Myocardial depression remains a major cause of morbidity and mortality following cardiopulmonary bypass (CPB). Mechanisms contributing to this myocardial depression are ill-defined, but appear to involve an inflammatory component. The acute inflammatory response to injury results in the synthesis and release of cytokines by a variety of immune and non- immune cells. The P.I., Co-P.I. and Consultant were the first to propose the hypothesis that cytokine-stimulated production of nitric oxide (NO) contributed to post-CPB myocardial depression. They provided support for this hypothesis by demonstrating for the first time that: (l) cytokines depressed myocardial contractility in isolated hamster papillary muscles. (2) a specific cytokine (IL-6) was elevated in patients following CPB. (3) IL-6 depressed myocardial contractility in humans. (4) L-NMMA (known inhibitor of NO synthesis) blocked the negative inotropic effects of cytokines on the heart. (5) Myocardial NO synthesis increased in patients following CPB. Considerably more work needs to be done to definitely confirm or refute this hypothesis. However, it is clear that IL-6 and NO have the potential to modulate myocardial contractility in animals and humans. The mechanisms of action of these newly described endogenous regulators of myocardial contractility have yet to be fully elucidated.
The specific aims for this project are: I. Identify the mechanism(s) responsible for the negative inotropic effect of IL-6 and NO on isolated hamster papillary muscles and human atrial pectinate muscles. II. Identify stimuli for myocardial NO production in isolated hamster papillary muscles and human atrial pectinate muscles. The results of these studies will provide important new insights into the mechanism of action of these newly identified endogenous regulators (IL-6; NO) of myocardial contractility.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL053372-01
Application #
2231246
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1995-01-01
Project End
1997-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kan, H; Finkel, M S (2001) Interactions between cytokines and neurohormonal systems in the failing heart. Heart Fail Rev 6:119-27
Kan, H; Xie, Z; Finkel, M S (2000) HIV gp120 enhances NO production by cardiac myocytes through p38 MAP kinase-mediated NF-kappaB activation. Am J Physiol Heart Circ Physiol 279:H3138-43
Kan, H; Xie, Z; Finkel, M S (1999) Norepinephrine-stimulated MAP kinase activity enhances cytokine-induced NO production by rat cardiac myocytes. Am J Physiol 276:H47-52
Kan, H; Xie, Z; Finkel, M S (1999) TNF-alpha enhances cardiac myocyte NO production through MAP kinase-mediated NF-kappaB activation. Am J Physiol 277:H1641-6
Haque, R; Kan, H; Finkel, M S (1998) Effects of cytokines and nitric oxide on myocardial E-C coupling. Basic Res Cardiol 93 Suppl 1:86-94
Oddis, C V; Finkel, M S (1997) Cytokines and nitric oxide synthase inhibitor as mediators of adrenergic refractoriness in cardiac myocytes. Eur J Pharmacol 320:167-74
Kanai, A J; Mesaros, S; Finkel, M S et al. (1997) Beta-adrenergic regulation of constitutive nitric oxide synthase in cardiac myocytes. Am J Physiol 273:C1371-7
Oddis, C V; Finkel, M S (1996) Glucose and pyruvate regulate cytokine-induced nitric oxide production by cardiac myocytes. Am J Physiol 271:C1244-9
Oddis, C V; Mayer, O H; Finkel, M S (1996) Inotropic, chronotropic, and radioligand binding characteristics of leukotriene B4 in cardiac myocyte, papillary muscle, and membrane preparations. Prostaglandins Leukot Essent Fatty Acids 54:223-8
Oddis, C V; Finkel, M S (1996) NF-kappa B and GTP cyclohydrolase regulate cytokine-induced nitric oxide production by cardiac myocytes. Am J Physiol 270:H1864-8

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