Mechanisms underlying chemoreceptor inhibition induced by atrial natriuretic peptide in rabbit carotid body.
1. Previous studies in our laboratory revealed the presence of atrial natriuretic peptide (ANP) in preneural chemosensory type I cells of the cat carotid body, and demonstrated that submicromolar concentrations of the peptide inhibited carotid sinus nerve (CSN) activity evoked by hypoxia. In the present study, we have evaluated the role of the cyclic nucleotide second messenger, cyclic GMP (cGMP), and the involvement of type I cells in rabbit chemosensory inhibition. 2. Submicromolar concentrations of the potent ANP analogue, APIII, greatly elevated both the content and release of cGMP from the carotid body. Denervation experiments confirmed earlier immunocytochemical studies which suggested that APIII-induced cGMP production occurs almost exclusively in type I cells; these experiments also indicate that both the sympathetic and sensory innervation to the carotid body exert a trophic influence on the metabolism of this second messenger. 3. Submicromolar concentrations of APIII inhibited the CSN activity evoked by hypoxia (79.8 +/- 3.2% (mean +/- S.E.M.) inhibition with 100 nM APIII) and nicotine (74.5 +/- 3.6% inhibition with 100 nM APIII), but did not affect basal CSN activity established in 100% O2-equilibrated superfusion solutions. 4. The biologically inactive analogue of ANP, C-ANP, failed to produce CSN inhibition; however, the inhibitory effects of APIII were mimicked by cell-permeant analogues of cGMP (dibutyryl-cGMP and 8-bromo-cGMP, 2 mM), which likewise did not alter basal CSN activity. Because we found that unmodified cGMP was an ineffective inhibitor of CSN activity, our data suggest that APIII inhibition is mediated intracellularly by cGMP produced within the type I cells. 5. APIII does not inhibit the CSN activity produced by 20 mM K+ (in zero Ca2+ media), which very probably results from direct depolarization of the sensory nerve terminals. 6. Catecholamine release from the carotid body evoked by hypoxia is likewise not altered by APIII (100 nM). 7. The data are consistent with the notion that APIII and analogues of cGMP alter the release of excitatory and/or inhibitory transmitters from chemosensory type I cells in the carotid body.
Department of Physiology, University of Utah School of Medicine, Salt Lake City 84108.
W J
WJ
Wang
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He
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Chen
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Dinger
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Fidone
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002344:Carotid Body / Q000187:drug effects / Q000378:metabolism*; D002628:Chemoreceptor Cells / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000494:pharmacology; D003714:Denervation; D003864:Depression, Chemical; D003995:Dibutyryl Cyclic GMP / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000860:Hypoxia / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D010446:Peptide Fragments; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits
D010446:Peptide Fragments; C062525:atrial natriuretic factor prohormone (103-126); C016276:8-bromocyclic GMP; D003995:Dibutyryl Cyclic GMP; D009538:Nicotine; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP; D011188:Potassium