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Supplementary Notes

Supplementary Notes - 20:01 Vascular tone is sum of...

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Vascular Endothelium and Nitric Oxide 20:01 Vascular tone is sum of simultaneous dilating and constictor effects What is going on in vessel-sum of neuronal and hormonal inputs=tone Shear stress, histamine, Ach, Bradykinin, Purigenics activates NO production Vasopressin influences amount of volume that is circulating Epi depending on receptors, cause constriction or dilation Consider complicated system change=feedback that tries to return system to normal. Drugs try to alter this. Some hormones simultaneously produce dilation via enhancing NO production and constriction via direct effects on smooth muscle Direct vs indirect effects Endothelial=important hormone receptors; Make a lot of NO; use a lot of O2; metabolically active! We learned w/ experiments lacking endothelial cells o Nature 1980 Discovery of EDRF Strips of vascular muscle add something to constrict (NE at alpha receptors) and something to relax them. Wash out and do again and again. NE at alpha 1 on smooth muscle causes constriction Gq mobilization of Ca contraction in any kind of muscle Added Ach=no relaxation. Some muscles he got contraction. Added less NE=partial contraction. Cuz tech rubbed away intimal lining=endothelial cells. In absense of ento, relaxant hormone Ach does not cause relaxation but contraction. Therefore, endothelium producing endothelium relaxant factor, later identified as NO. Classical experiment Took organ back of intact intimal lining and added Ach transferred fluid to other cells blocked off cholinergic receptor and still got relaxation=EDRF=NO Endothelial cell produces NO in response to certain hormones NO Diffusible messenger, made by endo cells, made on demand via Gq-PLC-Ca-CaM activation of NOS (isoforms 1 and 3) Endothelial cell has many specializations has nitric oxide synthase, a calcium sensitive calmodulin NO synthesis and Action Arginine + cofactors citrulline, whats left over is NO
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NOS inhibitors: L-NMMA NO Binds to heme groups hemoglobin from RBCs, also from soluble enzyme guanylyl cyclase (GTP cGMP). cGMP very similar to camp, causes vasodilation, inhibits platelet aggregation, and NOS (enzyme itself) 3 major Isoforms of NOS 1, 2, 3 chart 1,3 are calcium calmodulin sensitive 2 not present until inflammatory process occurs (interleukins, etc…) NO binding to G Cyclase stimulates Cyclic GMP synthesis NO + guanylyl cyclase increased cGMP + ?? Consequences of NO generation and cyclic GMP elevation in smooth muscle Inhibition of myosin light chain kinase by PKA and PKG. increased camp/cGMP activates PKG Activation of myosin light chain phosphatase Accelerated ca removal from cytosol Hyperpolarization of cell mb Smooth muscle contraction Ca + CaM. MLCK combines with them, is activated and causes myosin to be phosphorylated on their light chains. This form of myosin will combine well with actin. Myosin+ actin produces contraction
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