Role of released ATP in cardiovascular effects of nicotine
Abstracts
Initial Award Abstract |
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Users of tobacco have an increased incidence of cardiovascular diseases. These are thought to be referable to the nicotine in tobacco smoke. Nicotine acts by stimulating receptors on nerve cells that lead to the secretion of the neurotransmitter, norepinephrine (NE). Thus, conventional wisdom holds that the cardiovascular effects of nicotine result from excess norepinephrine, although studies establishing a detailed mechanism from NE release to cardiovascular disease are generally lacking. Previous studies neglect that NE is stored and released with another putative neurotransmitter, ATP. NE and ATP can act synergistically and possibly antagonistically on cells of the cardiovascular system. I propose to study effects of ATP + NE on transmembrane signalling in isolated cardiac cells (ventricular myocytes, fibroblasts and endothelial cells and vascular smooth muscle) cells. I will also assess activity and induction/repression of relevant proteins/enzymes in each cell type.
The data will establish whether ATP plays a role in the cardiovascular effects of nicotine (preliminary data suggest important interactions of NE and ATP) and will form the basis of a more focussed and detailed proposal in the future.
Understanding the biochemical and physiologic complexity of signals elicited by nicotine will offer new ways to block responses or ameliorate effects as well as teaching us about signal integration in cardiovascular cells. |
Final Report |
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Funding began in October, 2000. Since that time, I have used the funds in partial support in writing a review of signaling in the heart and to conduct research on the role of ATP (released with norepinephrine by the action of nicotine) in signaling, especially on cardiac fibroblasts and in renal epithelium. Following are the specific aims:
l. We find that ATP acts via multiple purinergic receptors to activate the Gq pathway to stimulate IP3 production and an elevation of cell Ca . ATP can also activate the GS pathway both directly and indirectly (via eicosanoid intermediates).
2. ATP enhances effects of the neurotransmitter, norepinephrine (NE), with which it is co-released, doubling cyclic AMP accumulation.
3. In cardiac fibroblasts, ATP and NE together also activate NO production (NO is a cardiac depressant).
In the future, we plan to study the mechanism of the effect of ATP on cyclic AMP metabolism. We will also extend these studies to cardiac myocytes and endothelium. |
Publications
| Compartmentation of G-protein-coupled signaling pathways in cardiac myocytes |
| Periodical: Annual Review of Pharmacology and Toxicology |
Index Medicus: |
| Authors: Steinberg SF, Brunton LL |
ART |
| Yr: 2001 |
Vol: 41 |
Nbr: |
Abs: |
Pg: 751-773 |
| Cloning, expression, signaling mechanisms and membrane target of P2Y11 receptors in madin darby canine kidney cells |
| Periodical: Molecular Pharmacology |
Index Medicus: |
| Authors: Zambon A, Brunton LL, et al |
ART |
| Yr: 2001 |
Vol: 60 |
Nbr: |
Abs: |
Pg: 26-35 |
| Compartmentation of G-protein-coupled signaling pathways in cardiac myocytes |
| Periodical: Annual Review of Pharmacology and Toxicology |
Index Medicus: |
| Authors: Steinberg SF, Brunton LL |
ART |
| Yr: 2001 |
Vol: 41 |
Nbr: |
Abs: |
Pg: 751-773 |
| Cloning, expression, signaling mechanisms and membrane target of P2Y11 receptors in madin darby canine kidney cells |
| Periodical: Molecular Pharmacology |
Index Medicus: |
| Authors: Zambon A, Brunton LL, et al |
ART |
| Yr: 2001 |
Vol: 60 |
Nbr: |
Abs: |
Pg: 26-35 |
