Abstract
Nitrite (NO(2)(-)) functions as an important nitric oxide (NO) donor under hypoxic conditions. Both nitrite and NO have been found to protect the mammalian heart and other tissues against ischemia (anoxia)-reoxygenation injury by interacting with mitochondrial electron transport complexes and limiting the generation of reactive oxygen species upon reoxygenation. The crucian carp naturally survives extended periods without oxygen in an active state, which has made it a model for studying how evolution has solved the problems of anoxic survival. We investigated the role of nitrite and NO in the anoxia tolerance of this fish by measuring NO metabolites in normoxic, anoxic, and reoxygenated crucian carp. We also cloned and sequenced crucian carp NO synthase variants and quantified their mRNA levels in several tissues in normoxia and anoxia. Despite falling levels of blood plasma nitrite, the crucian carp showed massive increases in nitrite, S-nitrosothiols (SNO), and iron-nitrosyl (FeNO) compounds in anoxic heart tissue. NO(2)(-) levels were maintained in anoxic brain, liver, and gill tissues, whereas SNO and FeNO increased in a tissue-specific manner. Reoxygenation reestablished normoxic values. We conclude that NO(2)(-) is shifted into the tissues where it acts as NO donor during anoxia, inducing cytoprotection under anoxia/reoxygenation. This can be especially important in the crucian carp heart, which maintains output in anoxia. NO(2)(-) is currently tested as a therapeutic drug against reperfusion damage of ischemic hearts, and the present study provides evolutionary precedent for such an approach.
Highlights
Problems with anoxia and how to overcome them It has long been recognized that a major problem for a vertebrate in anoxia is the stop in oxidative phosphorylation, leading to a severely impaired capacity for ATP production and an inability to match it to ATP demand
Paper I: Dramatic increase of nitrite levels in hearts of anoxia-exposed crucian carp supporting a role in cardioprotection Am
Jensen This study demonstrated that, despite that no oxygen were available for NO-production from arginine via NO synthase (NOS), the NO metabolite nitrite increased 10-fold in anoxic crucian carp hearts after 1, 3 and 5 days of anoxia exposure
Summary
Problems with anoxia and how to overcome them It has long been recognized that a major problem for a vertebrate in anoxia is the stop in oxidative phosphorylation, leading to a severely impaired capacity for ATP production and an inability to match it to ATP demand. The pumping of ions requires ATP, and as ATP levels fall, ionic gradients over nerve cell membranes are lost, causing uncontrolled firing of neurons (Hansen, 1985). This causes a cascade of catastrophic events, and most vertebrates die within minutes when exposed to anoxia. The crucian carp is a striking exception to this rule, as this teleost can survive in an active state for several months in anoxia at low temperatures (Blazka, 1958; Vornanen et al, 2009) This enables it to be the sole piscine inhabitant of small ponds that becomes anoxic in the winter, due to snow and ice coverage blocking oxygen diffusion from air and light for photosynthesis. The ATP and the ionic gradients in the neurons can be maintained, as long as glycogen is not depleted (Nilsson, 1990a)
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