{"id":689,"date":"2020-02-17T20:47:21","date_gmt":"2020-02-17T15:17:21","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=689"},"modified":"2020-02-17T20:47:21","modified_gmt":"2020-02-17T15:17:21","slug":"nitric-oxide-and-drugs","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/nitric-oxide-and-drugs\/","title":{"rendered":"Nitric oxide and Drugs"},"content":{"rendered":"\n<p><strong>Nitric oxide<\/strong><\/p>\n\n\n\n<ul><li>It is one of the oxides of nitrogen with molecular formula NO indicating that it is a <strong>free radical <\/strong>with an unpaired electron.<\/li><li>smallest endogenous <strong>signal molecule<\/strong> and the only one which is a <strong>gas <\/strong>at normal temperature.<\/li><li><strong>Furchgott and Zwadzki<\/strong> ( 1980) demonstrated that <strong>ACh caused vascular smooth muscle relaxation only when the endothelial lining was intact,<\/strong> but not when it was denuded by rubbing.<\/li><li>They proposed that on activation by ACh, the endothelial cells released a soluble <strong>&#8216;endothelium derived relaxing factor&#8217; (EDRF)<\/strong> which diffused to the underlying smooth muscle cell causing relaxation.<\/li><li>A little earlier Farid Murad ( 1977) had already shown that GTN caused vasodilatation by releasing N0.<\/li><li>lgnarro in 1987 confirmed that EDRF infact was NO. All three, <strong>Furchgott, Murad and lgnarro received Nobel Prize in 1998 for these discoveries.<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Generation and fate of NO:<\/strong><\/p>\n\n\n\n<ul><li>Nitric oxide is produced in the cells from the <strong>amino acid L-arginine<\/strong> by the <strong>enzyme nitric oxide synthase (NOS<\/strong>) using molecular oxygen and <strong>NADPH, FAD, haeme act as coenzyme to NOS.<\/strong><\/li><li><strong>Three isoforms of NOS, viz<\/strong>.<\/li><li><strong>neuronal NOS<\/strong> (nNOS or NOS- I ),<\/li><li><strong>inducible NOS<\/strong> (iNOS or NOS-2) and (found in macrophages, monocytes, neutrophils, hepatocytes, etc. is induced by bacterial endotoxins, cytokines and TNFa)<\/li><li><strong>endothelial NOS<\/strong> (eNOS or NOS-3).<\/li><li>Activation of eNOS and nNOS is Ca2+-calmodulin dependent.<\/li><li>Agents and mediators activate eNOS\/nNOS by raising cytosolic Ca2+.<\/li><li>In contrast, iNOS is active as such, and not Ca2+ dependent.<\/li><\/ul>\n\n\n\n<p><strong>Actions and roles of NO<\/strong><\/p>\n\n\n\n<p><strong>Vascular system:<\/strong><\/p>\n\n\n\n<ul><li>Potent vasodilator and serves to regulate vascular tone.<\/li><li>Produced in the endothelium<\/li><li>freely diffuses to the nearby smooth muscle cell and<\/li><li>activates a soluble guanylyl cyclase (sGC) raising cytosolic cGMP concentration<\/li><li>This in turn activates a cGMP-dependent protein kinase (PKG) which dephosphorylates the myosin light chain kinase (MLCK) \u00e0 reduced availability of phosphorylated (active) MLCK<\/li><li>actin-myosin interaction is interfered<\/li><li>resulting in muscle relaxation.<\/li><li>Bronchial, gastrointestinal and other visceral smooth muscles are also relaxed by NO, but the effect is less marked than in blood vessels<\/li><\/ul>\n\n\n\n<p><strong>Platelets:<\/strong><\/p>\n\n\n\n<ul><li>Just as in smooth muscle, NO activates the cGMP pathway in platelets to <strong>inhibit aggregation and thrombus formation.<\/strong><\/li><li>Defective endothelial and platelet NOS-NO function increases the risk of thrombosis.<\/li><li>NO also has <strong>antiatherogenic property<\/strong>.<\/li><li>Adhesion of leucocytes to the endothelium and cellular proIiferation\/migration are suppressed by NO, conferring it a <strong>protective effect on plaque formation<\/strong>.<\/li><\/ul>\n\n\n\n<p><strong>Infection, inflammation and immune function:<\/strong><\/p>\n\n\n\n<ul><li>Normally the iNOS activity in macrophages, etc. is very low.<\/li><li>Bacterial endotoxins, TNFa, interferon and interleukins induce iNOS in macrophages and other inflammatory cells \u00e0 generate large quantities of NO.<\/li><li>Activated macrophages also produce superoxides that combine with NO \u00e0 decomposes to release free radicals \u00e0 broad antimicrobiaI action on bacteria, viruses, fungi and protozoa.<\/li><li>Thus, N0 <strong>helps in combating infection.<\/strong><\/li><li>N0 has many <strong>proinflammatory actions, viz. vasodilatation, increased vascular permeability and enhanced PG production<\/strong>.<\/li><li>excess and prolonged NO production \u00e0 detrimental consequences \u00e0 tissue injury.<\/li><li>Excessive production of NO has been implicated in causing severe hypotension attending septic shock<\/li><\/ul>\n\n\n\n<p><strong>Nervous system:<\/strong><\/p>\n\n\n\n<ul><li>NO serves as neurotransmitter\/ neuromodulator in central as well as in peripheral nervous system.<\/li><li>Activation of NMDA glutamate receptors causes long-lasting Ca2+ influx triggering NO release<\/li><li>Function <strong>\u00e0 nociception, increased cerebral blood flow, learning and memory.<\/strong><\/li><li>NO is believed to mediate <strong>&#8216;synaptic plasticity<\/strong> &#8216; a process by which junctional transmission is strengthened in a use dependent manner.<\/li><li>Excessive production of NO has been implicated in <strong>promoting &#8216;excitotoxicity&#8217;<\/strong> due to over- stimulation of glutamate neurones.<\/li><li><strong>Aberrant NO generation<\/strong> \u00e0 causative role in <strong>degenerative neurological diseases like Huntington &#8216;s disease, Parkinson\u2019s disease, amyotrophic lateral sclerosis<\/strong>, etc.<\/li><li>pelvic nerve stimulation causes <strong>penile erection<\/strong> by releasing NO from neurones in the corpora cavernosa.<\/li><li>NO relaxes cavernosal smooth muscle, filling the sinusoids with blood and causing penile tumescence<\/li><li>Accordingly, sildenafil and other PDE-5 inhibitors are effective in the treatment of erectile dysfunction, because they inhibit degradation of cGMP which mediates NO action.<\/li><li><strong>Defective NO signaling<\/strong> is believed to be involved in <strong>pyloric stenosis and gastric dilatation.<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Lungs:<\/strong><\/p>\n\n\n\n<ul><li>NO appears to play a prominent role in the regulation of pulmonary vascular resistance and the development of pulmonary arterial hypertension (PAH)<\/li><li>Sildenafil \u00e0 indirectly potentiates the vasodilator action of NO by preventing inactivation of cGMP<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"343\" height=\"157\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-259.png?w=343\" alt=\"\" class=\"wp-image-712\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-259.png 343w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-259-300x137.png 300w\" sizes=\"(max-width: 343px) 100vw, 343px\" \/><\/figure>\n\n\n\n<p><strong>Nitric oxide donors<\/strong><\/p>\n\n\n\n<p>These are compounds which contain a NO or similar moiety in their structure, that is released in the body, mostly enzymatically, to elicit smooth muscle relaxation.<\/p>\n\n\n\n<ul><li><strong>Organic nitrates, nitrites and sodium nitroprusside<\/strong> are the clinically useful NO donors. They are also called &nbsp;&nbsp;&nbsp;&nbsp;<strong>&#8216;nitro-dilators&#8217;.<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Glyceryl trinitrate (GTN):<\/strong><\/p>\n\n\n\n<ul><li>rapidly acting \u00e0 antianginal drug \u00e0 mainly dilates veins and coronary arteries.<\/li><li>Mitochondrial aldehyde dehydrogenase is the most important enzyme which releases NO from GTN.<\/li><li>This enzyme is abundantly expressed in veins, offering an explanation for the preferential venodilator action of GTN.<\/li><\/ul>\n\n\n\n<p><strong>Isosorbide dinitrate and lsosorbide mononitrate<\/strong><\/p>\n\n\n\n<ul><li>slower acting, but the pattern of action is similar to GTN .<\/li><li>When administered continuously\u00e0 developing tolerance (within few hours), which also weans off rapidly.<\/li><\/ul>\n\n\n\n<p>\u00e0 reactive oxygen species generated during metabolism of organic nitrates inhibit mitochondrial aldehyde &nbsp;dehydrogenase and other enzymes which produce the NO species, limiting further action.<\/p>\n\n\n\n<p><strong>Sodium nitroprusside:<\/strong><\/p>\n\n\n\n<ul><li>Administered by i.v. infusion, nitroprusside equally dilates arterioles and veins by releasing NO as well as by directly activating guanylyl cyclase.<\/li><li>Rapidly lowers BP and the action is titratable.<\/li><\/ul>\n\n\n\n<p><strong>Nitic oxide as a therapeutic agent<\/strong>:<\/p>\n\n\n\n<ul><li>Apart from being an important signal molecule. exogenously administered N0 gas has limited therapeutic application as well.<\/li><li><strong>Inhaled NO <\/strong><strong>\u00e0 indicated in severe respiratory distress in neonates with elevated pulmonary arterial pressure.<\/strong><\/li><li>It dilates pulmonary vessels, particularly in areas of the lung that are better ventilated, reducing the ventilation-perfusion mismatch and improving gaseous exchange.<\/li><li>The elevated pulmonary artery pressure is lowered and cardiopulmonary function is improved.<\/li><li>Inhaled NO <strong>improves cardiopulmonary function in adult patients as well with severe PAH<\/strong>, but this can only be a short-term measure.<\/li><\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Nitric oxide It is one of the oxides of nitrogen with molecular formula NO indicating that it is a free radical with an unpaired electron. smallest endogenous signal molecule and the only one which is a gas at normal temperature. Furchgott and Zwadzki ( 1980) demonstrated that ACh caused vascular smooth muscle relaxation only when[&#8230;]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/689"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=689"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/689\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=689"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=689"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=689"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}