Blockade of nitrergic neuroeffector transmission in guinea-pig colon by a selective inhibitor of soluble guanylyl cyclase.
The role of soluble guanylyl cyclase in nitrergic inhibitory neuroeffector transmission was investigated in the longitudinal muscle from guinea-pig colon, by using an inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ). In preparations precontracted with histamine, electrical field stimulation (EFS) or exogenous nitric oxide (NO) induced relaxations. The relaxation induced by NO-application was abolished by ODQ. Both ODQ and the NO-synthase inhibitor N omega-nitro-L-arginine (L-NOARG) partially inhibited the EFS-evoked relaxation to a similar extent. These effects were dose-dependent. The inhibition was more pronounced in the late phase of the EFS-induced relaxation. The inhibitory effect of ODQ on EFS-induced relaxation was not affected by additional application of L-NOARG. When NO-formation was blocked by L-NOARG, a subsequent addition of ODQ gave no further inhibition of the relaxation. These findings suggest that inhibitory non-adrenergic, non-cholinergic neurotransmission in guinea-pig colon is dependent on endogenous formation of NO, and that the NO-effect is exclusively mediated via the soluble guanylyl cyclase pathway. The existence of an NO-independent inhibitory transmission, which is not mediated through the cyclic GMP pathway, is also indicated. Furthermore, it is demonstrated that the NO/soluble guanylyl cyclase-independent transmission has an earlier onset as compared with the NO/soluble guanylyl cyclase-dependent pathway.
Olgart
C
C
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Hallén
K
K
Wiklund
N P
NP
Iversen
H H
HH
Gustafsson
L E
LE
D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D010069:Oxadiazoles / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D012995:Solubility; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D009569:Nitric Oxide; D006162:Guanylate Cyclase