Muscarinic receptor-independent activation of cyclic adenosine monophosphate-dependent protein kinase in rostral ventrolateral medulla underlies the sympathoexcitatory phase of cardiovascular responses during mevinphos intoxication in the rat.
As inhibitors of acetylcholinesterase, clinical presentations of poisoning from organophosphate compounds are generally believed to entail overstimulation by the accumulated acetylcholine on muscarinic receptors at peripheral and central synapses. That some patients still yielded to acute organophosphate poisoning despite repeated dosing of atropine suggests that cellular mechanisms that are independent of muscarinic receptor activation may also be engaged in organophosphate poisoning. The present study was undertaken to test the hypothesis that muscarinic receptor-independent activation of cyclic adenosine monophosphate-dependent protein kinase A (PKA) in rostral ventrolateral medulla (RVLM), a medullary site where sympathetic vasomotor tone originates and where the organophosphate poison mevinphos (Mev) acts, is involved in the cardiovascular responses exhibited during organophosphate intoxication. In Sprague-Dawley rats, microinjection bilaterally of Mev (10 nmol) into the RVLM significantly augmented PKA activity in ventrolateral medulla that was not antagonized by coadministration of an equimolar concentration (1 nmol) of atropine or selective muscarinic receptor type M1 (pirenzepine), M2 (methoctramine), M3 (4-diphenyl-acetoxy-N-dimethylpiperidinium), or M4 (tropicamide) inhibitor. Comicroinjection of two selective PKA antagonists (100 pmol), N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide and (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolol[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-1][1,6]benzodiazocine-10-carboxylic acid, significantly blunted the initial sympathoexcitatory cardiovascular response and the accompanying augmentation of nitric oxide synthase (NOS I) expression in the ventrolateral medulla exhibited during Mev intoxication; the secondary sympathoinhibitory phase and associated elevation in NOS II expression were unaffected. We conclude that whereas a muscarinic receptor-independent augmentation of PKA activity in the ventrolateral medulla was manifested throughout acute Mev intoxication, this activation was preferentially involved in the sympathoexcitatory phase by an upregulation of NOS I expression.
Tsai
Ching-Yi
CY
Department of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan, Republic of China.
Wu
Carol H Y
CH
Chan
Samuel H H
SH
Chang
Alice Y W
AY
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D015153:Blotting, Western; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008799:Mevinphos / Q000008:administration & dosage / Q000633:toxicity*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013997:Time Factors; D014331:Tropicamide / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D018727:Muscarinic Antagonists; D010880:Piperidines; D011976:Receptors, Muscarinic; C015482:protein kinase modulator; D010890:Pirenzepine; D008799:Mevinphos; D001285:Atropine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D014331:Tropicamide