Climate change 2014 - Synthesis Report

Ecological and toxicological effects of inorganic nitrogen pollution in aquatic ecosystems: A global assessment.

The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adap...

Physiology of cell volume regulation in vertebrates.

http://www.uni-heidelberg.de/md/awi/professuren/intwipol/energy.pdf

Does higher economic and financial development lead to environmental degradation: Evidence from BRIC countries

https://eprints.ncl.ac.uk/file_store/production/230266/8E24C221-130A-415A-913E-43559E70DFF8.pdf

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Nitrite is a potential problem in aquatic environments. Freshwater fish actively take up nitrite across the gills, leading to high internal concentrations. Seawater fish are less susceptible but do take up nitrite across intestine and gills. Nitrite has multiple physiological effects. Its uptake is at the expense of chloride, leading to chloride depletion. Nitrite also activates efflux of potassium from skeletal muscle and erythrocytes, disturbing intracellular and extracellular K(+) levels. Nitrite transfer across the erythrocytic membrane leads to oxidation of haemoglobin to methaemoglobin (metHb), compromising blood O(2) transport. Other haem proteins are also oxidised. Hyperventilation is observed, and eventually tissue O(2) shortage becomes reflected in elevated lactate concentrations. Heart rate increases rapidly, before any significant elevations in metHb or extracellular potassium occur. This suggests nitrite-induced vasodilation (possibly via nitric oxide generated from nitrite) that is countered by increased cardiac pumping to re-establish blood pressure. Nitrite can form and/or mimic nitric oxide and thereby interfere with processes regulated by this local hormone. Steroid hormone synthesis may be inhibited, while changes in ammonia and urea levels and excretion rates reflect an influence of nitrite on nitrogen metabolism. Detoxification of nitrite occurs via endogenous oxidation to nitrate, and elimination of nitrite takes place both via gills and urine. The susceptibility to nitrite varies between species and in some cases also within species. Rainbow trout fall into two groups with regard to susceptibility and physiological response. These two groups are not related to sex but show significant different nitrite uptake rates.

Nitrite disrupts multiple physiological functions in aquatic animals.

The discovery of the S-shaped O2 equilibrium curve and the Bohr effect in 1904 stimulated a fertile and continued research into respiratory functions of blood and allosteric mechanisms in haemoglobin (Hb). The Bohr effect (influence of pH/CO2 on Hb O2 affinity) and the reciprocal Haldane effect (influence of HbO2 saturation on H+/CO2 binding) originate in the Hb oxy-deoxy conformational change and allosteric interactions between O2 and H+/CO2 binding sites. In steady state, H+ is passively distributed across the vertebrate red blood cell (RBC) membrane, and intracellular pH (pHi) changes are related to changes in extracellular pH, Hb-O2 saturation and RBC organic phosphate content. As the Hb molecule shifts between the oxy and deoxy conformation in arterial-venous gas transport, it delivers O2 and takes up CO2 and H+ in tissue capillaries (elegantly aided by the Bohr effect). Concomitantly, the RBC may sense local O2 demand via the degree of Hb deoxygenation and release vasodilatory agents to match local blood flow with requirements. Three recent hypotheses suggest (1) release of NO from S-nitroso-Hb upon deoxygenation, (2) reduction of nitrite to vasoactive NO by deoxy haems, and (3) release of ATP. Inside RBCs, carbonic anhydrase (CA) provides fast hydration of metabolic CO2 and ensures that the Bohr shift occurs during capillary transit. The formed H+ is bound to Hb (Haldane effect) while HCO3- is shifted to plasma via the anion exchanger (AE1). The magnitude of the oxylabile H+ binding shows characteristic differences among vertebrates. Alternative strategies for CO2 transport include direct HCO3- binding to deoxyHb in crocodilians, and high intracellular free [HCO3-] (due to high pHi) in lampreys. At the RBC membrane, CA, AE1 and other proteins may associate into what appears to be an integrated gas exchange metabolon. Oxygenation-linked binding of Hb to the membrane may regulate glycolysis in mammals and perhaps also oxygen-sensitive ion transport involved in RBC volume and pHi regulation. Blood O2 transport shows several adaptive changes during exposure to environmental hypoxia. The Bohr effect is involved via the respiratory alkalosis induced by hyperventilation, and also via the pHi change that results from modulation of RBC organic phosphate content. In teleost fish, beta-adrenergic activation of Na+/H+ exchange rapidly elevates pHi and O2 affinity, particularly under low O2 conditions.

Red blood cell pH, the Bohr effect, and other oxygenation‐linked phenomena in blood O2 and CO2 transport

In catalyzing the reversible hydration of CO2 to bicarbonate and protons, the ubiquitous enzyme carbonic anhydrase (CA) plays a crucial role in CO2 transport, in acid-base balance, and in linking local acidosis to O2 unloading from hemoglobin. Considering the structural similarity between bicarbonate and nitrite, we hypothesized that CA uses nitrite as a substrate to produce the potent vasodilator nitric oxide (NO) to increase local blood flow to metabolically active tissues. Here we show that CA readily reacts with nitrite to generate NO, particularly at low pH, and that the NO produced in the reaction induces vasodilation in aortic rings. This reaction occurs under normoxic and hypoxic conditions and in various tissues at physiological levels of CA and nitrite. Furthermore, two specific inhibitors of the CO2 hydration, dorzolamide and acetazolamide, increase the CA-catalyzed production of vasoactive NO from nitrite. This enhancing effect may explain the known vasodilating effects of these drugs and indicates that CO2 and nitrite bind differently to the enzyme active site. Kinetic analyses show a higher reaction rate at high pH, suggesting that anionic nitrite participates more effectively in catalysis. Taken together, our results reveal a novel nitrous anhydrase enzymatic activity of CA that would function to link the in vivo main end products of energy metabolism (CO2/H+) to the generation of vasoactive NO. The CA-mediated NO production may be important to the correlation between blood flow and metabolic activity in tissues, as occurring for instance in active areas of the brain.

Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation.

SUMMARY Vertebrate red blood cells (RBCs) seem to serve tissue oxygen delivery in
two distinct ways. Firstly, RBCs enable the adequate transport of
O 2 between respiratory surfaces and metabolizing tissues by means
of their high intracellular concentration of hemoglobin (Hb), appropriate
allosteric interactions between Hb ligand-binding sites, and an adjustable
intracellular chemical environment that allows fine-tuning of Hb O 2 
affinity. Secondly, RBCs may sense tissue O 2 requirements
 via their degree of deoxygenation when they travel through the
microcirculation and release vasodilatory compounds that enhance blood flow in
hypoxic tissues. This latter function could be important in matching tissue
O 2 delivery with local O 2 demand. Three main mechanisms
by which RBCs can regulate their own distribution in the microcirculation have
been proposed. These are: (1) deoxygenation-dependent release of ATP from
RBCs, which stimulates production of nitric oxide (NO) and other vasodilators
in the endothelium; (2) release of vasoactive NO from S -nitroso-Hb
upon deoxygenation; and (3) reduction of naturally occurring nitrite to
vasoactive NO by deoxygenated Hb. This Commentary inspects all three
hypotheses with regard to their mechanisms, experimental evidence in their
support and details that remain unresolved. The prime focus is on
human/mammalian models, where most evidence for a role of erythrocyte ATP and
NO release in blood flow regulation have accumulated. Information from other
vertebrate groups is integrated in the analysis and used to discuss the
evolutionary origin and general relevance of each hypothesis.

/pdf/the-dual-roles-of-red-blood-cells-in-tissue-oxygen-delivery-2aeequibyp.pdf

The dual roles of red blood cells in tissue oxygen delivery: oxygen carriers and regulators of local blood flow.

Hemoglobin (Hb) increases the O2 carrying capacity of the blood of ectothermic vertebrates by about twenty times compared to physically dis­ solved O2. This drastically raises the blood O2 capacitance coefficient ({30,= .leo /.lpo) and permits corresponding reductions in the cardiac output (Qh) 2 2 • required for a given convective O2 transfer (V 0) as predicted by the Fick • • 2 equation (V 0, = Qh . (30, . .lp 0,). The O2 transporting role of Hb, however, also depends on its qualitative properties, namely (a) its intrinsic O2 binding properties and (b) its interaction with factors that modulate these properties inside the red cells. Ectotherm erythrocytes contain a full complement of cellular apparatus (including nucleus, mitochondria, and endoplasmic reticu­ lum), exhibit high metabolic activity compared to mammalian erythrocytes, and greater potential for feedback regulation of tissue O2 supply via cellular metabolites that affect Hb-02 affinity. The molecular properties of Hb have been dealt with in recent treatises (1, 77, 84, lO7). This review focuses on the physiological function of ectotherm Hb in the red blood cells, particularly the interand intraspecific adaptations to exogenous and endogenous factors like ambient hypoxia (low O2 tension), temperature, activity, and dormancy, and illustrates these with representative examples.

Frank B. Jensen

Papers

Nitrite disrupts multiple physiological functions in aquatic animals.

Red blood cell pH, the Bohr effect, and other oxygenation‐linked phenomena in blood O2 and CO2 transport

Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation.

The dual roles of red blood cells in tissue oxygen delivery: oxygen carriers and regulators of local blood flow.

Functional Adaptations in Hemoglobins from Ectothermic Vertebrates