L21. Pharmacology - Vascular Pharmacology

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Questions and Answers

What initiates contraction in vascular smooth muscle?

Phosphorylation of myosin light chain (correct)

Depolarization of the membrane by chloride ions

Calcium influx through sodium channels

Activation of myosin light chain phosphatase

Which receptor plays a significant role in the pharmacological control of vascular contraction?

Dopaminergic receptors

Muscarinic receptors

α1-adrenergic receptors (correct)

β-adrenergic receptors

What characteristic of smooth muscle contraction is primarily observed compared to skeletal and cardiac muscle contraction?

Tonic contraction (correct)

Phasic contraction

Tetanic contraction

Isotropic contraction

How does an increase in transmural pressure affect vascular smooth muscle?

It stimulates contraction through stretch receptors. Signup and view all the answers

Which agent is particularly effective in reducing blood pressure due to its action on vascular smooth muscle?

Dihydropyridines Signup and view all the answers

What is the role of myosin light chain phosphatase in smooth muscle contraction?

It reverses the phosphorylation of myosin light chain. Signup and view all the answers

What effect does membrane depolarization have on vascular smooth muscle in response to pressure change?

Triggers calcium influx into the cell Signup and view all the answers

What class of channels is involved in the myogenic response of vascular smooth muscle?

Cation channels Signup and view all the answers

Which of the following accurately describes the primary function of nitroglycerin and isosorbide dinitrate?

They act as vasodilators by releasing NO. Signup and view all the answers

How do repeated uses of nitrovasodilators affect angina tolerance?

They lead to a decrease in angina threshold. Signup and view all the answers

What is the mechanism through which sacubitril, when combined with valsartan, is effective in treating heart failure?

It generates neprilysin inhibitor sacubitrilat. Signup and view all the answers

What role does sildenafil play in the context of cGMP regulation?

It inhibits PDE5 to raise cGMP levels. Signup and view all the answers

What is Hydralazine primarily thought to do in terms of blood pressure regulation?

Selectively dilate arterioles to lower blood pressure. Signup and view all the answers

What is the primary function of Angiotensin II in the cardiovascular system?

To regulate vascular resistance Signup and view all the answers

Which receptor does Angiotensin II predominantly act upon to exert its cardiovascular effects?

AT1 receptor Signup and view all the answers

What is a common adverse effect associated with ACE inhibitors?

Cough Signup and view all the answers

In which cellular process does Angiotensin II activation of the AT1 receptor primarily result?

Release of intracellular calcium Signup and view all the answers

Which drugs are considered Angiotensin Receptor Inhibitors (ARBs)?

Losartan and Irbesartan Signup and view all the answers

Which of the following best describes the main mechanism of action of ACE inhibitors?

Inhibiting the conversion of Angiotensin I to Angiotensin II Signup and view all the answers

Aliskiren is classified as which type of drug targeting the renin-angiotensin system?

Renin inhibitor Signup and view all the answers

What serious side effect can occur with ACE inhibitors affecting the tongue and larynx?

Angioedema Signup and view all the answers

The AT1 receptor predominantly couples to which G protein?

Gq Signup and view all the answers

Which of the following statements is true regarding the side effects of ARBs compared to ACE inhibitors?

ARBs have a much lower incidence of cough than ACE inhibitors Signup and view all the answers

What is not a mechanism for increasing intracellular calcium in smooth muscle?

Activation of calcium channels by G protein coupled receptors Signup and view all the answers

Which G protein family is primarily involved in smooth muscle contraction?

Gq Signup and view all the answers

What does RhoA/RhoA kinase signaling achieve in smooth muscle contraction?

Phosphorylates and inhibits myosin light chain phosphatase Signup and view all the answers

Which agent can be used to trigger a pressor response without activating β-adrenoceptors?

Phenylephrine Signup and view all the answers

What is a common adverse effect of α1-adrenergic antagonists upon initial administration?

Orthostatic hypotension Signup and view all the answers

Which drug is a prodrug metabolized in the CNS to reduce sympathetic outflow?

Methyldopa Signup and view all the answers

Which of the following pharmacological agents increases sympathetic output?

Nonselective sympathomimetics Signup and view all the answers

Which drug combines both α1-adrenergic and β-adrenergic antagonism?

Labetalol Signup and view all the answers

Which of the following describes the role of Gαq in vascular contraction?

Stimulates phospholipase C Signup and view all the answers

What mechanism mediates the relaxation response in vascular smooth muscle?

Enhanced activity of myosin light chain phosphatase Signup and view all the answers

Which of the following endothelins is primarily involved in controlling the pulmonary vasculature?

ET-1 Signup and view all the answers

What are the two types of receptors that endothelins act through?

ETA and ETB Signup and view all the answers

What is the significance of the heptahelical structure of the endothelin receptors?

It mediates G-protein coupling for cellular response. Signup and view all the answers

What role does nitric oxide (NO) play in vascular smooth muscle relaxation?

Activates soluble guanylate cyclase. Signup and view all the answers

Which enzyme is responsible for the hydrolysis of cGMP, terminating its signaling effect?

Phosphodiesterase type 5 (PDE5) Signup and view all the answers

What type of physiological response does Atrial Natriuretic Peptide (ANP) induce?

Vascular relaxation Signup and view all the answers

What are the receptors used by Atrial Natriuretic Peptide (ANP)?

Natriuretic Peptide Receptor A and B Signup and view all the answers

How is endothelin synthesized in the body?

From pre-pro hormones via a two-step enzymatic process Signup and view all the answers

Which pharmacological agents are approved for treating pulmonary arterial hypertension (PAH)?

Macitentan and Bosentan Signup and view all the answers

What is a significant adverse effect associated with endothelin receptor antagonists?

Liver toxicity Signup and view all the answers

Study Notes

Vascular Contraction

Smooth muscle contractions are usually tonic, not phasic
Calcium binding to calmodulin activates myosin light chain kinase which phosphorylates the myosin light chain initiating contraction
Myosin light chain phosphatase reverses the phosphorylation of myosin light chain causing contraction to end
Vascular smooth muscle (arteries and arterioles) contracts in response to increased transmural pressure (myogenic response)
Stretch receptors, ion channels, open upon membrane stretch
Stretch receptors depolarize the membrane, opening L-type calcium channels which results in calcium influx into the cell and subsequent muscle contraction
G protein coupled receptors activate G proteins of the Gq family which activate PLC𝛽 to break down PtdIns(4,5)P2, release IP3, and trigger the release of calcium from intracellular calcium stores
Gαq also binds RhoGEFs to activate RhoA/RhoA kinase signaling which phosphorylates and inhibits myosin light chain phosphatase thus potentiating the actions of myosin light chain kinase (Calcium sensitization)

Pharmacological Control of Vascular Contraction via α1-Adrenergic Receptors

Sympathetic activation causes contraction of many vascular beds (skin, kidneys) through the activation of α1-adrenergic receptors
α1-adrenergic receptors activate Gq and elicit vessel contraction through the mechanism outlined above.
Nonselective sympathomimetic agents such as epinephrine, norepinephrine, or high dose dopamine can be used to elicit a pressor response during septic shock (epinephrine, norepinephrine) or heart failure (dopamine).
Selective α1-adrenergic agonists such as phenylephrine or oxymetazoline can be used to trigger a pressor response while avoiding β-adrenoceptor activation.
Selective α1-adrenergic antagonists such as Prazosin can be used as antihypertensive agents, as can drugs such as Carvedilol and Labetalol that combine α1-adrenergic and β-adrenergic antagonist activity.
A common adverse effect of α1-adrenergic antagonists is orthostatic hypotension.

Centrally Acting Sympatholytic Drugs

Methyldopa, used to treat hypertension during pregnancy metabolizes into α-methyl-norepinephrine, which is thought to act on α2-adrenergic receptors in the brainstem to reduce sympathetic outflow.
Clonidine and Monoxidine are selective α2-adrenergic agonists that act in the brainstem to reduce sympathetic outflow.

The Renin-Angiotensin System

The renin–angiotensin hormone system links kidney function and the cardiovascular system.
Renin cleaves Angiotensinogen to generate Angiotensin I
Angiotensin converting enzyme (ACE) cleaves Angiotensin I to generate Angiotensin II (AngII)
AngII plays an essential role in the regulation of vascular volume
AngII exerts its biological effects via AT1 and AT2 receptors, both heptahelical G protein coupled receptors.
AT1 receptors couple predominantly to Gq and, in some cells, activate other G proteins.
In vascular smooth muscle AngII activation of AT1 receptors activates Gq, to release intracellular calcium and activate RhoA kinase thus producing a pressor response.

Pharmacological Targeting of the Renin-Angiotensin System

ACE inhibitors, such as Captopril and Benazepril are widely used, inhibit the formation of AngII.
Common adverse effects of ACE inhibitors include cough and angioedema.
Angiotensin Receptor Inhibitors (ARBs), drugs such as Losartan or Irbesartan, directly inhibit the AT1 receptors.
ARBs have a much lower incidence of cough and angioedema than ACE inhibitors.
Aliskiren is a selective Renin inhibitor approved by the FDA for the treatment of hypertension.

Endothelin

Endothelial cells signal dilation and contractions
Endothelin 1, 2, and 3 (ET-1, ET-2, and ET-3) act through two heptahelical G protein coupled receptors known as ETA and ETB
ETA is preferentially located on vascular smooth muscle cells and vasculature and ETB on endothelial cells.
ET1 and its receptors are especially important in the control of the pulmonary vasculature
Bosentan and Macitentan are ET receptor antagonists approved for the treatment of pulmonary arterial hypertension (PAH).
Bosentan and Macitentan carry considerable liver toxicity and are contraindicated during pregnancy.

Vascular Relaxation

Vascular smooth muscle relaxation requires a return of intracellular calcium to resting levels and dephosphorylation of myosin light chain
The release of nitric oxide (NO) causes muscle relaxation
NO is formed from arginine by nitric oxide synthases (NOS)
NO diffuses across the cell membrane and directly activates soluble guanylate cyclase
Intracellular cGMP activates Protein kinase G to counter calcium-induced contraction
cGMP is hydrolyzed by the cGMP-specific phosphodiesterase type 5 PDE5

Pharmacological Regulation of NO-cGMP Signaling

Organic nitrates, such as nitroglycerin and isosorbide dinitrate (nitrovasodilators), release NO upon reduction and consequently elicit vascular smooth muscle relaxation and vasodilation.
Nitrovasodilators preferentially dilate large veins and spares medium and small arterioles.
Nitrovasodilators are important agents in the control of angina.
Repeated use of organic nitrates leads to tolerance and a decrease in angina threshold
Sodium nitroprusside is another NO prodrug that acts along the same mechanism but its repeated use does not lead to tolerance.
Sodium nitroprusside is generally used in the treatment of acute hypertensive crises.
Sildenafil (Viagra), used for the treatment of erectile dysfunction and pulmonary arterial hypertension, is a PDE5 inhibitor.
ANP is released by the atria onto the circulation and degraded by the metalloprotease neprilysin.
Sacubitril, a prodrug generates sacubitrilat, a neprilysin blocker
Sacubitrilat with valsartan is effective in the treatment of heart failure.
Hydralazine selectively dilates arterioles reducing blood pressure
Hydralazine’s mechanism of action is not well understood but appears to involve directly or indirectly a reduction in intracellular calcium.

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Description

Test your understanding of the mechanisms underlying vascular smooth muscle contraction. This quiz covers key concepts such as calcium signaling, myogenic responses, and the role of stretch receptors in vascular contraction. Dive into the details of how these muscles function under different physiological conditions.