Accumulation of copper in kidney of spontaneously hypertensive rats, a preliminary study

Mineral levels such as Cu, Fe, Zn, Ca and Mg in organs of spontaneously hypertensive osteogenic disorder Shionogi rat (SHR-od) were compared with those of normotensive osteogenic disorder Shionogi rat (ODS). The effect of vitamin C deficiency was also examined for both strains. Cu levels in kidney of SHR-od increased to 2.2 times and 5.0 times that of ODS at 6-week old and 30-week old, respectively, although the effect of vitamin C deficiency was not observed in Cu levels of five organs examined. The effect of vitamin C deficiency appeared in the change in the other mineral levels almost similarly for both SHR-od and ODS rats at 30-week old; the decrease of Fe in liver, spleen and lung, whereas the increase of Zn in liver, Ca in heart and Mg in spleen, respectively.     

Age-related changes in antioxidant defence mechanisms and peroxidation in isolated hepatocytes from spontaneously hypertensive and normotensive rats

The effects of age and hypertension on the antioxidant defence systems and the lipid peroxidation in rat isolated hepatocytes were studied. Four different age groups (1,3,6 and 12 months) were considered in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Age-associated changes were observed on vitamin E status, glutathione (GSH) level, MDA formation and glutathione peroxidase (GSH-Px) activity in both strains. Maximal levels or activities of these parameters were found at 3 and 6 months, except for MDA which was low at 3 months. Then, a fall was observed at 12-month-old compared to 6-month values. In addition, GSH-Px activity was significantly lower in SHR than in WKY rats, except at the age of one month. The decrease of this enzyme activity could induce an increased cellular generation of radical species and lipid peroxidation, which might be link to hypertension.     

Factors influencing the expression of stress fibers in vascular endothelial cells in situ

The organization of actin and myosin in vascular endothelial cells in situ was studied by immunofluorescence microscopy. Examination of perfusion-fixed, whole mounts of normal mouse and rat descending thoracic aorta revealed the presence of axially oriented stress fibers containing both actin and myosin within the endothelial cells. In both species, the proportion of cells containing stress fibers varied from region to region within the same vessel. Some endothelial cells in mouse mesenteric vein and in rat inferior vena cava also contained stress fibers. Quantitative studies of the proportion of endothelial cells containing stress fibers in the descending thoracic aorta of age- matched normotensive and spontaneously hypertensive rats revealed significant differences. When animals of the same sex of the two strains were compared, the proportion was approximately two times greater in the spontaneously hypertensive rats. The proportion of endothelial cells containing stress fibers was about two times greater in males than in females of both strains. These observations suggest that multiple factors, including anatomical, sex, and hemodynamic differences, influence the organization of the endothelial cell cytoskeleton in situ.     

A missense mutation in the Abcg5 gene causes phytosterolemia in SHR,stroke-prone SHR,and WKY rats

Sitosterolemia is an autosomal recessive disorder caused by mutations in the ABCG5 or ABCG8 half-transporter genes. These mutations disrupt the mechanism that distinguishes between absorbed sterols and is most prominently characterized by hyperabsorption and impaired biliary elimination of dietary plant sterols. Sitosterolemia patients retain 15-20% of dietary plant sterols, whereas normal individuals absorb less than 1-5%. Normotensive Wistar Kyoto inbred (WKY inbred), spontaneously hypertensive rat (SHR), and stroke-prone spontaneously hypertensive rat (SHRSP) strains also display increased absorption and decreased elimination of dietary plant sterols. To determine if the genes responsible for sitosterolemia in humans are also responsible for phytosterolemia in rats, we sequenced the Abcg5 and Abcg8 genes in WKY inbred, SHR, and SHRSP rat strains. All three strains possessed a homozygous guanine-to-thymine transversion in exon 12 of the Abcg5 gene that results in the substitution of a conserved glycine residue for a cysteine amino acid in the extracellular loop between the fifth and sixth membrane-spanning domains of the ATP binding cassette half-transporter, sterolin-1. The identification of this naturally occurring mutation confirms that these rat strains are important animal models of sitosterolemia in which to study the mechanisms of sterol trafficking.     

Vitamin E, membrane fluidity, and blood pressure in hypertensive and normotensive rats

Vitamin E treatment was found to lower blood pressure, and increase membrane fluidity in rats. The objectives of this study were to investigate the effects of the antioxidant, vitamin E, on the blood pressure and erythrocyte membrane fluidity in spontaneously hypertensive (SHR) and normotensive (WKY) rats. Membrane fluidity was assessed using spin labeling technique and electron paramagnetic resonance (EPR) spectroscopy. Two different spin labels were used in this study, 5-doxylstrearic acid (5-SASL) and 16-doxylstearic acid (16-SASL). The rats were given vitamin E, 3 days/week for 3 weeks and blood pressure was measured once weekly, using the tail-cuff method. Subsequently, blood was taken via heart puncture and erythrocytes were prepared for spin labeling. The fluidity of the membrane in the nonpolar region of erythrocytes from hypertensive rats was found quite different from that of normal rats as judged by the spectra of 16-SASL. The values of maximum splitting parameter of the EPR spectra of the spin label 5-SASL incorporated in erythrocyte membrane from both SHR and WKY rats, and the effects of vitamin E on membrane fluidity were compared. The maximum splitting parameter calculated from EPR spectra was larger for SHR than WKY rats. Additionally, the maximum splitting parameter calculated for vitamin E treated SHR and WKY rats were lower than those of their respective controls. As expected, the blood pressure of the SHR rats was found to be higher than that of the WKY rats. Vitamin E treated SHR and WKY rats showed significantly lower blood pressure than their controls.     

Coexisting independent sodium-sensitive and sodium-insensitive mechanisms of genetic hypertension in spontaneously hypertensive rats (SHR)

Some essential hypertensive patients and genetic hypertensive rat strains have less than the normal levels of Mg2+ tightly bound to the plasma membranes of their erythrocytes and other cells, i.e., the magnesium binding defect (MgBD). This binding defect appears to cause increased passive permeability of the membrane to Na+ and thereby its increased intracellular concentration, particularly if the Na+-extrusion enzyme systems of the cell are also defective. The Na+-Ca2+ exchange system in the cell membrane exports Na+ and imports Ca2+, increasing the tone of the smooth muscle cell and thus producing hypertension (HTn). This HTn is Na+-sensitive. Evidence supporting this postulate was obtained by determining the intraerythrocyte total concentrations of Na+, Ca2+, K+, and Mg2+ in two strains of spontaneously hypertensive rats (SHR and SS/Jr rats, having the MgBD together with the other requisites of the Na+-sensitive pathway) and their respective controls (WKY and SR/Jr rats, in which this complete pathway is absent). The Na+ and Ca2+ concentrations in the hypertensive rats were increased, and that of K+ was decreased. The concentrations of these cations were very similar in the two hypertensive strains. The level of membrane tightly bound Ca2+ in SHR erythrocyte membranes was significantly higher than those in the other three rat strains, which were not statistically different from each other. These results support previously reported evidence of the existence of a novel HTn-generating mechanism in the SHR rat, in which the intracellular Ca2+ concentration is increased as the result of the enhanced diffusion of this ion into the cell and the accompanying deficiency of the Ca2+ extrusion enzyme systems. This pathway is therefore Na+-insensitive, i.e., Ca2+-sensitive.     

Whole-Genome Sequences of DA and F344 Rats with Different Susceptibilities to Arthritis,Autoimmunity, Inflammation and Cancer

DA (D-blood group of Palm and Agouti, also known as Dark Agouti) and F344 (Fischer) are two inbred rat strains with differences in several phenotypes, including susceptibility to autoimmune disease models and inflammatory responses. While these strains have been extensively studied, little information is available about the DA and F344 genomes, as only the Brown Norway (BN) and spontaneously hypertensive rat strains have been sequenced to date. Here we report the sequencing of the DA and F344 genomes using next-generation Illumina paired-end read technology and the first de novo assembly of a rat genome. DA and F344 were sequenced with an average depth of 32-fold, covered 98.9% of the BN reference genome, and included 97.97% of known rat ESTs. New sequences could be assigned to 59 million positions with previously unknown data in the BN reference genome. Differences between DA, F344, and BN included 19 million positions in novel scaffolds, 4.09 million single nucleotide polymorphisms (SNPs) (including 1.37 million new SNPs), 458,224 short insertions and deletions, and 58,174 structural variants. Genetic differences between DA, F344, and BN, including high-impact SNPs and short insertions and deletions affecting >2500 genes, are likely to account for most of the phenotypic variation between these strains. The new DA and F344 genome sequencing data should facilitate gene discovery efforts in rat models of human disease.     

Strain Differences in Superovulatory Response, Embryo Development and Efficiency of Transgenic Rat Production

The differences between rat strains in superovulation response, in vitro and in vivo development of preimplantation embryos and overall transgenic efficiency was studied. The protocols for induction of superovulation using single injections of pregnant mare’s serum gonadotropin (PMSG) or minipumps with follicle stimulating hormone (FSH) were compared in Lewis (LEW), Wistar-Kyoto (WKY), and stroke-prone spontaneously hypertensive rats (SHRSP) or Sprague–Dawley (SD) and Wistar rats as representative inbred or outbred strains, respectively. The percentage of mated animals with positive superovulatory response was similar in all strains (60.0–100%). The mean number of ova per donor was not dependent on the kind of hormonal treatment used within each rat strain. In general, females from outbred SD and Wistar rats were more responsive to hormonal treatments than animals from inbred rat strains. In addition, SD female rats produced a significantly higher number of embryos per female in response to PMSG-treatment compared to all other strains. Between the inbred strains, SHRSP was the most effective for superovulation. In vitro development of intact zygotes to the blastocyst stage was not different between SD, Wistar and SHRSP rats. In contrast, in vitro development of WKY zygotes was significantly less efficient than in other strains. However, 2-cell stage embryos in vivo produced from SD, SD × Wistar and WKY animals showed no difference in competence to develop to blastocyst stage in vitro. The proportion of offspring developing after oviduct transfer of intact zygotes was similar in all strains (44.0–56.4%) with the exception of WKY rats (35.9%). We also compared the survival rate after injection, ability of manipulated zygotes to develop to term and overall transgenic efficiency in various rat strains. SD and SHRSP zygotes survived after microinjection better than the WKY and Lewis zygotes. No differences were found in the efficiency of transgene integration per newborn in different strains ranging from 5.7 to 16.7%. The results of this study demonstrate that different rat strains have varying responses to superovulation, sensitivity to microinjection, capability to develop in vitro until blastocyst stage or in vivo to term after transfer to foster mothers. Despite these differences all studied strains can be used for efficient transgenic rat production.     

A review of changes in vascular smooth muscle functions in hypertension: isolated tissue versus in vivo studies

The role of altered vascular smooth muscle function in the etiology of essential hypertension has been extensively studied by a number of investigators. The results obtained from in vivo studies do not always correlate with results from in vitro studies and it is not always apparent whether the results reflect differences related to hypertension or to the genetic background of the animal model. In vitro and perfused vascular bed studies in our laboratory have utilized the spontaneously hypertensive rat (SHR), the normotensive Wistar Kyoto rat (WKY), genetically related crossbred rats (F1, F2, and BC1), and also Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The role of altered smooth muscle function in relation to the development of the elevated blood pressure (BP) of the SHR or DS rat was studied and emphasis was placed on determining the role of altered neuronal uptake1 (U1) in hypertensives in masking elevated postsynaptic sensitivity to noradrenaline. In addition, the relationship between postsynaptic sensitivity to cations and BP was assessed. Such studies have indicated that alterations in postsynaptic sensitivity, U1 activity, and sensitivity to cations are not entirely consistent with the etiology of hypertension in the SHR and DS rat but may simply reflect genetic strain differences between the hypertensive and normotensive animals.     

The rat STSL locus: characterization, chromosomal assignment, and genetic variations in sitosterolemic hypertensive rats

Background

Elevated plant sterol accumulation has been reported in the spontaneously hypertensive rat (SHR), the stroke-prone spontaneously hypertensive rat (SHRSP) and the Wistar-Kyoto (WKY) rat. Additionally, a blood pressure quantitative trait locus (QTL) has been mapped to rat chromosome 6 in a New Zealand genetically hypertensive rat strain (GH rat). ABCG5 and ABCG8 (encoding sterolin-1 and sterolin-2 respectively) have been shown to be responsible for causing sitosterolemia in humans. These genes are organized in a head-to-head configuration at the STSL locus on human chromosome 2p21.

Methods

To investigate whether mutations in Abcg5 or Abcg8 exist in SHR, SHRSP, WKY and GH rats, we initiated a systematic search for the genetic variation in coding and non-coding region of Abcg5 and Abcg8 genes in these strains. We isolated the rat cDNAs for these genes and characterized the genomic structure and tissue expression patterns, using standard molecular biology techniques and FISH for chromosomal assignments.

Results

Both rat Abcg5 and Abcg8 genes map to chromosome band 6q12. These genes span ~40 kb and contain 13 exons and 12 introns each, in a pattern identical to that of the STSL loci in mouse and man. Both Abcg5 and Abcg8 were expressed only in liver and intestine. Analyses of DNA from SHR, SHRSP, GH, WKY, Wistar, Wistar King A (WKA) and Brown Norway (BN) rat strains revealed a homozygous G to T substitution at nucleotide 1754, resulting in the coding change Gly583Cys in sterolin-1 only in rats that are both sitosterolemic and hypertensive (SHR, SHRSP and WKY).

Conclusions

The rat STSL locus maps to chromosome 6q12. A non-synonymous mutation in Abcg5, Gly583Cys, results in sitosterolemia in rat strains that are also hypertensive (WKY, SHR and SHRSP). Those rat strains that are hypertensive, but not sitosterolemic (e.g. GH rat) do not have mutations in Abcg5 or Abcg8. This mutation allows for expression and apparent apical targeting of Abcg5 protein in the intestine. These rat strains may therefore allow us to study the pathophysiological mechanisms involved in the human disease of sitosterolemia.     

Estradiol increases salt intake in female normotensive and hypertensive rats.

The objective of this study was to examine whether or not estradiol (E2) alters sodium intake in hypertensive and normotensive female rats. It was hypothesized that higher doses of E2 would increase sodium consumption and that this response would be greater in spontaneously hypertensive rats (SHR) compared with Wistar Kyoto (WKY) rats. The study involved female SHR and WKY (n = 12/group). All animals were ovariectomized. Six of twelve rats from each strain received three progressively larger doses of beta-estradiol propionate (each dose lasting 2 wk), whereas the other six rats from each strain received sham implants. Blood E2 levels were measured by radioimmunoassay after each 2-wk period, allowing a 10-day washout period before the next E2 dose. Rats had access to 0.0, 0.5, 1.0, and 1.5% NaCl solutions to drink throughout the experiment. There was a significant positive correlation between sodium intake and plasma E2 (r = 0.8, P < 0.001). Both strains avoided the 1.5% NaCl, and the increased sodium intake was achieved by an increase in consumption of the 0.5% NaCl. SHR females consumed more sodium than WKY females, which is similar to what has been observed in males of these strains. In conclusion, E2 was positively correlated with sodium intake in both strains of rat, with the hypertensive rats consuming more sodium than the normotensive rats.     

Analgesic activity of morphiceptin, beta-casomorphin-4, and deltakephalin in normotensive Wistar-Glaxo and spontaneously hypertensive rats

The effects of intraventricular injection of beta-casomorphin-4, morphiceptin and deltakephalin (DTLET) on hot water tail flick and tail compression responses were investigated in Wistar Albino Glaxo (WAG) and spontaneously hypertensive rats (SHR). The effects of the mu agonist morphiceptin (20 nmol/rat), as assessed by the tail compression test, were significantly greater in SHR rats but did not differ between both strains when measured by tail flick latency. Opioid agonist deltakephalin (2 nmol/rat) in both tests elicited stronger analgesic effects in SHR as compared to WAG and these effects were blocked by naloxone in both tests used. beta-Casomorphin-4 exhibits moderate activity for mu receptors. In the tail flick test peptide (60 nmol/rat) produced an increase in latencies in SHR rats that was significantly greater than was observed in WAG rats. Naloxone pretreatment abolished the analgesic activity of beta-casomorphin-4 solely in the tail compression test in SHR. Analysis of the slopes of the dose-response curves seems to suggest that differences between the activity of these opioid peptides in SHR and WAG rats are based on a difference in the density and affinity of the subpopulation of the opioid receptors in these strains of rats.     

Sodium-induced rise in blood pressure is suppressed by androgen receptor blockade

Our objective was to test the hypothesis that 1) a high Na (HNa, 3%) diet would increase blood pressure (BP) in male Wistar-Kyoto (WKY) and spontaneously hypertensive Y chromosome (SHR/y) rat strains in a territorial colony; 2) sympathetic nervous system (SNS) blockade using clonidine would lower BP on a HNa diet; and 3) prepubertal androgen receptor blockade with flutamide would lower BP on a HNa diet. A 2 x 4 factorial design used rat strains (WKY, SHR/y) and treatment [0.3% normal Na (NNa), 3% HNa, HNa/clonidine, and HNa/flutamide]. BP increased in both strains on the HNa diet (P < 0.0001). There was no significant decrease in BP in either strain with clonidine treatment. Androgen receptor blockade with flutamide significantly decreased BP in both strains (P < 0.0001) and normalized BP in the SHR/y colony. Neither heart rate nor activity could explain these BP differences. In conclusion, a Na sensitivity was observed in both strains, which was reduced to normotensive values by androgen blockade but not by SNS blockade.     

Vitamin E concentrations in different regions of the spinal cord and sciatic nerve of the rat

Since the spinal cord and peripheral nerves are vulnerable to the effects of vitamin E deficiency, vitamin E concentrations in various discrete regions of these parts of the nervous system of the rat were determined. Furthermore, as acrylamide toxicity and vitamin E deficiency share some neuropathological features, tissue vitamin E concentrations in acrylamide-treated rats were also studied. Male Sprague Dawley rats (200 to 250 g body weight) were fed normal rat chow with or without 0.03% acrylamide in their drinking water. After 24 days, the animals were sacrificed and the tissues assayed for vitamin E by a liquid chromatographic method. Vitamin E concentrations decreased from cerebral cortex to spinal cord with no concentration gradients between different levels of the spinal cord. Sciatic nerve concentration of alpha tocopherol was as high as that of cerebral cortex, and the former also contained measurable amounts of gamma tocopherol. Vitamin E concentrations in the majority of nervous tissue samples remained unchanged with acrylamide treatment.Presented in part at the Sixteenth Annual Meeting of the American Society for Neurochemistry, March 1985.     

Ion transport in erythrocytes of Prague hypertensive rat

The Prague hypertensive rat is a unique strain exhibiting genetic hypertension in which a hypertensive line (PHR) was bred in parallel with a normotensive one (Prague normotensive rat--PNR) from the same parental pair. Sodium efflux from Na(+)-loaded erythrocytes into Mg2(+)-sucrose medium was measured in these two strains as well as in spontaneously hypertensive rats (Okamoto-Aoki, SHR) and in normotensive outbred Wistar rats. Kinetic parameters--maximal velocity and apparent dissociation constant (reflecting the affinity for internal sodium)--were calculated. It was found that PHR as well as SHR had a higher Na+ leak and a decreased activity of the ouabain-sensitive Na+ transport as compared to Wistar rats. Furosemide-sensitive Na+ transport was substantially lower in erythrocytes of both hypertensive strains (PHR and SHR) than in the respective normotensive strains (PNR and Wistar).     

Zinc,iron, vitamin E,and erythrocyte stability in the rat

Previous studies have shown that deficiencies of zinc and vitamin E, as well as iron excess, contribute to peroxidative damage in several tissues in vivo. The present study reports on the sensitivity of red blood cells from young rats exposed to individual or concurrent imbalances of these three nutrients. For 21 d, rats were fed diets that were either deficient or replete in zinc and with or without excess iron or replete or deficient in vitamin E. When red blood cells from these rats were incubated in vitro, erythrocyte hemolysis, lipid peroxidation (assessed by MDA production), and hemoglobin degradation (assessed by alanine release), did not significantly increase unless vitamin E had been omitted from the diet. These results imply that either adequate tightly-bound zinc exists within the zinc-deficient cell to protect it from oxidative damage, or that other antioxidant defense mechanisms (including vitamin E) present within the plasma membrane and cytosol are sufficient to protect the cell from the otherwise damaging effects of zinc deficiency and/or iron excess.     

Central monoamine oxidase and phenolsulfotransferase activities in spontaneously hypertensive rats

The activities of monoamine oxidase and phenolsulfotransferase in the hypothalamus and anterior pituitary gland of spontaneously hypertensive rats and the normotensive control (Wistar Kyoto rat) rats were investigated. The monoamine oxidase activity (determined using dopamine as substrate) in both these tissues was not significantly different between the normo- and hypertensive animals. Hypothalamic phenolsulfotransferase does not sulfate-conjugate dopamine at pH of 6.5 and pituitary phenolsulfotransferase does not sulfate-conjugate dopamine or 3,4-dihydroxyphenylacetic acid at the same pH. Hypothalamic phenolsulfotransferase activity determined using 3,4-dihydroxyphenylacetic acid as substrate was significantly higher in the spontaneously hypertensive than the Wistar Kyoto rats, while pituitary enzyme (determined using phenol as substrate) was the same in both strains of animals. We proposed that in the spontaneously hypertensive rats the higher level of hypothalamic phenolsulfotransferase could (by removing 3,4-dihydroxyphenylacetic acid as sulfated acid) increase the deamination of dopamine by monoamine oxidase. This could in turn result in the presence of high amount of sulfated 3,4-dihydroxyphenylacetic acid in the anterior pituitary gland reported in our earlier study, and be partly responsible for the reduced central dopaminergic activity found in the hypertensive rats.     

Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats

Hypertension is a major risk factor for stroke, but the factors that contribute to the increased incidence and severity of ischemic stroke in hypertension remain to be determined. 20-hydroxyeicosatetraenoic acid (20-HETE) has been reported to be a potent constrictor of cerebral arteries, and inhibitors of 20-HETE formation reduce infarct size following cerebral ischemia. The present study examined whether elevated production of 20-HETE in the cerebral vasculature could contribute to the larger infarct size previously reported after transient middle cerebral artery occlusion (MCAO) in hypertensive strains of rat [spontaneously hypertensive rat (SHR) and spontaneously hypertensive stroke-prone rat (SHRSP)]. The synthesis of 20-HETE in the cerebral vasculature of SHRSP measured by liquid chromatography-tandem mass spectrometry was about twice that seen in Wistar-Kyoto (WKY) rats. This was associated with the elevated expression of cytochrome P-450 (CYP)4A protein and CYP4A1 and CYP4A8 mRNA. Infarct volume after transient MCAO was greater in SHRSP (36+/-4% of hemisphere volume) than in SHR (19+/-5%) or WKY rats (5+/-2%). This was associated with a significantly greater reduction in regional cerebral blood flow (rCBF) in SHR and SHRSP than in WKY rats during the ischemic period (78% vs. 62%). In WKY rats, rCBF returned to 75% of control following reperfusion. In contrast, SHR and SHRSP exhibited a large (166+/-18% of baseline) and sustained (1 h) postischemic hyperperfusion. Acute blockade of the synthesis of 20-HETE with N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016; 1 mg/kg) reduced infarct size by 59% in SHR and 87% in SHRSP. HET0016 had no effect on the fall in rCBF during MCAO but eliminated the hyperemic response. HET0016 also attenuated vascular O2*- formation and restored endothelium-dependent dilation in cerebral arteries of SHRSP. These results indicate the production of 20-HETE is elevated in the cerebral vasculature of SHRSP and contributes to oxidative stress, endothelial dysfunction, and the enhanced sensitivity to ischemic stroke in this hypertensive model.     

Non-antioxidative mechanism of cytochrome P-450 stabilization by alpha-tocopherol: the effectiveness in avitaminosis E

The efficiency of alpha-tocopherol as a 7-etoxycumarine deethylase protector in rat liver microsomes damaged by phospholipase A2 at various levels of vitamin E was studied. No selective damage of cytochrome P-450 isoforms possessing a catalytic activity towards 7-etoxycumarine under vitamin E deficiency was observed. Phospholipase A2 decreased the deethylase activity of cytochrome P-450, the efficiency of the damaging action being dependent on vitamin E content in the liver. Exogenous alpha-tocopherol exerts an antiphospholipase effect and protects 7-etoxycumarine deethylase; the protective action is inversely proportional to vitamin E level in the liver. Under normal conditions the damaging effect of phospholipase A2 on cytochrome P-450 is mainly provided for by lysophospholipids, while under vitamin E deficiency both lysophospholipids and free fatty acids exert a damaging action. A possible mechanism of the stabilizing effect of alpha-tocopherol may consist in the interaction of the chromanol nucleus in the vitamin E molecyule both with lysophospholipids and with free fatty acids.     

The Role of Preventing Nitric Oxide Deficiency in the Antihypertensive Effect of Adaptation to Hypoxia

Shortage of endothelial nitric oxide (NO) manifested as decreased daily urinary excretion of nitrate and nitrite as well as attenuated endothelium-dependent relaxation of conduit and resistance vessels progresses with age-related increase of blood pressure (BP) in stroke-prone spontaneously hypertensive rats (SHRSP). Simultaneous NO-dependent suppression of vascular contractions is, apparently, due to the inducible NO synthase activity in vascular smooth muscle specific for spontaneously hypertensive rat. The adaptation of rats to hypobaric hypoxia initiated at early hypertensive stage (at the age of 5–6 weeks) decelerates hypertension progress. The antihypertensive effect of the adaptation was accompanied by stimulation of endothelial NO synthesis and prevention of impaired NO-dependent response in isolated blood vessels. Nitric oxide stores were formed in the vascular wall of SHRSP and WKY rats at the same time. The obtained data indicate that the correction of endothelial NO deficiency plays a significant role in the antihypertensive effect of adaptation to hypoxia.