Nitric Oxide Flashcards

Question

Effects fo NO in platelets

Answer 1

Conflicting evidence for/against role of NO Decr platelet adhesion/aggregation/thrombus formation in vitro - Limits thrombus formation in Vivo? Hb prevents endothelial-derived NO from affecting platelet function under physiological conditions NO biosynthesis within platelets as autocrine agent? Increased nitroprusside or GTN required to alter platelet function? Addition of GTN to standard therapy does not improve mortality in patients with acute coronary thrombosis?

Answer 2

• non-specific host defence and cytotoxicity against numerous pathogens and tumour cells – excess ONOO- or NO can damage host tissues by nitration and nitrosylation • neuromodulator (and neurotransmitter) in peripheral nervous system • physiological role in central nervous system (memory, pain, sleep, appetite)

Answer 3

Protects from excessive bronchoconstriction Neurotransmission Memory and learning Cerebral blood flow Gastric mucosal blood flow Cutaneous blood flow Peristalsis, intestinal secretion Non-specific host defence Skin barrier function Cardioprotection Cell survival

Answer 4

=detrimental effects.. exacerbates Respiratory inflammation Neurodegenrative disorders Psychiatric disease Epilepsy and Brain injury Inflammatory bowel disease Inflammatory skin disorders Heart failure Apoptosis

Answer 5

• cells producing NO from cNOS – ↑ Ca2+ also inhibits GC – cells producing NO have limited capacity to respond? • cells producing NO from iNOS – ↑↑ levels of GSH than cells not producing NO • ↑Antioxidant enzyme activity – ↑expression of SOD (↓ superoxide, ↓ peroxynitrite), catalase and glutathione peroxidase • expression of NOS-associated protein NAP110 – inhibits catalytic activity of iNOS in macrophages

Answer 6

Excessive NO production Enhanced iNOS activity/benefit of iNOS inhibitors Neurological, bronchopulmonary diseases, tumourgenesis, ischaemia-reperfusion, sepsis, arthritis, inflammatory bowel

Answer 7

• endothelial NO biosynthesis impaired in disorders predisposing to atheroma (hypercholesteraemia, diabetes) – cause or effect? – impaired L-arginine transport into endothelium? – ↓ BH4/dysfunctional uncoupled eNOS produces O2- rather than NO? • NO deficiency contributes to hypertension, PAH, local vasospasm in variant angina, sub-arachnoid haemorrhage, pre-eclampsia – requirement for strategies to preserve/maintain NO signalling (eNOS gene transfer, L-arginine supplements?)

Answer 8

• Anti-atherogenic: excess NO terminates lipid peroxidation by interaction with LipidOO- to form non- radical stable end product LipidOONO • Pro-atherogenic: excess superoxide binds NO to form toxic peroxynitrite ONOO- – Oxidised LDL stimulates NADPH oxidase generating superoxide in blood vessel wall – ONOO- can damage BH4 and ‘uncouple’ eNOS antioxidants reduce O2- (and ONOO-) and spare NO

Answer 9

-elevation of NO levels Inhaled NO, precursors of synthesis (L-arginine), NH4 supplementation to decouple eNOS, NO donors -reduction of NO levels NO scavengers (Hb) NOS inhibitors (L-NNA, L-NAME, L-NMMA) Problem lack of selectivity for individual NOS isoforms

Answer 10

• nitric oxide (EDRF) - paracrine mediator – ↓vascular tone, cardiac contraction, platelet aggregation • impaired production of NO in man – ↑ hypertension, atherosclerosis • L-NAME (NOS inhibitor) given in drinking water – incr BP, incr LVH, myocardial ischemia and oxidative stress – incr cardiac, renal function • non-surgical, technically easy to perform, low mortality • relevance of experimental model? (insufficient data)

Answer 11

• Inhibitors of NO biosynthesis (L-NMMA) beneficial (depending on dose) in patients with hypotension from multiple organ failure secondary to sepsis • iNOS-specific inhibitors or gene therapies tospare constitutive NOS activity/physiological effects of NO?

Answer 12

• NO donors (nitroprusside, organic vasodilators) in angina (and severe hypertension, acute heart failure) – spontaneous or enzyme-associated release of NO (mitochondrial aldehyde dehydrogenase, mtADH?) • Inhaled NO in adult respiratory distress syndrome, acute right heart failure, neonatal PAH?

Answer 13

Esterases • NO-NSAID derivatives – Protect against NSAID-induced GI toxicity – Maintain mucus, bicarbonate barrier, promote gastric capillary blood flow, enhance ulcer healing – Retain anti-inflammatory, anti-pyretic, analgesic actions • NO donating drugs (NODDs) – NO-paracetamol, NO-prednisolone, NO-mesalamine – Nicorandil (NO donor and K+ATP channel opener, angina) – Nitrosylated analogs of a-adrenoceptor antagonists • Treatment of erectile dysfunction • Target similar signalling pathway to Viagra • Additive benefit derived from antagonist + NO – Nipradilol (NO donor and b-adrenoceptor antagonist) – NO-statins currently in development

Nitric Oxide Flashcards

(37 cards)