Blog 2.4

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

Endothelium cells respond to vasorelaxants by releasing soluble endothelium-derived relaxing factor (EDRF). EDRF acts on vascular muscle to cause relaxation. NO is the major bioactive component of EDRF. So Endothelium-dependent vasodilators increase the intracellular calsium levels in the endothelium. Endothelium-dependent vasodilation is stimulated by an increase in blood flow that increases shear stress on the endothelium, both in the resistance vessels conduit. 

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

iNOS are expressed through transcriptional induction when exposed to inflammatory mediators and this expression, and thus NO synthesis, is not regulated by calcium. eNOS and nNOS are expressed constituvely and NO synthesis is dependent on calcium regulation.

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

Sepsis is a systemic inflammatory response caused by  an infection. Endotoxins from the bacterial cell wall and other cytokines induce synthesis of iNOS in macrophages, neutrophils, T-cells, hepatocytes, smooth muscle cells, endothelial cells and fibroblasts. The synthesis of NO cause aggravated hypotension, septic shock and death. 

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

NO

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

Intracellular glutathione protects against tissue damage caused by scavenging peroxynitrite Peroxynitritecause tissue damage during inflammation.

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

NO stimulates the synthesis of inflammatory prostaglandins by activating the COX-2 pathway. Prostaglandins have vasodilatory effects and together with NO, it can increase vascular permeability and it can lead to perivascular edema. Excessive NO production may lead to tissue injury.

• In which possible neurological and psychiatric diseases is NO involved? 

Stroke, Parkinson's disease and Amyothropic lateral sclerosis

Blog 2.2

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

Hypertension is the disease in which angiotensinogen levels are increased. Angiotensinogen levels are increased with estrogens, thyroid hormones, corticosteroids, ANG II. It is also increased during pregnancy.

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

Drugs which blocks ACE will also lead to the inhibition of bradykinin breakdown. Increased bradykinin concentrations cause bradykinin 2 receptor mediated bronchoconstriction which cause the negative side-effect of a dry, irritating cough. Drugs which act specifically on angiotensin receptors will not inhibit bradykinin breakdown and thus will not have this adverse effect because due to the fact that the bradykinin concentration will not be increased.

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

ACE inhibitors block the conversion of angiotensin I to angiotensin II. Angiotensin II type I receptors are also blocked. This leads to vasodilation instead of vasoconstriction which leads to a decrease in peripheral resistance and BP. Aldosterone secretion decreases which leads to less salt and water retention and more excretion in the urine which lowers cardiac preload, decrease cardiac output and decrease BP. Left ventricular hypertrophy is also reversed.

Secondly, ACE inhibitors inhibit bradykinin breakdown. Increased bradykinin concentrations, increase prostaglandin synthesis which increase arterial vasodilation, decrease peripheral resistance and decrease BP. 

• 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 angiotensin II type 1 receptors. They have no affect on angiotensin II type 2 receptors , like Lorsartan and other similar drugs.

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

Yes, kinins cause vasodilation of arteries and vasoconstriction of veins. Yes, there are many other autacoids that also cause vasodilation such as : Natriuretic peptides, vasoactive intestinal peptides, substance P, neurokinin A, neurokinin B, Calcitonin gene-related peptide.

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

Bradykinin 2 receptors

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

Natriuretic peptides, such as carperitide and urodilatin causes natriuresis and diuresis. It will cause a decrease in angiotensin as well as aldosterone. This will relieve the oedema which is associated with congestive heart failure. The natriuretic peptides cause vasodilation which decrease peripheral resistance and decrease BP that can be effective in treating hypertension.

• 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 metabolizes the natriuretic peptides ANP and BNP which lead to a decrease in their concentrations. In reducing ANP and BNP, their positive therapeutic effects in congestive heart failure is also reduced. Thus neprilysin should be blocked so that the therapeutic positive effects of ANP and BNP can dominate.

Neprilysin inhibitor drug is Sacubitril

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

Endothelium derived vasodilators: PGI2, NO (nitric oxide)

Endothelium derived vasoconstrictors: Endothelin: ET1, ET2, ET3, ETA, ETB

Endothelium antagonists that cause vasodilation: Bosentan, macitentan, ambrisentan, sitaxsentan etc.

The 5-HT 1D/1B agonists, Triptans, are used for a Migraine headache. A migraine is characterized by nausea, vomiting and visual scotomas or even hemianopsia and speech abnormalities.

Migraine involves the trigeminal nerve distribution to instracranial, and possibly extracranial, arteries. These nerve release peptide neurotansmitters, especially calcitonin gene-related peptide, CGRP, an extremely powerful vasodilator. Substance P and neurokinin A may also be involved.

The triptans, ergot alkaloids and antidepressants may activate 5-HT 1D/B 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.

Sumatriptan and its congeners are currently first in line therapy for acute severe migraine attacks in most patients. They activate these receptors on the presynaptic trigeminal nerve ends to inhibit the release of the vasodilating peptides.

Anti-inflammatory analgesics such as aspirin and ibuprofen are often used to control the pain of migraine and not resolving the migraine itself.