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Inhibition of nitric oxide synthesis protects the isolated working rabbit heart from ischaemia-reperfusion injury.
Cardiovasc Res. 1995 Sep; 30(3):432-9.CR

Abstract

OBJECTIVES

Nitric oxide (NO) exerts both protective and detrimental actions in a variety of biological systems. During acute reperfusion following myocardial ischaemia, a rapid overproduction of free radicals, including NO, may occur. We investigated the effects of the NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA), and the substrate for NO synthesis, L-arginine, on heart function during ischaemia and reperfusion injury.

METHODS

Spontaneously beating, isolated working rabbit hearts, perfused with modified Krebs-Henseleit buffer containing 1.2 mM palmitate bound to 3% bovine serum albumin, were subjected to 15 min of aerobic perfusion followed by 35 min of global, no-flow ischaemia and 30 min of aerobic reperfusion.

RESULTS

Throughout the reperfusion period there was a marked impairment in the recovery of mechanical function, measured as the product of heart rate x peak systolic pressure (rate-pressure product). Addition of L-NAME (3 microM) prior to the onset of ischaemia, but not at reperfusion, caused an immediate and significant increase in the recovery of mechanical function throughout the reperfusion period. The protective action of L-NAME was abolished by L- (but not D-) arginine (100 microM). L-NAME did not cause ischaemia as it did not alter glycogen or lactate content of aerobically perfused hearts. Furthermore, it did not prevent glycogen loss or lactate accumulation during 35 min of ischaemia, suggesting that the effects of L-NAME were not due to metabolic alterations during ischaemia itself. L-NMMA (30 microM) added prior to ischaemia, but not at reperfusion, also had a protective effect which was seen later in the reperfusion period. Addition of L- (but not D-) arginine (100 microM) prior to the onset of ischaemia resulted in an improved recovery of mechanical function only at 15 min of reperfusion.

CONCLUSIONS

These results suggest that: (1) the recovery of mechanical function of hearts subjected to ischaemia-reperfusion injury can be improved by modulation of myocardial NO synthesis, (2) inhibition of NO synthesis (with L-NAME or L-NMMA) may offer prolonged protection whereas its stimulation (with L-arginine) provides only brief protection, and (3) the reasons for the pharmacological effectiveness of these divergent strategies may be due to the formation of peroxynitrite from NO and superoxide anion during reperfusion.

Authors+Show Affiliations

Department of Pediatrics, University of Alberta, Edmonton, Canada.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

7585835

Citation

Schulz, R, and R Wambolt. "Inhibition of Nitric Oxide Synthesis Protects the Isolated Working Rabbit Heart From Ischaemia-reperfusion Injury." Cardiovascular Research, vol. 30, no. 3, 1995, pp. 432-9.
Schulz R, Wambolt R. Inhibition of nitric oxide synthesis protects the isolated working rabbit heart from ischaemia-reperfusion injury. Cardiovasc Res. 1995;30(3):432-9.
Schulz, R., & Wambolt, R. (1995). Inhibition of nitric oxide synthesis protects the isolated working rabbit heart from ischaemia-reperfusion injury. Cardiovascular Research, 30(3), 432-9.
Schulz R, Wambolt R. Inhibition of Nitric Oxide Synthesis Protects the Isolated Working Rabbit Heart From Ischaemia-reperfusion Injury. Cardiovasc Res. 1995;30(3):432-9. PubMed PMID: 7585835.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of nitric oxide synthesis protects the isolated working rabbit heart from ischaemia-reperfusion injury. AU - Schulz,R, AU - Wambolt,R, PY - 1995/9/1/pubmed PY - 1995/9/1/medline PY - 1995/9/1/entrez SP - 432 EP - 9 JF - Cardiovascular research JO - Cardiovasc. Res. VL - 30 IS - 3 N2 - OBJECTIVES: Nitric oxide (NO) exerts both protective and detrimental actions in a variety of biological systems. During acute reperfusion following myocardial ischaemia, a rapid overproduction of free radicals, including NO, may occur. We investigated the effects of the NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA), and the substrate for NO synthesis, L-arginine, on heart function during ischaemia and reperfusion injury. METHODS: Spontaneously beating, isolated working rabbit hearts, perfused with modified Krebs-Henseleit buffer containing 1.2 mM palmitate bound to 3% bovine serum albumin, were subjected to 15 min of aerobic perfusion followed by 35 min of global, no-flow ischaemia and 30 min of aerobic reperfusion. RESULTS: Throughout the reperfusion period there was a marked impairment in the recovery of mechanical function, measured as the product of heart rate x peak systolic pressure (rate-pressure product). Addition of L-NAME (3 microM) prior to the onset of ischaemia, but not at reperfusion, caused an immediate and significant increase in the recovery of mechanical function throughout the reperfusion period. The protective action of L-NAME was abolished by L- (but not D-) arginine (100 microM). L-NAME did not cause ischaemia as it did not alter glycogen or lactate content of aerobically perfused hearts. Furthermore, it did not prevent glycogen loss or lactate accumulation during 35 min of ischaemia, suggesting that the effects of L-NAME were not due to metabolic alterations during ischaemia itself. L-NMMA (30 microM) added prior to ischaemia, but not at reperfusion, also had a protective effect which was seen later in the reperfusion period. Addition of L- (but not D-) arginine (100 microM) prior to the onset of ischaemia resulted in an improved recovery of mechanical function only at 15 min of reperfusion. CONCLUSIONS: These results suggest that: (1) the recovery of mechanical function of hearts subjected to ischaemia-reperfusion injury can be improved by modulation of myocardial NO synthesis, (2) inhibition of NO synthesis (with L-NAME or L-NMMA) may offer prolonged protection whereas its stimulation (with L-arginine) provides only brief protection, and (3) the reasons for the pharmacological effectiveness of these divergent strategies may be due to the formation of peroxynitrite from NO and superoxide anion during reperfusion. SN - 0008-6363 UR - https://www.unboundmedicine.com/medline/citation/7585835/Inhibition_of_nitric_oxide_synthesis_protects_the_isolated_working_rabbit_heart_from_ischaemia_reperfusion_injury_ DB - PRIME DP - Unbound Medicine ER -