PM 719 Pharmacology II - Chapter 19 Nitric Oxide Lecture Notes

PM 719 Pharmacology II Lecture Notes (LN) Chapter 19 Nitric Oxide The role of nitric oxide (NO) in the human body is one of the most interesting discoveries in modern medicine. It won the Nobel Prize in Medicine for the three persons who discovered it. But, first, the terms to prevent confusion:...

PM 719 Pharmacology II Lecture Notes (LN) Chapter 19 Nitric Oxide The role of nitric oxide (NO) in the human body is one of the most interesting discoveries in modern medicine. It won the Nobel Prize in Medicine for the three persons who discovered it. But, first, the terms to prevent confusion: nitric oxide NO gaseous signaling molecule the topic of this Chap 19 nitrous oxide N~2~O a gas anesthetic nitrogen dioxide NO~2~ a toxic pulmonary gas NO is synthesized within a wide range of different cells and activates specific intracellular signaling pathways. The observations that led to the discovery of the role of NO include: \(a) macrophages treated with bacterial endotoxin produced NO metabolites (nitrate and nitrite) \(b) Ach relaxes blood vessels and leads to the generation of endothelial-derived relaxing factor (EDRF). The nature of EDRF was unknown. \(c) Administration of NO gas to cells in culture induced vasorelaxation. \(d) NO was found to be the major biological component of EDRF. **NO Synthesis:** Three different isoforms of **nitric oxide synthase (NOS**), the enzyme that produces NO in tissues are listed below: neuronal NOS nNOS or NOS-1 macrophage inducible NOS iNOS or NOS-2 endothelial NOS eNOS or NOS-3 L-arginine NOS nitric oxide (NO) iNOS, the inducible form means it is turned on by injury, inflammation etc. NO is a molecule with an unpaired electron in its structure which makes it very reactive. **Targets of NO:** The cell components that NO binds to and what happens **Metalloproteins** (proteins with a metal in its structure): NO interacts with the metal in a wide range of proteins, all called metalloproteins, among which are: the iron in hemoglobin the iron in guanyl cyclase which becomes activated to make cGMP which leads to vascular relaxation. **Thiols** (the sulfa molecules in many proteins): NO binds to sulfa (-SH) and forms nitrosothiols. This nitrosothiols in proteins can lead to protein inactivation. This reaction of NO with -SH in vascular glutathione leads to decreased glutathione activity (a major problem, diabetics have reduced glutathione and higher rates of cardiac complications compared to non-diabetics). **Tyrosine Nitration**: NO synthesis is increased in numerous inflammatory and in degenerative disease conditions. NO can lead to peroxynitrite levels which interact with tyrosine on proteins. Protein inhibition or activation can result from this. **NO Inactivation** can occur through numerous pathways including NO + O~2~ nitrogen dioxide **Drug Inhibitors of Nitric Oxide Synthesis:** Inhibitors of the enzyme nitric oxide synthase (NOS) No drugs yet, many in development. **Drugs That Promote NO Production:** Used to increase NO levels and promote smooth muscle relaxation. \(1) Organic Nitrates **nitroglycerin, isosorbide dinitrate** **Nitroglycerin** converted into NO by enzymes in the cell walls, venous smooth muscle relaxation. Used to treat angina. **Isosorbide dinitrate** generates NO after taken PO or used as a spray topical. Used by podiatrists to promote better blood flow in legs. \(2) Organic Nitrites **amyl nitrite** Is converted into NO, used as an inhalant, abused as "poppers". \(3) Sodium Nitroprusside **Sodium Nitroprusside** Used to treat severe hypertension. Generates NO, covered in the hypertension chapter. Drug dilates arterioles and venules. \(4) NO Gas Inhalation **NO Gas** Reduces pulmonary artery pressure and improved perfusion of ventilated areas of the lung. Gas drug used to treat pulmonary hypertension. **Nitric Oxide in Disease:** Vascular Effects Acts as a major vasodilator and controller of blood pressure (BP) NO also inhibits platelet aggregation NO also acts as an antioxidant, protecting from free radical active compounds And many many more effects (good and bad, but mostly good). Septic Shock Endotoxins produced by bacteria induce iNOS to produce high levels of NO. This massive excess production of NO can lead to extensive vasodilation, lowered BP up to hypotensive crisis and death. Infection & Inflammation Infection and injury can induce iNOS in white cells and other cells. This can lead to a stimulation of the beneficial immune response, but, excess NO can lead to exacerbation of cell injury. **The CNS:** In the CNS NO acts as a neurotransmitter. NO appears to act as a presynaptic neurotransmitter, this results in enhancing neurotransmitter release (increasing neurotransmitter levels) **The PNS:** Nonadrenergic, noncholinergics receptors are widely distributed in the PNS many of **Respiratory Disorders:** NO as a gas inhalant has been covered above and is used to treat pulmonary The Required Drugs are in **Bold below and in the above Lecture Note** These drugs promote the production of NO which leads to vasodilation. These drugs have been covered above and in previous chapters and all are required. **nitric oxide (NO)** **nitroglycerin** **isosorbide dinitrate** **amyl nitrate** **sodium nitroprusside**