Abstract
Natriuretic peptides suppress evoked catecholamine efflux by a mechanism attributed to activation of the natriuretic peptide receptor (NPR)-C, but this designation relies on the absolute specificity of truncated natriuretic peptide analogs for the NPR-C. The NPR-C involvement in evoked catecholamine efflux was defined better in this study by selectively ablating the NPR-C in pheochromocytoma cells with antisense oligodeoxynucleotides. This treatment suppressed NPR-C levels by 52 ± 4% relative to missense treatment. The reduction of NPR-C levels suppressed evoked catecholamine efflux 33 ± 6% and eliminated the effect of C-type natriuretic peptide to suppress evoked catecholamine efflux. The native peptide, C-type natriuretic peptide, reduced evoked catecholamine efflux 39 ± 3% in cells with a normal complement of NPR-C. The NPR-C reduction failed to alter neuromodulatory effects ofN-nitro-l-arginine methyl ester or an active fragment of the NPR-C receptor administered in permeabilized cells. Furthermore, the NPR-C reduction did not prevent guanylyl cyclase activation in response to C-type natriuretic peptide. These latter experiments indicate that the antisense treatment resulted in a specific suppression of the NPR-C and did not affect alternative neuromodulatory pathways or guanylyl cyclase receptors. The novel aspects of this study include both the inhibitory effect of NPR-C reduction on basal-evoked neurotransmitter efflux and the ablation of natriuretic peptide effects on neurotransmitter efflux by NPR-C reduction. The results are consistent with the notion of a key signal-transducing role of the NPR-C in mediating inhibitory effects of natriuretic peptides on neurotransmitter efflux.
Footnotes
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Send reprint requests to: George J. Trachte, Department of Pharmacology, University of Minnesota-Duluth, School of Medicine, 10 University Dr., Duluth, MN 55812. E-mail: gtracht1{at}d.umn.edu
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↵1 This study was supported by U.S. Public Health Service Grant HL42525.
- Abbreviations:
- NPR
- natriuretic peptide receptor
- PC
- Pheochromocytoma
- l-NAME
- N-nitro-l-arginine methyl ester
- ANP
- atrial natriuretic peptide
- Received August 9, 1999.
- Accepted March 14, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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