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

• Heart failure and Inflammatory diseases like rheumatologic disease.

• This increase in angiotensinogen results in the increased conversion of angiotensinogen into angiotensin 1 by renin.
• It also leads to increased conversion of angiotensin 1 to angiotensin 2 by ACE (Angiotensin Conversion Enzyme).
• Increased levels of angiotensin 2 cause constriction of the arteries and veins resulting in an increase in blood pressure.
• Increased levels of angiotensin 2 also result in reduced urine output due to decreased glomerular filtration. It also stimulates the release of aldosterone which acts on the kidney and increases Sodium and water reabsorption which increases blood pressure.

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

• Because the ACE inhibitors also cause the increase in bradykinin due to inhibiting the Angiotensin Converting Enzyme (ACE) which converts bradykinin to an inactive metabolite. While the drugs that act by inhibiting the angiotensin receptor do not inhibit any other systems.

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

• They inhibit the metabolism of bradykinin which has a big contribution in treating hypertension due to the hypotensive action of bradykinin.
• They also decrease systemic vascular resistance without increasing the heart rate which helps lower hypertension.

4. 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?

• They act on the Angiotensin 2 receptors.
• They are also competitive antagonists at Angiotensin 1 receptors.

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

• They dilate the arteries and veins.
• Other autocoids like nitric oxide or vasodilator prostaglandins (PGE₂ & PGI₂) can also play a role in this action by acting as mediators.

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

• B₂ receptors.

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

• They cause a compensatory increase in renin secretion and plasma angiotensin 2 levels, which will then reduce blood pressure and help in the treatment of hypertension.
• In heart failure, they cause vasodilation and natriuresis.

8. What is Neprilysin 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 is an enzyme that metabolizes the atrial natriuretic peptide and the brain natriuretic peptide.
• Inhibiting the actions of Neprilysin causes a stronger vasodilatory effect and natriuresis.
• Sacubitril is one of the drugs used to inhibit Neprilysin

9. Give examples of endothelium-derived vasodilators and vasoconstrictors.

• NO (Nitric Oxide) is an endothelium-derived vasodilator.
• ET-1 is an endothelium-derived vasoconstrictor.

Migraine pathology

Migraine involves the trigeminal nerve distribution to intracranial (and possibly extracranial) arteries, which release peptide neurotransmitters especially CGRP (Calcitonin Gene-Related Peptide) which is a strong vasodilator. Substance P and neurokinin A may also be involved. Extravasation of plasma and plasma proteins into the perivascular space is a common feature of animal migraine models and is found in biopsy specimens from migraine patients. The mechanical stretching caused by this perivascular edema may be the immediate cause of activation of pain nerve endings in the dura.

The onset of headache is sometimes associated with a marked increase in the amplitude of temporal artery pulsations, and relief of pain by administration of effective therapy is sometimes accompanied by diminution of these pulsations.

Current Treatment for migraines and how it works

The triptans (Sumatriptan, Rizatriptan), the Ergot Alkaloids (Ergotamine, Dihydroergotamine), and the Antidepressants (Amitriptyline, Nortriptyline) may activate 5-HT_1D/1B receptors on presynaptic trigeminal nerve endings to inhibit the release of vasodilating peptides, and antiseizure agents may suppress excessive firing of these nerve endings. The vasoconstrictor actions of direct 5-HT agonists (the triptans and ergot) may prevent vasodilation and stretching of the pain endings. It is possible that both mechanisms contribute in the case of some drugs.