title: Nitric oxide and ventilatory response to hypoxia.
abstract: It is believed that hypoxia results in the release of neurotransmitters in the central nervous system, which can excite or inhibit breathing. Recent evidence indicates that nitric oxide (NO) is a physiological messenger molecule that may serve as a neurotransmitter in the CNS. In this study we examined (1) the localization of nitric oxide synthase (NOS) within the nucleus tractus solitarius, and (2) the role of the NO-cGMP pathway in the respiratory response to oxygen deprivation. Nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry was used to determine the distribution of neurons that express NOS, an enzyme involved in NO formation. The NOS inhibitor N omega-nitro-L-arginine was used as tool to assess the NOS activity in the medulla, and to define the role of NO in the respiratory response to acute oxygen deprivation. In the rat and the cat brainstem, histochemical studies showed the presence of NADPH-diaphorase reactive neurons within subnuclei of the nucleus tractus solitarius which receive peripheral chemoreceptor inputs. Chronic pretreatment of rats with N omega-nitro-L-arginine (75 mg/kg, ip, twice daily for 7 days) caused a significant decrease in cGMP, and attenuated the ventilatory response to hypoxia. In anesthetized, paralyzed, vagotomized and artificially ventilated cats with intact carotid sinus nerves (n = 8), administration of N omega-nitro-L-arginine (30-100 mg/kg) attenuated the response to hypoxia, and caused the hypoxia induced roll-off of phrenic nerve activity to occur significantly earlier than when NOS activity was not inhibited. In sinoaortic denervated cats (n=9) blockage of NOS potentiated the decline of the phrenic nerve output. The data suggest that oxygen deprivation leads to activation of NO-cGMP pathway in the central nervous system, which contributes to the induction and maintenance of hypoxia-induced increase in respiratory output. In addition, these findings indicate that NO may inhibit inhibitory synaptic transmission that is triggered by CNS hypoxia, and this is not directly related to peripheral chemoreceptor inputs.
authors.affiliation: Department of Medicine, School of Medicine Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Haxhiu
authors.forename: C H
authors.initials: CH
authors.lastname: Chang
authors.forename: I A
authors.initials: IA
authors.lastname: Dreshaj
authors.forename: B
authors.initials: B
authors.lastname: Erokwu
authors.forename: N R
authors.initials: NR
authors.lastname: Prabhakar
authors.forename: N S
authors.initials: NS
authors.lastname: Cherniack
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002344:Carotid Body / Q000502:physiology; D002415:Cats; D006152:Cyclic GMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008526:Medulla Oblongata / Q000201:enzymology; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019335:Nitroarginine; D010100:Oxygen / Q000502:physiology; D010313:Partial Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000502:physiology; D017552:Solitary Nucleus / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D009252:NADPH Dehydrogenase; D006152:Cyclic GMP; D010100:Oxygen