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

Too much angiotensin II is a common problem resulting in excess fluid being retained by the body and, ultimately, raised blood pressure. This often occurs in heart failure where angiotensin is also thought to contribute to growth in the size of the heart.

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

An advantage of ARBs over ACE inhibitors is fewer adverse effects: in general, ARBs are better tolerated than ACE inhibitors. There are also ethnic differences in the risks of adverse reactions to these medications. African Americans have a higher risk of developing angio-edema with ACE inhibitors compared with the rest of the US population, and Chinese Americans have a higher risk than whites of developing cough with ACE inhibitor.

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

ACE inhibitors and bradykinin

ACE is also involved in the breakdown of bradykinin, a vasodilator. ACE inhibitors block the breakdown of bradykinin, causing levels of this protein to rise and blood vessels to widen (vasodilation) which aids to treat hypertension.

ACE inhibitors and the RAAS system

ACE inhibitors work by interfering with the body’s renin-angiotensin-aldosterone system (RAAS). RAAS is a complex system responsible for regulating the body's blood pressure. The kidneys release an enzyme called renin in response to low blood volume, low salt (sodium) levels or high potassium levels. Angiotensinogen, which is Renin catalytically cleaves these circulating angiotensinogen and forms angiotensin I. Angiotensin-converting enzymes then convert angiotensin I to its physiologically active form, angiotensin II. Angiotensin II causes contraction of the muscles surrounding blood vessels, effectively narrowing vessels and increasing blood pressure. It also stimulates the release of aldosterone, which stimulates water and sodium reabsorption, thereby, increasing blood volume and blood pressure.

ACE inhibitors stimulate the dilation of blood vessels by inhibiting the production of angiotensin II. The major organs that ACE inhibitors affect are the kidney, blood vessels, heart, brain, and adrenal glands. The inhibitory effects lead to increased sodium and urine excreted, reduced resistance in kidney blood vessels, increased venous capacity, and decreased cardiac output, stroke work, and volume.

Synthesized in the liver, is the main substrate for renin.

• 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 an angiotensin II receptor antagonist (AIIRA) with antihypertensive activity due mainly to selective blockade of AT1 receptors and the consequent reduced pressor effect of angiotensin II.

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

Kinins are not involved in the regulation of systemic blood pressure but participate in other aspects of arterial physiology, especially flow-mediated vasodilatation, a critical feature of arterial function, which is endothelium mediated, ensuring the proper delivery of blood to organs.

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

Kinins induce inflammatory responses via inducible B1 and constitutive B2 receptors in injured tissues

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

Many medications used to treat heart failure (e.g., diuretics such as spironolactone [Aldactone], angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers) reduce natriuretic peptide concentrations. Pharmacological natriuretic peptide augmentation lowers blood pressure. Less recognized is the fact that natriuretic peptides potently affect lipid and glucose metabolism. Through these metabolic actions, natriuretic peptides may provide a pathophysiological link between cardiovascular and metabolic disease.

• 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 is a neutral endopeptidase and its inhibition increases bioavailability of natriuretic peptides, bradykinin, and substance P, resulting in natriuretic, vasodilatory, and anti-proliferative effects. (Valsartan/sacubitril) is a first-in-class angiotensin II-receptor neprilysin inhibitor.

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

The endothelium releases various vasoactive factors. These can be vasodilatory factors such as nitric oxide (NO), prostacyclin (PGI2) and endothelium derived hyperpolarizing factor (EDHF) or vasoconstrictive factors such as thromboxane (TXA2) and endothelin-1 (ET-1).