Vascular tone regulation

Question 1

Contraction in vascular SMCs

Answer 1

• Increase of calcium concentration coming from ouside and intracellular stores. Calcium + CaM activates MLCK that phosphorylate the myosin light chain and allows contraction

Question 2

Relaxation in vascular SMCs

Answer 2

NO activate guanylyl cyclase -> cGMP -> activation of MLCP -> dephosphorylation of the myosin light chain -> relaxation

Relaxation can be induce by preventing MLCK activation, thus by using ca2+ channel blocker

Question 3

Endothelin action

Answer 3

Endothelin receptors are:
- on SMCs, coupled to PLC and thus leading to an incrase in Ca2+
- on endothelial cells. -> increase of prostacyclin and NO production which act on on SMCs to induce relaxation.
2 counteracting processes

Question 4

Antagonists of endothelin receptors

Answer 4

Used in CV medicine (e.g. HT, HF), but mainly in pulmonary hypertension.

By blocking the endothelin receptors, these agents inhibit endothelin-1-induced vasoconstriction in the pulmonary circuit.

Examples: Bosentan, Macitentan and Ambrisentan

Question 5

Potassium channel openers

Answer 5

K+ channels are activated- > outflux of potassium -> hyperpolarisation of SMC -> voltage gated calcium channels remain closed

Question 6

Which molecule plays the major role in basal vasodilation? what about vaso constriction?

Answer 6

NO rather than the sympathetic nervous system (release regulated by blood flux acting on stretch receptors).
Counteracted by the sympathetic NS (noradrenaline and adrenaline).

Question 7

Riociguat

Answer 7

Stimulates guanylys cyclase.

Indication: primary pulmonary hypertension

Question 8

NO donors

Answer 8

• Sodium nitroprusside: spontaneously release NO
• Organic nitrats
  Administration: orally. IV only in severe cases.
  Lipophilic subtances that pass easily through the lingual mucosa into the systemic circulation and rapidly accumulate in coronary arteries (short-acting). In the systemic circulation they act more on the venous compartment.
  Indication: stable angina (causing rapid vasodilation in coronary arteries).
  Adverse drug reactions: flushing, headache, generalized hypotension, headache, edema

Question 9

Organic nitrates

Answer 9

Need other enzymes to release NO.
Actions:
- Dilation of veins (-> decreased preload and myocardial oxygen demand)
- Dilation of epicardial coronary arteries
NITROGLYCERIN

Question 10

Isosorbide dinitrate

Answer 10

• Nitrate
• First ethnic drug released by the FDA, especially used in black people
• Administered orally in combination with hydralazine

Question 11

Drug-drug interaction of nitrates

Answer 11

with PDE5 inhibitors. they insist on the same pathway.

Consequence: extensive vasodilation and shock

Question 12

Calcium channels types

Answer 12

3-4 types
N-type and T-type in the NS
L type: in peripheral tissues, especially in the heart and SMCs of vessels

Question 13

Calcium channel blockers

Answer 13

Blockers of L-type.
- Dilation of coronary arteries and peripheral arterioles (decreased TPR), not veins -> increased myocardial oxygen supply and decreased afterload (-> decreasedoxygen demand) respectively
- decrease in cardiac contractility, in automaticity at the SA node and in conduction at the AV node
Indication: hypertension
Not used in case of congestive heart failure.

Common adverse drug reaction: peripheral edema

Question 14

Nifedipine

Answer 14

Calcium channel blocker

• Indication: hypertension and angina
• Strong dilatatory effect on peripheral arterioles and coronary arteries, very low effect on contractractility and automaticity of the heart

Question 15

Verapamil and diltiazem

Answer 15

Calcium channel blocker

• Dilatatory effect on peripheral arterioles and coronary arteries, but they act also on contractractility and automaticity of the heart
• Indication: arrhythmias
• CI: heart failure

Question 16

Dihydropyridines

Answer 16

Class of calcium channel blockers: nifedipine, amlodipine, felodipine, clevidipine
Indications: hypertension, coronary spasms,..

Question 17

Which drugs affect the remodelling and the evolution of heart failure and hypertension

Answer 17

ACE inhibitors, sartans, beta-blockers.

Calcium channels blockers and alpha1 antagonist do not.

Question 18

Alpha 1 antagonists

Answer 18

Used in combination with other therapies.
alpha 1 receptors are blocked causing vasodilation and decreased blood pressure.
E.g. Prazosin, Doxazosin, Terazosin -> mainly used in prostatic hyperplasia. Also for emptying more easily the bladder and for hypertension.

Question 19

Beta1 receptors blockers

Answer 19

Beta 1 receptors are involved in the progression of HF and HT.
Heart starts to decompensate -> sympathetic NS tries to compensate -> increase in noradrenaline release -> increased stimulation leads to decrease expression of the receptors -> compensatory effect progressively decreases.
To block beta 1 R allows to change the remodelling and thus the hisoty of the disease.

Indication: hypertension in patients with higher basal sympathetic activity.

E.g.

• Carvedilol (act on beta 1 and 2, endothelin system, and alpha1) -> decreases heart contractility, causes vasodilation and bronchoconstriction.
• propanolol
• Atenolol, Metoprolol

Question 20

Clonidine

Answer 20

alpha 2 adrenergic receptor agonist
Used in pregnant hypertensive patients.
Work around all the CNS,including brainstem centres and regulating sympathetic activity.

Question 21

Aldomet (alpha-methyldopa)

Answer 21

Fake NTs. It substitutes noradrenaline in the vesicles but the has no effect on receptors -> antihypertensive action