V. D. Mikoyan

HYPOTENSIVE EFFECT AND TISSUE DISTRIBUTION OF THE DINITROSYL IRON COMPLEXES, A NITRIC OXIDE DONOR

Hypotensive effect of the dinitrosyl iron complexes, an NO donor, is compared with distribution of these complexes in organs and tissues after their intravenous administration to wakeful animals. Hypotensive effect of iron complexes depended on dose and postinjection time. There was a strong correlation between hypotensive effect and the content of dinitrosyl iron complex in the studied organs. Effective dose of dinitrosyl iron complexes that did not provoke adverse effects was about 200 mg/kg. This preparation is a prospective source of NO to treat and prevent pathological states related to NO deficiency.

Can Summary Nitrite+Nitrate Content Serve as an Indicator of NO Synthesis Intensity in Body Tissues?

Studies with the use of a highly specific enzymatic sensor demonstrated that, contrary to the common opinion, normally nitrate is in fact not present in the most important physiological fluids. NO metabolites in the amniotic fluid and semen are mainly presented by NO donor compounds. Therefore, the intensity of NO synthesis can be evaluated by the total content of all its metabolites, but not by the widely used summary nitrite+nitrate content.

Differences in NO generation during heat shock in genetically different populations of rats

The content of NO in the kidneys, heart, and spleen of intact August rats surpasses that of Wistar rats. After heat shock the content of NO rises: in the kidneys 15.5-fold, in the liver 3.2-fold, in the heart 10-fold, in the spleen 6.4-fold, in the intestine 2.8-fold, and in the brain 1.9-fold. Thus, August rats, which are less resistant to heat shock than Wistar rats, are characterized by a more pronounced activation of NO synthesis in response to heat shock.

Enhanced production of nitric oxide in rat organs in heat shock

Heat shock is shown to lend a marked boost to the production of nitric oxide (NO), which attains the maximal level 1 hour after exposure and returns to the initial level after 24 hours. The generation of NO in all studied organs is completely blocked by Nω-nitro-L-arginine, an inhibitor of NO synthase, both in the control and after hyperthermia. Thus, heat shock markedly stimulates NO synthesis. This generalized effect may underlie the drop in the peripheral vascular tone that is characteristic of heat shock.

Endothelial function and nitric oxide production in rats adapted to intermittent hypoxia

Adaptation to intermittent hypoxic hypoxia did not affect the endothelium-dependent relaxation of the aorta in rats, but significantly increased the relaxation of their tail artery. Following the adaptation, the NO level fell in the liver, intestine, and kidneys and remained unchanged in the spleen. Adaptation to hypoxia presumably limits NO synthesis and/or release in the vascular endothelium or enhances the capacity of this oxide to bind in a physiologically active depot.

Long-term cardiac protective effect of nitric oxide

We have examined the effect of the dinitrosyl iron complexes, the NO donors, on the resistance of isolated heart to ischemia and reperfusion, as well as the effect of quercetin, an inhibitor of HSP70 transcription, on NO-induced enhancement of cardiac resistance to ischemia and reperfusion. The iron complexes were found to produce dose-and time-dependent protective effect and enhance the resistance of isolated heart to rhythm and contraction disorders during reperfusion. The maximum protective effect was observed 12–24 h postinjection of the 200 mg/kg dose. Quercetin completely prevented protective effect of the NO donor. The property of NO donors to stimulate HSP70 synthesis and the present data indicate that NO-dependent activation of HSP70 synthesis is a natural mechanism of cardiac protection against disturbances provoked by ischemia and reperfusion.

NITRIC OXIDE LEVEL DRAMATICALLY INCREASES IN THE RAT BRAIN DURING EPILEPTIFORM SEIZURES

Nitric oxide (NO), a highly reactive, short-lived radical, is believed to be a trans- neuronal messenger in the central nervoussystem. NO is generated by the enzyme NO- synthase, which was shown to occur widely in the central nervous system. NO has been implicated in several brain disorders such as Alzheimer’s and Parkinson’s deseases, stroke, trauma, epilepsy, etc. Under these pathological conditions excessive release of excitatory amino acid glutamate results in increase of NO content in the brain to a toxic level. Epilepsy is one of the diseases in which excitatory amino acids are implicated and NO could be an important pathogenetic factor in the mechanisms that underlie seizure induction, propagation and progression. However, acute effects of neuronal NO overflow on brain functions are still a matter of controversy. NO-synthase, the enzyme responsible for NO synthesis in mammalian brain from L-arginine, can be blocked by arginine analogues such as L-NNA. These compounds can be used as a tool to investigate the role of nitric oxide in various cellular mechanisms. Recent reports claim NO to be either pro- or anticonvulsant (1,2). The aim of the present study was to prove whether model convulsive states of different origin in rats may involve any alteration in NO content and in content of secondary products of lipid peroxidation in the brain cortex.

Enhanced expression of sarcoplasmic reticulum Ca2+-ATPase gene plays a role in protective effects of nitric oxide

This study verifies the hypothesis that NO-dependent regulation of sarcoplasmic reticulum Ca2+-ATPase gene (SERCA) plays an important role in preventing Ca2+ overload after exposure to damaging factors. The data confirmed NO-dependent activation of SERCA expression and important role of this mechanism in the reduction of calcium overload.

Thermal adaptation activates HSP70 synthesis, inhibits overproduction of nitric oxide, and protects the body from acute hypotension during heat shock

The role of HSP70 and nitric oxide in antihypotensive effects of thermal adaptation was studied. Western blot analysis and electron paramagnetic resonance were used to determine the contents of HSP70 and nitric oxide. Protective effect of adaptation was evaluated by the limitation of blood pressure drop after heat shock. The formation of protective effects, accumulation of HSP70, and development of the ability to decrease nitric oxide overproduction had similar dynamic patterns and appeared at the same period. Quercetin, an inhibitor of HSP70 synthesis, prevented the development of protective effects. The data suggest that HSP70 accumulated during adaptation prevents heat shock-induced hypotension by restricting NO over-production and interfering with its cytotoxic effects.

IS NITRIC OXIDE INVOLVED IN THE ADAPTATION TO THE STRESS-INDUCED DAMAGE ?

The iron dinitrosyl complex (a NO donor), adaptation to stress, and their combination suppress the stress-induced ulcer formation. Nω-nitro-L-arginine, a NO synthetase inhibitor, reduce the antistress effect of adaptation. Severe stress induces a sharp decrease in the NO production in the liver and brain. After adaptation to stress, the NO production in the liver and brain does not differ significantly from control levels. However, adaptation attenuates a decrease in the NO production in the liver caused by severe stress.