Influence of the selective neuronal NO synthase inhibitor ARL 17477 on nitrergic neurotransmission in porcine stomach.
Selective neuronal NOS (nNOS) inhibitors have been developed for possible application in cerebral ischemia and neurodegenerative disorders. To investigate the degree of interference with peripheral nNOS, the influence of the selective nNOS inhibitor ARL 17477 was studied on electrically induced nitrergic relaxations in pig gastric fundus strips and on gastric fundic compliance in conscious pig. Circular muscle strips of porcine gastric fundus were electrically stimulated (10 s trains at 4 Hz, 0.1 ms and 40 V). ARL 17477 inhibited the electrically induced relaxations in a concentration-dependent way (3x10(-6) M-10(-4) M). The inhibitory effect of ARL 17477 developed more progressively than that of N(G)-nitro-L-arginine methyl ester (L-NAME; 3x10(-4) M). In conscious pigs, instrumented with a fundic cannula, L-NAME (20 mg/kg i.v.) significantly increased mean arterial blood pressure and decreased fundic compliance in the fasted state (71+/-13 ml/mm Hg versus 185+/-37 ml/mm Hg after saline; P<0.05). ARL 17477 (3 mg/kg, i.v.) did not influence blood pressure but influenced gastric fundic volume-pressure curves in a similar way as L-NAME. Plasma concentration analysis of ARL 17477 indicated a half-life of less than 30 min in pig. ARL 17477 thus inhibits the effect of nitrergic neurons in the pig gastric fundus in vitro, leading to inhibited gastric compliance in the conscious pig. The study indicates that selective nNOS inhibitors, applied for cerebral disorders, might also interfere with neuronal nitrergic regulation of gastrointestinal motility.
Lefebvre
Romain A
RA
Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, B-9000 Gent, Belgium. Romain.Lefebvre@UGent.be
Dick
Joëlle M C
JM
Guérin
Sylvie
S
Malbert
Charles-Henri
CH
D000578:Amidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003187:Compliance / Q000187:drug effects; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005748:Gastric Fundus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D026602:Nitrergic Neurons / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D013552:Swine
C102136:ARL 17477; D000578:Amidines; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D019331:NG-Nitroarginine Methyl Ester