Nitrergic-purinergic interactions in rat distal colon motility.
Responses of rat distal colon circular muscle strips to exogenous nitric oxide (NO) and adenosine 5'-triphosphate (ATP) and to electrical field stimulation (EFS) were assessed in the absence/presence of various agents that interfere with nitrergic-purinergic pathways. Exogenous NO (10-6 to 10-4 mol L-1) elicited concentration-dependent, tetrodotoxin (TTX)-insensitive relaxations. The soluble guanylyl-cyclase (sGC) inhibitor 1H[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced duration and amplitude; the small conductance Ca2+-sensitive K+ (SK)-channel blocker apamin (APA) only shortened the relaxations. ODQ + APA showed a marked inhibitory effect on duration and amplitude. TTX, APA, the NO-synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) and the purinergic receptor P2Y antagonist Reactive Blue 2 (RB2) shortened the relaxations by exogenous ATP (10-3 mol L-1) but did not influence the amplitude. ODQ had no effect. TTX + l-NAME did not yield a more pronounced inhibitory effect than TTX alone. The effect of ATP-gamma-S was similar to that of ATP. Electrical field stimulation (EFS) (40 V, 0.05 ms, 0.5-4 Hz for 30 s) yielded TTX-sensitive relaxations that were not altered by l-NAME, ODQ or RB2. APA shortened the relaxations. l-NAME + APA nearly abolished these relaxations. ODQ + APA and RB2 +l-NAME reduced the duration. These results suggest that distinct sets of small conductance SK-channels are involved in the amplitude and the duration of the relaxations and that NO increases their sensitivity to NO and ATP via guanosine 3',5'-cyclic monophosphate (cGMP). ATP elicits relaxations via P2Y receptors with subsequent activation of SK-channels and induces neuronal release of NO. Both nitrergic and purinergic pathways must be blocked to inhibit EFS-induced relaxations.
Van Crombruggen
K
K
Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
Lefebvre
R A
RA
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D045462:Endothelium-Dependent Relaxing Factors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology*; D009924:Organ Culture Techniques; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000502:physiology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*
D045462:Endothelium-Dependent Relaxing Factors; D004791:Enzyme Inhibitors; D024681:Potassium Channels, Calcium-Activated; D011687:Purines; D001030:Apamin; D009569:Nitric Oxide; D000255:Adenosine Triphosphate