• What do you understand by the term “endothelium-dependent” vasodilation?  Explain.

Nitric Oxide is a potent vasodilator.  NO mediates its regulatory vasorelaxing effects through guanilyl cyclase activation. Also, thiol S-nitrosation by NO is increasingly evident as an effector mechanism. An increase in blood flow stimulates endothelium-dependent vasodilation. This is done by increasing shear stress on the endothelium.

When we talk about the NOS enzyme, what is meant by “constitutive” and “inducible” enzymes and what are the pathological and physiological implications thereof?

Constitutive – Any enzyme that is formed at a constant rate and in constant amount in a given cell, regardless of the metabolic state of the cell or organism.

Inducible - Inducible NOS is not usually expressed in cells, but its expression can be induced by bacterial lipopolysaccharide, cytokines, and other agents. Although primarily identified in macrophages expression of the enzyme can be stimulated in virtually any cell or tissue, provided that the appropriate inducing agents have been identified. Once expressed, iNOS is constantly active and not regulated by intracellular Ca²⁺ concentrations.

Constitutive enzymes are said to have a greater physiological effects than inducible enzymes.

• Explain how NO contributes to the fatal pathology of septic shock.

In sepsis, nitric oxide synthesis is dysregulated with exaggerated production leading to cardiovascular dysfunction, bioenergetic failure and cellular toxicity whilst at the same time impaired microvascular function may be driven in part by reduced nitric oxide synthesis by the endothelium. Nitric oxide (NO) is believed to play a key role in the pathogenesis of septic shock, although many aspects of NO's involvement remain poorly defined

• Which autacoids’ mechanism of action depends on effects on the guanylyl cyclase-cGMP system?

Nitrogen Monoxide

• NO may be toxic to the cell.  Which mechanisms are available to the body to counter this detrimental effect of NO?

If NO reacts with oxygen it will form NO2 which thereby deactivates NO to ensure no toxic effects. If NO reacts with haemoglobin the body will oxidize it to a nitrate which therefore also deactivates NO and the toxic effects. NO also reacts with metals in the body.

• Name a way in which NO can act pro-inflammatory.  Give examples of where it will have advantages or disadvantages.

NO is considered as a pro-inflammatory mediator that induces inflammation due to over production in abnormal situations. NO is synthesized and released into the endothelial cells by the help of NOSs that convert arginine into citrulline producing NO in the process. Oxygen and NADPH are necessary co-factors in such conversion. NO is believed to induce vasodilatation in cardiovascular system and furthermore, it involves in immune responses by cytokine-activated macrophages, which release NO in high concentrations. The response to injury or infection leads to the activation of leukocytes and the release of inflammatory mediators, resulting in an increase in iNOS levels and activity in leukocytes.

Nitric oxide and its oxidation products are toxic and can cause tissue injury. The endocrine system can protect against nitric-oxide-mediated tissue damage by producing corticosteroids, growth factors, and cytokines that are potent inhibitors of nitric oxide production.

In which possible neurological and psychiatric diseases is NO involved? 

Stroke, amyotrophic lateral sclerosis and Parkinson’s disease.

• In which diseases are angiotensinogen levels increased?  What are the implications of this?

Hypertension

The production of angiotensinogen is increased by corticosteroids, estrogens, thyroid hormones, and ANG II.

It can increase blood pressure by constricting the blood vessels. It can also trigger thirst or the desire for salt. Angiotensin is responsible for the release of the pituitary gland's anti-diuretic hormone.

• Why do drugs which inhibit the angiotensinogen system by acting on angiotensin receptors have fewer side effects than those that inhibit ACE?

Angiotensin blockers do not affect the metabolism of bradykinin which is responsible for the side effect of a dry cough, it decreases the renin produced. ACE inhibitors affect the metabolism of bradykinin therefore the side effect of dry cough is experienced. It also has a serious vasodilating effect.

• In which way do ACE inhibitors have a two-fold mechanism of action in the treatment of hypertension?

ACE inhibitors block the conversion ANG I and ANG II it also blocks the metabolism of bradykinin to an inactive metabolite. ANG II causes an increase in Blood pressure thus by blocking the conversion of ANG I to ANG II ACE inhibitors decrease blood pressure significantly.

• At which type of angiotensin receptor do losartan and similar drugs act?  Do they have any effect, direct or indirect, at other angiotensin II receptors?

Losartan, is a selective non-peptide antagonist blocking the AT1 receptors. They influence AT2 receptors when Angiotensin 2 is increased.

• What are the physiological effects of kinins on arteries and veins?  Do other autacoids play a role in this action?  Explain.

Kinins are proteins in the blood that cause inflammation and affect blood pressure (especially low blood pressure). They also: Increase blood flow throughout the body. Make it easier for fluids to pass through small blood vessels. Through bradykinin ability to elevate vascular permeability and to cause vasodilatation in some arteries and veins. Kinins are potent vasodilators and increase the blood flow in the body.Autocoids such as Histamine and Serotonin also play a role in this action Histamine - H1 and H2 receptors dilatate blood vessels and capillaries.

• Which receptor is probably the most involved in the important clinical effects of kinins?

Kinins are a family of peptides implicated in several pathophysiological events. Most of their effects are likely mediated by the activation of two G-protein-coupled receptors: B₁ and B₂.

• In which way are natriuretic peptides possibly effective in the treatment of hypertension, as well as congestive heart failure?

Agonists binding to ANP receptors cause vasodilation with increased glomerular filtration rate and enhanced Na⁺ and water excretion, while BNP receptor stimulation inhibits renin production. These peptides reduce blood pressure through vasodilation of both the arterial and venous systems 

• What is neprylisine and what is the rationale for inhibiting its action in the treatment of heart failure? Can you name the drug being used as such? Refer to Study unit 1 where you have also come across this drug.

Neprilysin enzyme is also called neutral endopeptidase that plays a role in the degradation of natriuretic peptides and other vasoactive peptides including bradykinin. Natriuretic peptides remove sodium from the blood and excrete it in the urine.

Neprilysin inhibitors are a new class of drugs used to treat high blood pressure and heart failure. They work by blocking the action of neprilysin thus preventing the breakdown of natriuretic peptides. The drug used is sacubitril  

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

Vasodilators – Nitric Oxide

Vasoconstrictors - ET1

Migraine is recurrent, severe headache without or with

• Aura (20%) (reversible focal neurological symptoms that usually develop gradually over 5 - 20 min before the onset of the headache and last for less than 60 min)

• Followed by severe throbbing headache, mostly on one side of head

Involves, among other things, involvement of trigeminal nerve distribution to intracranial arteries, with release of powerful vasodilators (CGRP) that cause vasodilation and edema, thus activating pain nerve endings

Treatment of migraine

Analgesia: Paracetamol, NSAID’s(Aspirin) - ( This works for pain by blocking the enzyme cyclooxygenase which prevents the formation of prostaglandins )

 Anti-emetics: Metoclopramide(The antiemetic action of metoclopramide is due to its antagonist activity at D₂ receptors in the chemoreceptor trigger zone in the central nervous system — this action prevents nausea and vomiting triggered by most stimuli

 Domperidone(The DA2-receptor antagonist domperidone antagonizes the inhibitory effect of dopamine, resulting in stimulation of gastric muscle contraction

 Cyclizine ( Cyclizine is a histamine H₁ receptor antagonist of the piperazine class which is characterised by a low incidence of drowsiness. It possesses anticholinergic and antiemetic properties.

Ergotamine (Vasoconstriction is produced by an agonist activity and this effect varies with different vascular beds.)

5-HT1D agonist: Sumatriptan, Zolmitriptan, Eletriptan, Naratriptan, Rizatriptan

Sedative drugs: Diazepam