Vascular tone regulation Flashcards
Contraction in vascular SMCs
- Increase of calcium concentration coming from ouside and intracellular stores. Calcium + CaM activates MLCK that phosphorylate the myosin light chain and allows contraction
Relaxation in vascular SMCs
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
Endothelin action
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
Antagonists of endothelin receptors
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
Potassium channel openers
K+ channels are activated- > outflux of potassium -> hyperpolarisation of SMC -> voltage gated calcium channels remain closed
Which molecule plays the major role in basal vasodilation? what about vaso constriction?
NO rather than the sympathetic nervous system (release regulated by blood flux acting on stretch receptors).
Counteracted by the sympathetic NS (noradrenaline and adrenaline).
Riociguat
Stimulates guanylys cyclase.
Indication: primary pulmonary hypertension
NO donors
- 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
Organic nitrates
Need other enzymes to release NO.
Actions:
- Dilation of veins (-> decreased preload and myocardial oxygen demand)
- Dilation of epicardial coronary arteries
NITROGLYCERIN
Isosorbide dinitrate
- Nitrate
- First ethnic drug released by the FDA, especially used in black people
- Administered orally in combination with hydralazine
Drug-drug interaction of nitrates
with PDE5 inhibitors. they insist on the same pathway.
Consequence: extensive vasodilation and shock
Calcium channels types
3-4 types
N-type and T-type in the NS
L type: in peripheral tissues, especially in the heart and SMCs of vessels
Calcium channel blockers
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
Nifedipine
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
Verapamil and diltiazem
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
Dihydropyridines
Class of calcium channel blockers: nifedipine, amlodipine, felodipine, clevidipine
Indications: hypertension, coronary spasms,..
Which drugs affect the remodelling and the evolution of heart failure and hypertension
ACE inhibitors, sartans, beta-blockers.
Calcium channels blockers and alpha1 antagonist do not.
Alpha 1 antagonists
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.
Beta1 receptors blockers
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
Clonidine
alpha 2 adrenergic receptor agonist
Used in pregnant hypertensive patients.
Work around all the CNS,including brainstem centres and regulating sympathetic activity.
Aldomet (alpha-methyldopa)
Fake NTs. It substitutes noradrenaline in the vesicles but the has no effect on receptors -> antihypertensive action
