The role of nitric oxide in ischaemia/reperfusion injury of isolated hearts from severely atherosclerotic mice.
Nitric oxide (NO) may play an essential role for maintenance of cardiac function and perfusion, while endothelial dysfunction of atherosclerotic vessels may aggravate ischaemia/reperfusion injury. This paper investigates the role of nitric oxide in ischaemia/reperfusion injury in hearts with coronary atherosclerosis. Hearts of apolipoprotein E/LDL receptor double knockout (ApoE/LDLr KO) mice fed an atherogenic diet for 7-9 months were isolated and Langendorff-perfused with 40 minutes of global ischaemia and 60 minutes reperfusion, and funtion and infarction compared with hearts of C57BL/6 controls in the prescence or abscence of the NO-donor SNAP or the NOS inhibitor L-NAME. Hearts of animals with atherosclerosis were more susceptible to ischaemia/reperfusion injury than hearts of animals with healthy vessels, evident as more impaired left ventricular performance. SNAP protected function and reduced infarct size in atherosclerotic hearts, but the same concentration of SNAP was detrimental in normal hearts, perhaps due to NO-overproduction and peroxynitrite formation demonstrated immunohistochemically as increased formation of nitrosylated tyrosine. A low concentration of SNAP protected against ischaemia/reperfusion dysfunction in normal hearts. L-NAME decreased left ventricular performance in atherosclerotic hearts. These findings suggest that impaired endothelium dependent function contributes to reperfusion injury in coronary atherosclerosis.
Tokuno
S
S
Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden.
Thorèn
P
P
Löwbeer
C
C
Valen
G
G
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D001161:Arteriosclerosis / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D015153:Blotting, Western; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics; D015427:Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D020107:Troponin T / Q000378:metabolism
D001057:Apolipoproteins E; D020030:Nitric Oxide Donors; D011973:Receptors, LDL; C110881:S-nitro-N-acetylpenicillamine; D020107:Troponin T; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D010396:Penicillamine; D019331:NG-Nitroarginine Methyl Ester