The purpose of this proposal is to test the hypothesis that angiotensin II (AII) stimulates adenosine release and that the adenosine release by AII serves to inhibit renin release and to attenuate at least some of the biological effects of AII. Stated differently, I wish to examine the physiological role of AII- induced adenosine release as a modulator of the renin-angiotensin system. The significance of the hypothesis is that adenosine may play an important role in restraining the activity of the renin- angiotensin system, so that blockade of this adenosine-mediated restraint, e.g., caffeine consumption, could have adverse cardiovascular effects. The rationale for this hypothesis is provided by several observations recently made in my laboratory: (1) Adenosine is a potent inhibitor of renal ischemia-induced renin release; (2) Adenosine attenuates, whereas AII potentiates, noradrenergic neurotransmission in vivo; (3) Plasma levels of adenosine are elevated six-fold in renovascular hypertension, yet are normal in genetic hypertension; (4) Caffeine, a widely consumed adenosine receptor antagonist, markedly exacerbates renovascular hypertension, but not genetic hypertension; (5) Caffeine causes a sustained elevation of plasma renin activity in renovascular, but not genetic, hypertension; and (6) Caffeine augments the slow- pressor effect of low-dose infusions of AII in normal, but not sympathectomized, animals. These data suggest that activation of the renin-angiotensin system enhances adenosine production, and adenosine acts both to limit renin release and to limit the effects of AII on the sympathetic nervous system. The physiological role of AII-induced adenosine release will be assessed in vivo in several ways. First, I will determine if AII can release adenosine from the pulmonary, mesenteric and renal vascular beds in vivo following either acute infusions of exogenous AII or during chronic activation of the endogenous renin- angiotensin system. Second, I will determine if adenosine serves to limit the ability of AII to enhance noradrenergic neurotransmission. Initially, I will determine if exogenous adenosine can modify AII-induced potentiation of sympathetically-mediated vascular contractions and norepinephrine release. Subsequently, I will compare the ability of exogenous and endogenous AII to facilitate noradrenergic neurotransmission in the absence and presence of specific and novel adenosine receptor antagonists. Finally, I will determine if adenosine mediates the """"""""short-loop"""""""" negative feedback control of renin release by examining this feedback loop in the absence and presence of adenosine receptor blockade.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL040319-01
Application #
3357424
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1988-04-01
Project End
1992-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
Jackson, E K; Mi, Z; Gillespie, D G et al. (1997) Metabolism of cAMP to adenosine in the renal vasculature. J Pharmacol Exp Ther 283:177-82
Imthurn, B; Rosselli, M; Jaeger, A W et al. (1997) Differential effects of hormone-replacement therapy on endogenous nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol valerate and cyproterone acetate or medroxyprogesterone acetate. J Clin Endocrinol Metab 82:388-94
Kost Jr, C K; Herzer, W A; Li, P et al. (1996) Angiotensin II-induced structural and functional alterations in spontaneously hypertensive rat kidney. Am J Physiol 270:F229-36
Dubey, R K; Gillespie, D G; Mi, Z et al. (1996) Smooth muscle cell-derived adenosine inhibits cell growth. Hypertension 27:766-73
Dubey, R K; Gillespie, D G; Osaka, K et al. (1996) Adenosine inhibits growth of rat aortic smooth muscle cells. Possible role of A2b receptor. Hypertension 27:786-93
Jackson, E K; Koehler, M; Mi, Z et al. (1996) Possible role of adenosine deaminase in vaso-occlusive diseases. J Hypertens 14:19-29
Vyas, S J; Mi, Z; Jackson, E K (1996) The inhibitory effect of angiotensin II on stimulus-induced release of cAMP is augmented in the genetically hypertensive rat kidney. J Pharmacol Exp Ther 279:114-9
Rosselli, M; Imthurn, B; Keller, P J et al. (1995) Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol and norethisterone acetate. A two-year follow-up study. Hypertension 25:848-53
Pfeifer, C A; Suzuki, F; Jackson, E K (1995) Selective A1 adenosine receptor antagonism augments beta-adrenergic-induced renin release in vivo. Am J Physiol 269:F469-79
Mi, Z; Jackson, E K (1995) Metabolism of exogenous cyclic AMP to adenosine in the rat kidney. J Pharmacol Exp Ther 273:728-33

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