The goal of this proposal is to investigate the actions of atrial natriuretic factor (ANF) on sympathetic neurotransmission in isolated neuronal cells and in isolated tissues. The proposed work will investigate the intracellular mechanism by which ANF suppresses catecholamine release in differentiated PC12 cells and rabbit isolated vasa deferentia and portal veins to determine if the neuromodulatory pathways defined in the PC12 cells occur in other sympathetically innervated organs. Specifically, the principal investigator will investigate whether ANF suppresses evoked neurotransmitter release is mediated through a G protein which 1) increases cyclic GMP accumulation; 2) alters cyclic AMP accumulation or 3) alters phospholipase products. Binding experiments will test for the presence of ANF receptors on PC12 cells. Pertussis toxin, and GTP and GDP analogues will be utilized to assess the role of inhibitory G proteins in mediating the neuromodulatory effects of ANF. It has been ascertained that pertussis toxin eliminates the suppression of adenylate cyclase and neurotransmission caused by ANF. ANF-induced alterations of second messenger synthesis and evoked catecholamine release will be correlated to test for potential cause and effect relationships. Cause and effect relationships among ANF effects on second messengers and neurotransmission will be tested further using pertussis toxin and ANF """"""""clearance receptor antagonists"""""""". The compound originally termed the ANF clearance receptor antagonist suppresses both adenylate cyclase activity and neurotransmission by a pertussis toxin-sensitive mechanism but does not activate guanylate cyclase. Potential interactions among the proposed second messengers also will be tested to discriminate between second messenger pathways which are in parallel or in series.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL042525-02
Application #
3360787
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1991-06-01
Project End
1994-05-31
Budget Start
1992-06-01
Budget End
1993-05-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Trachte, George J (2003) Natriuretic peptides suppress protein kinase C activity to reduce evoked dopamine efflux from pheochromocytoma (PC12) cells. Endocrinology 144:94-100
Trachte, G J (2000) Depletion of natriuretic peptide C receptors eliminates inhibitory effects of C-type natriuretic peptide on evoked neurotransmitter efflux. J Pharmacol Exp Ther 294:210-5
Kanwal, S; Lowe, D G; Trachte, G J (1999) Intracellular fragments of the natriuretic peptide receptor-C (NPR-C) attenuate dopamine efflux. Endocrinology 140:1118-24
Kanwal, S; Elmquist, B J; Trachte, G J (1997) Atrial natriuretic peptide inhibits evoked catecholamine release by altering sensitivity to calcium. J Pharmacol Exp Ther 283:426-33
Trachte, G J; Kanwal, S; Elmquist, B J et al. (1995) C-type natriuretic peptide neuromodulates via ""clearance"" receptors. Am J Physiol 268:C978-84
Trachte, G J; Drewett, J G (1994) C-type natriuretic peptide neuromodulates independently of guanylyl cyclase activation. Hypertension 23:38-43
Trachte, G J (1993) Atrial natriuretic factor alters neurotransmission independently of guanylate cyclase-coupled receptors in the rabbit vas deferens. J Pharmacol Exp Ther 264:1227-33
Anand-Srivastava, M B; Trachte, G J (1993) Atrial natriuretic factor receptors and signal transduction mechanisms. Pharmacol Rev 45:455-97
Drewett, J G; Ziegler, R J; Trachte, G J (1992) Neuromodulatory effects of atrial natriuretic peptides correlate with an inhibition of adenylate cyclase but not an activation of guanylate cyclase. J Pharmacol Exp Ther 260:689-96