilation when inhibited?

Answer 20

• Voltage-gated calcium channels lead to vasodilation when inhibited.

Question 21

Which is more effective for vasodilation: calcium or cGMP?

Answer 21

• cGMP is more effective for vasodilation than calcium, as it promotes muscle relaxation.

Question 22

What enzymes, if inhibited, can lead to vasodilation?

Answer 22

• Inhibiting ACE and phosphodiesterase enzymes can lead to vasodilation.

Question 23

How do nitrates affect the vascular system?

Answer 23

• Nitrates (including industrial nitrates) activate guanylate cyclase, increasing cGMP and causing vasodilation. Side effects may include headaches, dizziness, and tolerance development.

Question 24

What toxicants affect the bone marrow and what are their effects?

Answer 24

• Toxicants like chloramphenicol, lindane, and benzene can damage bone marrow, leading to pancytopenia and aplastic anemia.

Question 25

How does lead affect hemoglobin?

Answer 25

• Lead inhibits the enzyme ALA-D, which is important for heme production, thus interfering with hemoglobin synthesis.

Question 26

What effect does carbon monoxide have on hemoglobin?

Answer 26

• Carbon monoxide binds to the iron in heme, reducing the oxygen-carrying capacity of hemoglobin. Smokers may have up to 10% of their hemoglobin saturated with CO.

Question 27

What substances oxidize heme molecules and how do they affect oxygen binding?

Answer 27

• Substances like nitrites, nitrates, and aromatic amines oxidize heme molecules, converting iron from the ferrous to the ferric state, which cannot bind oxygen.