title: Pre-synaptic NO-cGMP pathway modulates vagal control of heart rate in isolated adult guinea pig atria.
abstract: The role of nitric oxide (NO) in the vagal modulation of heart rate (HR) is controversial. We tested the hypothesis that NO acts via a pre-synaptic, guanylyl cyclase (GC) dependent pathway. The effects of inhibiting NO synthase (NOS) and GC were evaluated in isolated atrial/right vagal nerve preparations from adult (550-750 g) and young (150-250 g) female guinea pigs. Levels of NOS protein were quantified in right atria using Western blotting and densitometry. The non-specific NOS inhibitor N- omega -nitro- L -arginine (L -NA, 100 microM, n=5) significantly reduced the negative chronotropic response to vagal nerve stimulation (VNS) at 3 and 5 Hz in the adult guinea pig. This effect was reversed with 1 m ML -arginine. Similar results were observed with the specific neuronal NOS inhibitor vinyl-N5-(1-imino-3-butenyl)- L -ornithine (L -VNIO, 100 microM, n=7). Inhibition of GC with 1H-(1,2,4)-oxadiazolo-(4, 3-a)-quinoxalin-1-one (ODQ, 10 microM, n=7) also significantly reduced the negative chronotropic response to VNS at 3 and 5 Hz in adult guinea pigs. Neither L -NA (n=6), L -VNIO (n=5) nor ODQ (n=6) changed the HR response to cumulative doses of carbamylcholine in adult guinea pig atria suggesting that the action of NO is pre-synaptic. The HR response to VNS was unaffected by L -NA (n=7) or ODQ (n=7) in young guinea pigs and Western blot analysis showed significantly lower levels of nNOS protein in right atria from young animals. These results suggest a pre-synaptic NO-cGMP pathway modulates cardiac cholinergic transmission, although this may depend on the developmental stage of the guinea pig.
authors.affiliation: University Laboratory of Physiology, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
authors.forename: N
authors.initials: N
authors.lastname: Herring
authors.forename: S
authors.initials: S
authors.lastname: Golding
authors.forename: D J
authors.initials: DJ
authors.lastname: Paterson
mesh_terms: D000367:Age Factors; D000818:Animals; D001016:Aortic Bodies / Q000187:drug effects* / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology; D015153:Blotting, Western; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D004064:Digestive System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D016548:Prosencephalon / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; C111862:N(5)-(1-imino-3-butenyl)ornithine; D010069:Oxadiazoles; D011810:Quinoxalines; D019335:Nitroarginine; D009569:Nitric Oxide; D002217:Carbachol; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP