While investigating the renal effects of BG9928 (a selective antagonist of adenosine type A1 receptors that is being developed as a diuretic for heart failure patients) we observed that in vivo BG9928 profoundly reduces renal vasoconstriction induced by renal sympathetic nerve stimulation (RSNS). This finding suggests to us that A1 receptors in the renal neuroeffector junction augment renal sympathetic neurotransmission. Although this hypothesis is consistent with our published reports that RSNS increases adenosine release and published reports by others that sympathetic nerve stimulation releases the adenosine precursor ATP as well as enzymes that form adenosine from ATP, numerous studies by others clearly establish that prejunctional A1 receptors inhibit, not augment, NE release. Taken together, these observations suggest that if A1 receptors participate in enhancing renal sympathetic neurotransmission, the effect must be post-junctional. Because A1 receptors are well known to enhance angiotensin II-induced renal vasoconstriction, we postulate that RSNS increases adenosine and NE in the neuroeffector junction, and that adenosine, via the post-junctional A1 receptor, enhances NE-induced vasoconstriction (through coincident signaling, i.e., convergence of signaling) resulting in A1 receptor-intensification of RSNS-induced renal vasoconstriction. Accordingly, the overall objective of this project is to determine whether endogenous adenosine in the renal neuroeffector junction and via the A1 adenosine receptor significantly intensifies the renal vasoconstrictor response to renal sympathetic nerve stimulation. We will investigate this hypothesis using multiple approaches: 1) We will determine in rat and mouse kidneys the effects of selective A1 receptor antagonists on RSNS-induced renal vasoconstriction and purine release (by mass spectrometry);2) We will determine in mouse kidneys the effects of A1 receptor knockout on RSNS-induced renal vasoconstriction and purine release;3) We will determine in rat and mouse (both wild-type and A1 receptor knockout) kidneys the effects of a highly selective A1 receptor agonist on norepinephrine-induced renal vasoconstriction in the presence and absence of selective A1 receptor antagonists;4) We will determine in mouse kidneys from A1 receptor knockout mice whether lentiviral-based reconstitution of the A1 receptor selectively in renal vascular smooth muscle cells augments renovascular responses to RSNS;and 5) We will determine in mouse kidneys from wild-type mice whether lentiviral-based shRNA knockdown of the A1 receptor selectively in renal vascular smooth muscle cells inhibits renovascular responses to RSNS. This project will identify a MAJOR mechanism that contributes to renal sympathetic neurotransmission. Because the renal sympathetic nervous system is involved in most renal physiological and pathophysiological processes, this discover would enlighten and inform renal physiologists working in all aspects of renal function and dysfunction and would provide a strong rationale for using A1 receptor blockers as diuretics in conditions associated with increased renal sympathetic tone.

Public Health Relevance

This project will identify a MAJOR mechanism that contributes to renal sympathetic neurotransmission. Because the renal sympathetic nervous system is involved in most renal physiological and pathophysiological processes, this discover would enlighten and inform renal physiologists working in all aspects of renal function and dysfunction and would provide a strong rationale for using A1 receptor blockers as diuretics in conditions associated with increased renal sympathetic tone (for example heart failure, renal failure, liver disease and some forms of hypertension).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091190-04
Application #
8727532
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ketchum, Christian J
Project Start
2011-09-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Tofovic, Stevan P; Salah, Eman M; Smits, Glenn J et al. (2016) Dual A1/A2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction. J Pharmacol Exp Ther 356:333-40
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