Chronic nitric oxide synthase blockade desensitizes the heart to the negative metabolic effects of nitric oxide

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 O₂ consumption was determined from coronary flow (microspheres) and O₂ 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 O₂ consumption (SNAP 5.9 ± 0.6 vs. control 8.4 ± 0.8 ml O₂/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 O₂ 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 O₂ 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.