Vascular mechanism of hypertension Mohammad Saifur Rohman MD

Vascular mechanism of hypertension Mohammad Saifur Rohman MD. Ph. D. FICA Department of Cardiology and Vascular Medicine Faculty of medicine Brawijaya University

Vasoconstriction • Alterations in the structure and function of both small and large arteries plays a pivotal role in the origin and progression of hypertension

Cellular Mechanism of Vasoconstriction

Vascular vs. Renal • Increased vascular resistance in genetically altered mice blood vessel constriction alone-without renal involvement, can cause hypertension

Endothelial dysfunction • Impaired release of endothelial derived relaxing factors (NO, endothelial-derived relaxing factor) • Super oxide anion production reducing NO bioavailability Enzymatic source of superoxide : • NADPH osidases • Uncoupled e. NOS • Xantine oxidase • Mitochondria electron trasnport • Inflamed in hypertension : genesis and complication of high BP

Normal Endothelial Function

Endothelial Dysfunction

Ang II induced Vasoconstriction

Stretch Receptor (↑ = opens. ↓ = closes) [3] On vascular smooth muscle cellsif not otherwise specified ↑Stretch-activated ion channels ATP (intracellular) ↓ATP-sensitive K+ channel ATP (extracellular) muscarinic agonists e. g. acetylcholine ↑P 2 X receptor NPY receptor adrenergic agonists e. g. epinephrine, norepinephrine anddopamine ↑α 1 adrenergic receptor thromboxane endothelin ↑thromboxane receptor ↑endothelin receptor ETA Vasoconstrictor [3] angiotensin II ↑muscarinic receptor M 2 ↑Angiotensin receptor 1 Asymmetric dimethylarginine Antidiuretic hormone (ADH or Vasopressin) • Products of platelet activation [4] • Endotoxin[4] • Thrombin[4] • insulin[4] • Hypoxia [4] Arginine vasopressin receptor 1(V 1) on smooth muscle cells Transduction (↑ = increases. ↓ = decreases) [3] • depolarization -->open VDCCs (primarily) --> ↑intracellular Ca 2+ • ↑Voltage-gated Na+ channels --> • more depolarization --> open VDCCs -> ↑intracellular Ca 2+ • ↓Na+-Ca 2+ exchanger activity --> ↑intracellular Ca 2+ ↑Ca 2+ Activation of Gi --> ↓c. AMP --> ↓PKA activity --> ↓phosphorylation of MLCK --> ↑MLCK activity --> ↑phosphorylation of MLC (calcium-independent) Activation of Gq --> ↑PLC activity --> ↑IP 3 and DAG --> activation of IP 3 receptor in SR --> ↑intracellular Ca 2+ • On smooth muscle cells: Activation of Gq --> ↑PLC activity --> ↑IP 3 and. DAG --> activation of IP 3 receptor in SR --> ↑intracellular Ca 2+ • On endothelium: endothelin synthesis[4] open VDCCs --> ↑intracellular Ca 2+[5] Reduced production of nitric oxide Activation of Gq --> ↑PLC activity --> ↑IP 3 and DAG --> activation of IP 3 receptor in SR --> ↑intracellular Ca 2+ Arginine vasopressin receptoron endothelium Endothelin production[4] Various receptors onendothelium[4] Endothelin production[4]

Structure: Vascular Remodeling

Cytoplasmic vs. Nuclear events

Ang II induced Remodeling

Super oxide and remodeling

Vascular remodeling in Hypertension

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