CVS Physiology Lecture # 11 Study Notes: Autoregulation – Nitric Oxide

Nitric Oxide is called an endothelium derived relaxing factor (EDRF) as it is released by the endothelium of the blood vessel. EDRF cause relaxation of the vascular smooth muscle, and as a result cause vasodilation of the blood vessel. The following factors contribute to the release of nitric oxide from the endothelium:

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1. Blood travelling at high velocity causes a shearing effect on the wall of the blood vessels. As the endothelial cells endure a drag force produced due to friction. This results in a mechanical trigger which stimulates release of nitric oxide.
2. Vasoactive Amines are chemical mediators that mediate the release of nitric oxide.
3. The endothelium possesses Histamine H1 receptors that also take part in nitric oxide release.
4. Prostacyclins are also said to be responsible for the release of nitric oxide.

Mechanism of Action of Nitric Oxide

Nitric oxide, when released, triggers the soluble guanylate cyclase to convert cGTP to cGMP. The increased levels of cGMP cause activation of cGMP dependent kinases which activate the enzyme Myosin Light Chain Phosphatase (MLCP). The activated MLCP enzyme in turn dephosphorylates myosin light chains which results in relaxation of the contractile apparatus. As a result, the vessels become dilated.

Atherosclerosis is the formation of fibromuscular plaques on the endothelium lining of the blood vessel. These atherosclerotic plaques render the endothelium non functional. The endothelium is therefore unable to produce sufficient amounts of nitric oxide. Consequently, the levels of cGMP reduce as less cGTP is converted to cGMP. This reduction in cGMP levels in turn leads to increased levels of Myosin Light Chain Kinases (MLCK) which are enzymes with activity opposite to that of MLCP. The contractile apparatus is activated as MLCK causes cross bridging of actins and myosin heads. The tension produced within the vascular smooth muscle as a result of the vascular smooth muscle contraction in turn causes vasoconstriction of the blood vessel.

Angiotensin II receptors are present on both the vessel endothelium and also the smooth muscle surrounding the blood vessel. Depending on the receptor activated, Angiotensin II can have vasodilating or vasoconstricting effects. At times these opposing effects are balanced out and one effect compensates for the other.   

• The vasoconstricting activity of Angiotensin II is mediated via two pathways. If Angiotensin II binds to the Gq-coupled receptors on the vascular smooth muscle, it will cause direct deactivation of MLCP enzyme. It also causes the production of IP3 which enables the release of calcium ions from the sarcoplasmic reticulum. The calcium ions activate MLCK. The activation of MLCK and inactivation of MLCP results in contraction of the smooth muscles surrounding the blood vessel. This is the vasoconstricting effect.
• The vasodilating effect of Angiotensin II occurs simultaneously to mitigate the vasoconstricting effects to some extent. This effect is mediated by binding of the Angiotensin II to its receptor on the vascular endothelium. This activation of endothelial Angiotensin II receptor cause active release of nitric oxide from the endothelium. This NO diffuses into the vascular smooth muscle and stimulates the activity of guanylate cyclase enzyme which converts cGTP to cGMP. The increases cGMP levels cause activation of the MLCP enzyme. The activated MLCP enzyme in turn dephosphorylates myosin light chains, which results in relaxation of the contractile apparatus of the blood vessel. As a result, the vessels become dilated.

Sildenafil (Viagra) is a drug that is used to treat erectile dysfunction. It is a Phosphodiesterase-5 (PDE-5) inhibitor. PDE-5 is an enzyme that binds to and cleaves cGMP. As a result, the half life of cGMP is reduced as its levels fall. Sildenafil acts by binding to PDE-5 and antagonizes its function. As a result, the cGMP levels remain high for a longer period of time. Therefore, the penile vasculature remains dilated and engorged with blood and, hence, erection is maintained.