Although caffeine is the most widely consumed drug in Western society, its precise mechanism of action is still not known. It has been proposed that many or all of its effects are due to antagonism of endogenous adenosine. Although there has been much investigative interest in the effects of adenosine in animals, the cardiovascular clinical pharmacology of adenosine is almost entirely unknown. The proposed studies seek to establish the dose-response relationship for adenosine in human subjects and determine the nature and extent of its shift by concomitantly administered antagonists (caffeine and theophylline) and adenosine uptake blockade (dipyridamole). Clinically, we and others have reported postprandial hypotension in elderly subjects, hypertensive subjects and patients with abnormal autonomic function. We have demonstrated that caffeine attenuates this hypotension and, in normal subjects, caffeine reduces liver blood flow. Since adenosine has been proposed to be an importance regulator of splanchnic blood flow, we propose to evaluate systematically the effect of adenosine infusion, adenosine uptake blockade, and adenosine receptor blockers on liver blood flow and on the hemodynamic response to food ingestion. Studies to determine the relation between the effects of adenosine and caffeine on the one hand and the function of the sympathetic nervous system will also be carried out. These will include assessments of the release and clearance of norepinephrine, measurement of forearm blood flow and venous capacitance, quantitation of sympathetic activity by intraneural recording of sympathetic fibers, and determination of plasma catecholamines, renin and aldosterone. In summary, these studies will elucidate the cardiovascular and autonomic physiology and pharmacology of adenosine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034021-03
Application #
3346542
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1985-12-01
Project End
1990-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
3
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
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Robertson, D; Cavalcante, J W (1992) [Orthostatic hypotension] Arq Bras Cardiol 58:255-61
Feoktistov, I A; Paul, S; Hollister, A S et al. (1992) Role of cyclic AMP in adenosine inhibition of intracellular calcium rise in human platelets. Comparison of adenosine effects on thrombin- and epinephrine-induced platelet stimulation. Am J Hypertens 5:147S-153S
Biaggioni, I; Killian, T J; Mosqueda-Garcia, R et al. (1991) Adenosine increases sympathetic nerve traffic in humans. Circulation 83:1668-75
Perry, S E; Phillips 3rd, J A; Robertson, D (1991) FnuD II RFLP at the human dopamine-beta-hydroxylase (D beta H) locus. Nucleic Acids Res 19:1162
Mosqueda-Garcia, R; Tseng, C J; Appalsamy, M et al. (1991) Cardiovascular excitatory effects of adenosine in the nucleus of the solitary tract. Hypertension 18:494-502
Mosqueda-Garcia, R; Oates, J A; Appalsamy, M et al. (1991) Administration of carbamazepine in the nucleus of the solitary tract inhibits the antihypertensive effect of clonidine. Eur J Pharmacol 197:213-6
Perry, S E; Summar, M L; Phillips 3rd, J A et al. (1991) Linkage analysis of the human dopamine beta-hydroxylase gene. Genomics 10:493-5
Paul, S; Feoktistov, I; Hollister, A S et al. (1990) Adenosine inhibits the rise in intracellular calcium and platelet aggregation produced by thrombin: evidence that both effects are coupled to adenylate cyclase. Mol Pharmacol 37:870-5

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