Cellular mechanisms involved in carotid body inhibition produced by atrial natriuretic peptide.

Abstract

Atrial natriuretic peptide (ANP) and its analog, atriopeptin III (APIII), inhibit carotid body chemoreceptor nerve activity evoked by hypoxia. In the present study, we have examined the hypothesis that the inhibitory effects of ANP and APIII are mediated by cyclic GMP and protein kinase G (PKG) via the phosphorylation and/or dephosphorylation of K(+) and Ca(2+) channel proteins that are involved in regulating the response of carotid body chemosensory type I cells to low-O(2) stimuli. In freshly dissociated rabbit type I cells, we examined the effects of a PKG inhibitor, KT-5823, and an inhibitor of protein phosphatase 2A (PP2A), okadaic acid (OA), on K(+) and Ca(2+) currents. We also investigated the effects of these specific inhibitors on intracellular Ca(2+) concentration and carotid sinus nerve (CSN) activity under normoxic and hypoxic conditions. Voltage-dependent K(+) currents were depressed by hypoxia, and this effect was significantly reduced by 100 nM APIII. The effect of APIII on this current was reversed in the presence of either 1 microM KT-5823 or 100 nM OA. Likewise, these drugs retarded the depression of voltage-gated Ca(2+) currents induced by APIII. Furthermore, APIII depressed hypoxia-evoked elevations of intracellular Ca(2+), an effect that was also reversed by OA and KT-5823. Finally, CSN activity evoked by hypoxia was decreased in the presence of 100 nM APIII, and was partially restored when APIII was presented along with 100 nM OA. These results suggest that ANP initiates a cascade of events involving PKG and PP2A, which culminates in the dephosphorylation of K(+) and Ca(2+) channel proteins in the chemosensory type I cells.

• Authors: L He, B Dinger, S Fidone
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 278 Issue 4 Pg. C845-52 (Apr 2000) ISSN: 0363-6143 [Print] United States
• PMID: 10751332 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alkaloids
• Carbazoles
• Enzyme Inhibitors
• Indoles
• Peptide Fragments
• Protein Kinase Inhibitors
• KT 5823
• Okadaic Acid
• atrial natriuretic factor prohormone (103-126)
• Atrial Natriuretic Factor
• Cyclic GMP-Dependent Protein Kinases
• Phosphoprotein Phosphatases
• Protein Phosphatase 2
• Potassium
• Calcium

Topics

• Alkaloids (pharmacology)
• Animals
• Atrial Natriuretic Factor (pharmacology)
• Calcium (metabolism, physiology)
• Carbazoles
• Carotid Body (cytology, drug effects, physiology)
• Carotid Sinus (innervation)
• Cells, Cultured
• Cyclic GMP-Dependent Protein Kinases
• Drug Synergism
• Electrophysiology
• Enzyme Inhibitors (pharmacology)
• Hypoxia (physiopathology)
• Indoles
• Nervous System (drug effects, physiopathology)
• Okadaic Acid (pharmacology)
• Patch-Clamp Techniques
• Peptide Fragments
• Phosphoprotein Phosphatases (antagonists & inhibitors)
• Potassium (physiology)
• Protein Kinase Inhibitors
• Protein Phosphatase 2
• Rabbits
• Reference Values