Engagement of inducible nitric oxide synthase at the rostral ventrolateral medulla during mevinphos intoxication in the rat.
We evaluated the relationship between the toxicity induced by the organophosphate mevinphos (Mev) and inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic neurogenic vasomotor tone. Adult Sprague-Dawley rats that were anesthetized and maintained with propofol were used. Laser scanning confocal microscopic analysis revealed colocalization of the M2 subtype of muscarinic receptors (M(2)R) and iNOS immunoreactivity in RVLM neurons. Comicroinjection bilaterally of Mev (10 nmol) and artificial cerebrospinal fluid (aCSF) into the RVLM elicited a progressive decline in systemic arterial pressure (SAP) and heart rate. This was accompanied during phase 1 Mev intoxication by an increase in the power density of the very high-frequency (VHF; 5-9 Hz), high-frequency (HF; 0.8-2.4 Hz), low-frequency (LF; 0.25- 0.8 Hz) and very low-frequency (VLF; 0-0.25 Hz) components of SAP signals. Phase 2 exhibited a reversal of the VHF and VLF power to control levels and a further reduction in the power density of both HF and LF components to below baseline. Hypotension and bradycardia promoted by Mev were significantly blunted on coadministration into the RVLM of the selective iNOS inhibitors S-methylisothiourea (250 pmol) or aminoguanidine (250 pmol). Not only was the augmented power density of HF and LF components during phase 1 Mev intoxication further enhanced, the reduced power of these two spectral components during phase 2 was appreciably antagonized. On the other hand, the temporal changes in VHF and VLF power were essentially the same as with coadministration of Mev and aCSF. We conclude that, as a cholinesterase inhibitor, Mev may induce toxicity via nitric oxide produced by iNOS on activation of the M(2)R by the accumulated acetylcholine in the RVLM.
Chang
A Y
AY
Center for Neuroscience, Department of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC. achang@mail.nsysu.edu.tw
Chan
J Y
JY
Kao
F J
FJ
Huang
C M
CM
Chan
S H
SH
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004594:Electrophysiology; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D007306:Insecticides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008526:Medulla Oblongata / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D008799:Mevinphos / Q000008:administration & dosage / Q000633:toxicity*; D008845:Microinjections; D008855:Microscopy, Electron, Scanning; D009474:Neurons / Q000737:chemistry; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000378:metabolism; D014666:Vasomotor System
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D009569:Nitric Oxide; D008799:Mevinphos; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000109:Acetylcholine