Pre-synaptic NO-cGMP pathway modulates vagal control of heart rate in isolated adult guinea pig atria.

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.

Herring N ，Golding S ，Paterson DJ 《JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY》

Comparison of two soluble guanylyl cyclase inhibitors, methylene blue and ODQ, on sodium nitroprusside-induced relaxation in guinea-pig trachea.

Hwang TL ，Wu CC ，Teng CM 《BRITISH JOURNAL OF PHARMACOLOGY》

Peripheral vagal control of heart rate is impaired in neuronal NOS knockout mice.

Choate JK ，Danson EJ ，Morris JF ，Paterson DJ ... -  《AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY》

Nitric oxide-cGMP pathway facilitates acetylcholine release and bradycardia during vagal nerve stimulation in the guinea-pig in vitro.

Herring N ，Paterson DJ 《-》

Celecoxib dilates guinea-pig coronaries and rat aortic rings and amplifies NO/cGMP signaling by PDE5 inhibition.

Klein T ，Eltze M ，Grebe T ，Hatzelmann A ，Kömhoff M ... -  《CARDIOVASCULAR RESEARCH》