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, g uanylyl cyclase (GC) dependent pathway. The effects of inhibiting NO syntha se (NOS) and GC were evaluated in isolated atrial/right vagal nerve prepara tions From adult (550-750 g) and young (150-250 g) female guinea pigs. Leve ls 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 muM, n = 5) significantly reduced the negative chronotropic respons e to vagal nerve stimulation (VNS) at 3 and 5 Hz in the adult guinea pig. T his effect was reversed with 1 mM L-arginine. Similar results were observed with the specific neuronal NOS inhibitor vinyl-N5-(1-imino-3-butenyl)-L-or nithine (L-VNIO, 100 muM, n = 7). Inhibition of GC with 1H-(1,2,4)-oxadiazo lo-(4,3-a)-quinoxalin-1-one (ODQ, 10 muM, n = 7) also significantly reduced the negative chronotropic response to VNS at 3 and 5 Hz in adult guinea pi gs. Neither L-NA (n = 6), L-VNIO (n = 5) nor ODQ (n = 6) changed the HR res ponse to cumulative doses of carbamylcholine in adult guinea pig atria sugg esting that the action of NO is pre-synaptic. The IIR response to VNS was u naffected by L-NA (n = 7) or ODQ (n = 7) in young guinea pigs and Western b lot analysis showed significantly lower levels of nNOS protein in right atr ia from young animals. These results suggest a pre-synaptic NO-cGMP pathway modulates cardiac cholinergic transmission, although this may depend on th e developmental stage of the guinea pig. (C) 2000 Academic Press.