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Chronic nitric oxide synthase blockade desensitizes the heart to the negative metabolic effects of nitric oxide.
- Source :
-
Life sciences [Life Sci] 2006 Sep 20; Vol. 79 (17), pp. 1674-80. Date of Electronic Publication: 2006 Jun 08. - Publication Year :
- 2006
-
Abstract
- The consequences of chronic nitric oxide synthase (NOS) blockade on the myocardial metabolic and guanylyl cyclase stimulatory effects of exogenous nitric oxide (NO) were determined. Thirty-three anesthetized open-chest rabbits were randomized into four groups: control, NO donor S-nitroso-N-acetyl-penicillamine (SNAP, 10(-4 )M), NOS blocking agent N(G)-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg/day) for 10 days followed by a 24 hour washout and L-NAME for 10 days followed by a 24 hour washout plus SNAP. Myocardial O(2) consumption was determined from coronary flow (microspheres) and O(2) extraction (microspectrophotometry). Cyclic GMP and guanylyl cyclase activity were determined by radioimmunoassay. There were no baseline metabolic, functional or hemodynamic differences between control and L-NAME treated rabbits. SNAP in controls caused a reduction in O(2) consumption (SNAP 5.9+/-0.6 vs. control 8.4+/-0.8 ml O(2)/min/100 g) and a rise in cyclic GMP (SNAP 18.3+/-3.8 vs. control 10.4+/-0.9 pmol/g). After chronic L-NAME treatment, SNAP caused no significant changes in O(2) consumption (SNAP 7.1+/-0.8 vs. control 6.4+/-0.7) or cyclic GMP (SNAP 14.2+/-1.8 vs. control 12.1+/-1.3). In controls, guanylyl cyclase activity was significantly stimulated by SNAP (216.7+/-20.0 SNAP vs. 34.4+/-2.5 pmol/mg/min base), while this increase was blunted after L-NAME (115.9+/-24.5 SNAP vs. 24.9+/-4.7 base). These results demonstrated that chronic NOS blockade followed by washout blunts the response to exogenous NO, with little effect on cyclic GMP or myocardial O(2) consumption. This was related to reduced guanylyl cyclase activity after chronic L-NAME. These results suggest that, unlike many receptor systems, the NO-cyclic GMP signal transduction system becomes downregulated upon chronic inhibition.
- Subjects :
- Animals
Blood Flow Velocity drug effects
Enzyme Inhibitors pharmacology
Female
Guanylate Cyclase metabolism
Heart drug effects
Heart Ventricles chemistry
Heart Ventricles drug effects
Heart Ventricles metabolism
Hemodynamics drug effects
Male
Microspectrophotometry
Microspheres
NG-Nitroarginine Methyl Ester pharmacology
Nitric Oxide Donors pharmacology
Oxygen analysis
Oxygen Consumption drug effects
Penicillamine analogs & derivatives
Penicillamine pharmacology
Rabbits
Cyclic GMP metabolism
Heart physiology
Myocardium metabolism
Nitric Oxide metabolism
Nitric Oxide Synthase antagonists & inhibitors
Oxygen Consumption physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0024-3205
- Volume :
- 79
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Life sciences
- Publication Type :
- Academic Journal
- Accession number :
- 16831448
- Full Text :
- https://doi.org/10.1016/j.lfs.2006.06.004