When heart failure develops following an insult to the myocardium, a number of neurohormonal mechanisms are activated in an attempt to preserve circulatory homeostasis. Previous work has characterized the nature of these reactions, but little work has been done to determine how these mechanisms interact in specific target organs or how tissue agonist sensitivity may be altered in response to prolonged neurohormonal activation. The goal of this research proposal is (1) to determine if abnormalities of the beta- receptor/adenylate cyclase complex modulate neuro-hormonal responsiveness in heart failure, and thus may explain the pharmacologic resistance to inotropic drugs seen in these patients; and (2) to elucidate whether neurohormonal activation may modify the response to exogenous and endogenous vasodilators in heart failure, and thus may contribute to the development of tolerance to nitroglycerin and resistance to atrial natriuretic peptide. In a series of hemodynamic investigations in patients with heart failure undergoing right heart catheterization, tolerance will be induced to intravenous nitroglycerin to determine if its occurrence is the result of sulfhydryl depletion in vascular smooth muscle (by use of the sulfhydryl donors, N-acetylcysteine and methionine) or due to neurohormonal activation (by monitoring circulating neurohormones and attenuating their effects by the use of the neurohormonal antagonist, captopril). Abnormalities of the receptor-cyclase complex in circulating lymphocytes will be characterized (with particular emphasis on the guanine nucleotide binding proteins) and correlated with the responsiveness of patients of cyclic A MP-dependent inotropic drugs (dobutamine, glucagon and amrinone). Serial measurements of the receptor- cyclase complex will be made to determine if its components may change in response to prolonged neurohormonal stimulation, produced either by a sustained infusion of dobutamine or as a result of progression of the underlying disease. These serial measurements will be used to determine if changes in receptor-cyclase complex can predict survival in heart failure and if its prognostic utility compares favorably with conventional hemodynamic and hormonal variables. To determine the importance of neurohormonal activation in limiting the effects of atrial natriuretic peptide, the natriuretic effects of an infusion of the peptide will be assessed before and after the administration of indomethacin and captopril. By elucidating the biochemical and physiologic mechanisms by which the circulation reacts and adapts to pharmacologic interventions in chronic heart failure, this proposal should help to explain the heterogenous effects of treatment in these patients and should assist in the development of specific strategies designed to enhance the efficacy of a variety of therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025055-10
Application #
3337953
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1980-06-01
Project End
1992-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
10
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Packer, M (1992) Lack of relation between ventricular arrhythmias and sudden death in patients with chronic heart failure. Circulation 85:I50-6
Packer, M; Kukin, M L (1991) Management of patients with heart failure and angina: do coexistent diseases alter the response to cardiovascular drugs? J Am Coll Cardiol 17:740-2
Neuberg, G W; Kukin, M L; Penn, J et al. (1991) Hemodynamic effects of renin inhibition by enalkiren in chronic congestive heart failure. Am J Cardiol 67:63-6
Haber, H L; Leavy, J A; Kessler, P D et al. (1991) The erythrocyte sedimentation rate in congestive heart failure. N Engl J Med 324:353-8
Packer, M (1990) What causes tolerance to nitroglycerin? The 100 year old mystery continues. J Am Coll Cardiol 16:932-5
Packer, M (1990) Why do the kidneys release renin in patients with congestive heart failure? A nephrocentric view of converting-enzyme inhibition. Eur Heart J 11 Suppl D:44-52
Levine, B; Kalman, J; Mayer, L et al. (1990) Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323:236-41
Packer, M (1990) Calcium channel blockers in chronic heart failure. The risks of ""physiologically rational"" therapy. Circulation 82:2254-7
Packer, M (1990) Role of the sympathetic nervous system in chronic heart failure. A historical and philosophical perspective. Circulation 82:I1-6
Packer, M (1990) Are nitrates effective in the treatment of chronic heart failure? Antagonist's viewpoint. Am J Cardiol 66:458-61

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