Vascular Tone - Cardio Pharma

Vascular tone controlled by sympathetic neurotransmitters, hormones and other mediators

• location of sympathetic neurotransmitter receptors

Receptors in tunica media

• stimulates smooth muscles cells in the tunica media

  (endothelium = tunica intima)

Goal of PHYSIOLOGICAL vasodilation → decrease intracellular calcium

(via cAMP or cGMP)

• less intracellular Ca2+

• Ca2+ cannot activate Calmodulin

• less MLCK activation (myosin light chain kinase)

• prevents myosin binding to actin

• reduced contraction

High cAMP cell → less Ca2+ → less contraction

( [low] PDE breaks down cAMP)

Methods of reducing intracellular calcium

1. vasodilator ligand binds to adenylyl cyclase coupled receptor (g-protein-coupled receptor)

   • ATP → cAMP

   • stimulated Ca2+ efflux

2. ligand binds to GC (gauanylate cyclase)

   • GTP → cGMP

   • (a) inhibit phospholipase C (PLC) → reduced release of intracelluar calcium stores

   • (b) directly inhibits MLCK

[K+ efflux hyperpolarising current]

Goal of PHYSIOLOGICAL vasoconstriction → increase calcium

(via cAMP or cGMP)

• more intracellular Ca2+

• more Ca2+ activates Calmodulin

• more MLCK activation (myosin light chain kinase)

• more myosin binds to actin

• increased contraction (of vascular smooth muscle)

LOW cAMP cell → more Ca2+ → more contraction

( [high] PDE breaks down cAMP)

Ligand binds to PLC-coupled receptor

• PI turnover: PI → IP3 + DAG

• IP3 increases intracellular calium (release of stores)

• more Ca2+ activates Calmodulin receptor etc

  • Ca2+ = calmodulin cofactor

Na+ and Ca2+ ligand gated channels

• increase intracellular caldium

Vasodilators & their receptors

1. (N)Ad → β2-adrenoceptors

2. Prostacyclin PGI2 → receptors

3. NO

4. ANP (atrial naturetic peptide) → ANPA receptors

5. Adenosine → A2 receptors

   (low dose dopamine → peripheral vasodilation)

Vasoconstrictors & their receptors

(N)Ad → α1 or α2 adrenoceptors

Angiotensin II → AT1 receptors

Vasopressin (ADH) → V1

Endothelin-1 → ETA

Thromboxane A2 → TXA2 Receptors

5-hydroxy-tryp-tamine → 5-HT2

high dose dopamine → constriction

Vasodilation Methods

• inhibiting vasoconstriction

(receptors and enzymes)

Inhibit natural vasoconstictors

1. α1-selective adrenoceptor antagonists

2. prevent endothelin-1 production → ECE inhibitor (endothelin converting enzyme)

3. ETA-selective antagonist (Endothelin-1 receptors theoretical)

Inhibiting RAAS

1. Block renin secretion → β antagonists [no angiotensiogen → Angiotensin I]

2. Angiotensin I → Angiotensin II → ACE inhibitor

3. Antagonists of vascular and adrenocortico AT1 (angiotensin II receptors)

   → decreased vasoconstriction

   → reduced aldosterone secretion → decreased plasma volume

   • (high Na+ & H20 excretion → low blood pressure)

Vasodilation Methods

• inhibiting vasoconstriction

(ions channels and intracellular mechanisms)

1. block L-type (v-g) Ca2+ channels

   • less Ca2+ entry

   • decreased depolarisation

Vasodilation Methods

• increase cAMP

1. β2-adrenoceptor & PGI AGONSITS

   • analogues that stimulate normal physiological pathway

   • high cAMP

     • Ca2+ efflux

     • MLCK inhibition

2. PDE inhibitors

   • more cAMP → more Ca2+ efflux → less Ca-Calmodulin → less MLCK → less myosin and actin binding → less contraction → dilation

Vasodilation Methods

• increase cGMP levels

Drugs that stimulate production of cGMP

• NO synthase agonists

• Organic nitrates (+ nitro-glycerin)

  • GTN = gly-ceryl tri-nitrate (GTN cardiac patients)

    • metabolised in BV wall to produce NO

    • mostly veins → reduce preload (heart demand)

    • used for acute pulmonary oedema

• Sodium nitroprusside

  • decomposes to produce NO precursors

  • mixed vasodilator (decomposition without blood vessel involvement → both veins and arteries)

• Atrial natri-uretic peptide analogues (ANP development analogues)

NO synthase agonists

NOS (nitric oxide synthase) WITHIN endothelial cell

• L-arginine → NO

• NO enters smooth muscle

• NO → nitro-so-thiols → guanylate cyclase

• GTP → cGMP

• protein kinase G

• promotes smooth muscle relaxation = vasodilation

Organic nitrates

• active on venous side to increase venous capacitance → reduces preload

• GTN = gly-ceryl tri-nitrate → metabolised NO2- in BV wall

• NO2- → NO

• NO → nitro-so-thiols → guanylate cyclase

• GTP → cGMP

• protein kinase G

• promotes smooth muscle relaxation = vasodilation

Nitroprusside from Sodium nitroprusside

(mixed)

• naturally decomposes

Nitroprusside → NO

• NO → nitro-so-thiols → guanylate cyclase

• GTP → cGMP

• protein kinase G

• promotes smooth muscle relaxation = vasodilation

Di-uretics

• treatment for congestive heart failure

• decreases preload and afterload

  • volume overload due to defective lymphatic drainage

  • fluid remains in interstitial space

  • pressure overload → high hydrostatic pressure → damages capillary endothelium → increased capillary permeabilty → increase oedema

  • defective reaborption → low plasma proteins due to leaking vessels → low oncotic pressure

Mechanism

• increases NaCl excretion

• water follows - osmosis

• reduced venous return (preload)

• reduced afterload

• prevents high blood plasma conc

• decreases interstitial fluid

• prevents oedema

Different targets of diuretics

• loop diuretics → Furosemide

• Thia-zide → DCT

• Potassium sparing → aldosterone receptor anatagonists

  • prevents Na+ reabsorption in DCT

  • less fluid reabsoprtion

  • → Spiro-no-lactone

Praz-o-sin

alpha 1 selective adrenoceptor antagonist

Phosphoramidon

ECE inhibitor (antagonist)

• Capto-pril

• En-ala-pril

• Ben-aze-pril

ACE inhibitors

Clen-bute-rol

B2 adrenoceptor agonist

ilo-prost

prostacyclin agonist

• Am-lo-di-pine

• Nif-edi-pine

Ca2+ L type slow voltage gated channel antagonists