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K 305

2 June 03

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Vascular Smooth Muscle Cells

• Endothelium

• Neural

• Other Tissues

• Intrinsic Factors

Regulation of Flow (Q)

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Vascular Smooth Muscle Cells

• Endothelium

• Neural

• Other Tissues

• Intrinsic Factors

Regulation of Flow (Q)

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Vascular Smooth Muscle Cells

• Endothelium

• Nitric Oxide

• Endothelin

• EDRF

Regulation of Flow (Q)

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Nitric Oxide•NO (EDRF) synthesized in endothelial cells by NOS

•NOS stimulated by elevated [Ca2+]i

•NOS converts arginine to NO

•NO freely permeates out of endothelial cell into VSM

•In VSM stimulates guanylyl cyclase increasing cGMP

• cGMP activates PKG which stimulates:

•SERCA (through phospholamban) and PMCA

• Reduces [Ca2+]i - relaxation - VASODILATION

• vasodilator drugs nitroglycerin and nitroprusside

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Nitric Oxide – Ca2+ independent•Activates GC in VSM to stimulate PKG

•PKG prevents Rho A from being activated

•Prevents inhibition of MLC Phosphatase

•Dephosporylates MLK

•Induces relaxation in VSM - VASODILATION

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Vascular Smooth Muscle Contraction

Receptor Activation

Ca2+/calmodulin

MLCK (active)

MLC (contracted)

MLC (relaxed)

P

IP3 PKC

myosin phosphatase (active)

phospholipase C/ heterotrimeric G-protein

Rho-kinase

myosin phosphatase (inactive)

ATP

• Ca2+ dependent activation Ca2+/calmodulin activation of MLCK • Ca2+ independent activation Inhibition of myosin phosphatase by Rho-kinase

(small G-protein)RhoA GDP

RhoA GTPGTP

P

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RhoA-GDP (inactive)RhoA-GTP

(active)

guanylate cyclase

cGMPcG-kinase

Vascular smooth muscle cell

Endothelial cell

xanthine oxidaseNADPH oxidaseuncoupled eNOS

Rho-kinase ATP

contraction

Superoxide activates RhoA

Nitric oxide inhibits the migration of RhoA

O2

NO

relaxation

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Vascular Smooth Muscle Cells

• Endothelium

• Nitric Oxide

• Endothelin

• EDRF

Regulation of Flow (Q)

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Vascular Smooth Muscle Cells

• Endothelium

• Neural

• Other Tissues

• Intrinsic Factors

Regulation of Flow (Q)

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Vascular Smooth Muscle Cells• Neural

• NA – adrenergic receptor

• NA – adrenergic receptor

• ACh – muscarinic receptor

Regulation of Flow (Q)

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Vascular Smooth Muscle Cells

• Endothelium

• Neural

• Other Tissues

• Intrinsic Factors

Regulation of Flow (Q)