The study is designed to determine the physiologic and pathophysiologic importance of adenosine in the control of heart rate. It will examine the negative chronotropic effect of exogenous and endogenous adenosine on the sinoatrial node, the physiological cardiac pacemaker, both in intact animals with chronic cardiovascular instrumentation and in isolated sinoatrial node preparations. In addition to measuring the final effect on heart rate, the experiments will examine the electrophysiological effects of adenosine on the resting membrane and action potentials of single SA node cells in situ and also the possibility of adenosine-induced shifts in the pacemaker locus to sites outside the sinoatrial node. The membrane receptors responsible for adenosine's sinoatrial action will be cahracterized by measuring the ralative potencies of a series of structural adenosine analogues in terms of their physiological and biochemical effects. The role of cyclic nucleotides in mediating adenosine's negative chronotropic effect will be determined using cyclic nucleotide measurements and pharmacological probes. Interaction between adenosine and cholinergic control of heart rate will be defined. Finally, by use of pharmacological modulators of adenosine's action and also measurements of adenosine levels, the importance of endogenous adenosine in the bradycardia responses to hypoxia and focal ischemia and in certain bradyarhythmias secondary to myocardial hypertrophy and dilatation will be determined. The study will contribute to our basic understanding of heart rate control and will also contribute to a better understanding of the etiology and possible treatment of certain cardiac arrhythmias found in man.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034167-03
Application #
3346840
Study Section
Cardiovascular and Pulmonary Research B Study Section (CVB)
Project Start
1985-04-01
Project End
1990-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
New York Medical College
Department
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Brown, I P; Thompson, C I; Belloni, F L (1993) Role of nitric oxide in hypoxic coronary vasodilatation in isolated perfused guinea pig heart. Am J Physiol 264:H821-9
Stewart, J M; Patel, M B; Wang, J et al. (1992) Chronic elevation of norepinephrine in conscious dogs produces hypertrophy with no loss of LV reserve. Am J Physiol 262:H331-9
Belloni, F L; Wang, J; Hintze, T H (1992) Adenosine causes bradycardia in pacing-induced cardiac failure. Circulation 85:1118-24
Warner, E L; Galasso, F; Thompson, C I et al. (1992) Vasodilative and anti-adrenergic effects of adenosine in diabetic rat hearts. Can J Physiol Pharmacol 70:13-9
Brown, I P; Thompson, C I; Belloni, F L (1992) Mechanisms of coronary vasodilatation produced by ATP in guinea-pig isolated perfused heart. Br J Pharmacol 105:211-5
Patel, M B; Stewart, J M; Loud, A V et al. (1991) Altered function and structure of the heart in dogs with chronic elevation in plasma norepinephrine. Circulation 84:2091-100
Wang, J; Ochoa, M; Patel, M B et al. (1991) Carotid baroreceptor function in dogs with chronic norepinephrine infusion. Hypertension 17:745-54
Belloni, F L; Hintze, T H (1991) Glibenclamide attenuates adenosine-induced bradycardia and coronary vasodilatation. Am J Physiol 261:H720-7
Stewart, J M; O'Dea, D J; Shapiro, G C et al. (1991) Atrial compliance determines the nature of passive atrial stretch and plasma atrial natriuretic factor in the conscious dog. Cardiovasc Res 25:784-92
Stewart, J M; Wang, J; Singer, A et al. (1990) Regulation of plasma ANF after increases in afterload in conscious dogs. Am J Physiol 259:H1736-42

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