Gene transfer of a novel vasoactive natriuretic peptide stimulates cGMP and lowers blood pressure in mice

Dendroaspis natriuretic peptide (DNP) is a recently described peptide produced by Dendroaspis angusticeps with structural and functional similarities to mammalian natriuretic peptides. These similarities suggest a potential role for DNP in cardiovascular therapeutics. To determine the physiological effects of chronic delivery of DNP, a gene transfer approach using first generation adenoviral vectors was utilized. Although the gene for DNP has not been cloned in any species, the peptide sequence in the snake is known. Preferred mammalian codons for snake DNP were cloned downstream of either the leader sequence (referred to as pBDNP-1) or prepropeptide sequence of human brain natriuretic peptide (BNP) cDNA (referred to as pBDNP-2). Transfections with pBDNP-1 or pBDNP-2 resulted in expected forms of chimeric DNP (cDNP) in cell lysates and conditioned media. Functional studies demonstrated the ability of both forms of cDNP within conditioned media to stimulate cGMP production in human vascular smooth muscle cells (hVSMC). Expressed cDNP inhibited hVSMC proliferation and stimulated vasorelaxation in a similar fashion. To investigate the chronic physiological effects of administration of cDNP, an adenoviral vector expressing cDNP (Ad-BDNP) was generated. Intravenous delivery of Ad-BDNP in mice resulted in dose-dependent systemic expression of cDNP. The highest level of expression was associated with consistent elevation of its presumed second messenger (cGMP) for 21 days but with transient lowering of systolic blood pressure in normotensive mice. This study demonstrates the biological features of the expression of the xenogenic peptide DNP.     

Ferulic acid supplementation prevents trimethyltin-induced cognitive deficits in mice

This study's objective was to clarify the ameliorative effects ferulic acid (4-hydroxy-3-methoxycinnamic acid) has against cognitive deficits and ChAT activation in trimethyltin (TMT) induced, memory injured mice following a 28-d ferulic acid treatment. After administering TMT for 3 d, each mouse performed Y-maze and passive avoidance tests to check immediate working memory performance and cognitive function. The results showed that ferulic acid administration attenuated TMT-induced memory injury and a decline in ChAT activity in the mice. This suggests that ferulic acid might be useful for preventing cognitive dysfunction as well as for boosting the activation of ChAT in dementia.     

Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

The effect of pyruvate dehydrogenase kinase-4 (PDK4) deficiency on glucose homeostasis was studied in mice fed a high-fat diet. Expression of PDK4 was greatly increased in skeletal muscle and diaphragm but not liver and kidney of wild-type mice fed the high-fat diet. Wild-type and PDK4(-/-) mice consumed similar amounts of the diet and became equally obese. Insulin resistance developed in both groups. Nevertheless, fasting blood glucose levels were lower, glucose tolerance was slightly improved, and insulin sensitivity was slightly greater in the PDK4(-/-) mice compared with wild-type mice. When the mice were killed in the fed state, the actual activity of the pyruvate dehydrogenase complex (PDC) was higher in the skeletal muscle and diaphragm but not in the liver and kidney of PDK4(-/-) mice compared with wild-type mice. When the mice were killed after overnight fasting, the actual PDC activity was higher only in the kidney of PDK4(-/-) mice compared with wild-type mice. The concentrations of gluconeogenic substrates were lower in the blood of PDK4(-/-) mice compared with wild-type mice, consistent with reduced formation in peripheral tissues. Diaphragms isolated from PDK4(-/-) mice oxidized glucose faster and fatty acids slower than diaphragms from wild-type mice. Fatty acid oxidation inhibited glucose oxidation by diaphragms from wild-type but not PDK4(-/-) mice. NEFA, ketone bodies, and branched-chain amino acids were elevated more in PDK4(-/-) mice, consistent with slower rates of oxidation. These findings show that PDK4 deficiency lowers blood glucose and slightly improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity.     

HO-1 induction lowers blood pressure and superoxide production in the renal medulla of angiotensin II hypertensive mice

Heme oxygenase-1 (HO-1) induction can attenuate the development of angiotensin II (ANG II)-dependent hypertension. However, the mechanism by which HO-1 lowers blood pressure in this model is not clear. The goal of this study was to test the hypothesis that induction of HO-1 in the kidney can attenuate the increase in reactive oxygen species (ROS) generation in the kidney that occurs during ANG II-dependent hypertension. Mice were divided into four groups, control (Con), cobalt protoporphyrin (CoPP), ANG II, and ANG II + CoPP. CoPP treatment (50 mg/kg) was administered in a single subcutaneous injection 2 days prior to implantation of an osmotic minipump that infused ANG II at a rate of 1 microg x kg(-1) x min(-1). At the end of this period, mean arterial blood pressure (MAP) averaged 93 +/- 5, 90 +/- 5, 146 +/- 8, and 105 +/- 6 mmHg in Con, CoPP-, ANG II-, and ANG II + CoPP-treated mice. To determine whether HO-1 induction resulted in a decrease in ANG II-stimulated ROS generation in the renal medulla, superoxide production was measured. Medullary superoxide production was increased by ANG II infusion and normalized in mice pretreated with CoPP. The reduction in ANG II-mediated superoxide production in the medulla with CoPP was associated with a decrease in extracellular superoxide dismutase protein but an increase in catalase protein and activity. These results suggest that reduction in superoxide and possibly hydrogen peroxide production in the renal medulla may be a potential mechanism by which induction of HO-1 with CoPP lowers blood pressure in ANG-II dependent hypertension.     

Fenofibrate lowers blood pressure in two genetic models of hypertension

Fenofibrate, a commonly used lipid lowering drug, induces the expression of the gene coding for cytochrome P450-4A, whose major product is 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a potassium channel antagonist, could increase or decrease blood pressure (BP). We studied the effects of four weeks of oral fenofibrate on BP, urine output (UVol), plasma renin activity (PRA), and urine protein excretion in young (4-5 weeks) stroke prone spontaneously hypertensive rats (SHRSP), older (25 weeks) SHRSP, Dahl salt sensitive rats (Dahl S) on a high salt diet, Dahl S rats on a normal salt diet, and normotensive Sprague-Dawley (SD) rats. Fenofibrate prevented the increase in BP in 4-5 week old SHRSP, reduced BP in 25 week old SHRSP, but had no effect on BP in normotensive SD rats. Similarly, fenofibrate prevented the increase in BP in Dahl S rats on a high salt diet, but had no effect in Dahl S rats on a low salt diet. Fenofibrate increased UVol (and reduced weight gain) in young SHRSP and tended to increase it in other groups. It also increased PRA 2 to 5-fold in all groups except older SHRSP. Young SHRSP receiving fenofibrate excreted significantly less urine protein than control rats. The drug reduced proteinuria in Dahl S rats on high salt diet, but had no significant effect on proteinuria in other groups. In summary, fenofibrate reduced blood pressure and weight gain, increased UVol and PRA, and reduced urine protein excretion in young SHRSP. Other groups of animals showed these changes to a variable, but directionally similar extent. These findings are consistent with a natriuretic effect of fenofibrate.     

Modulation by insulin rather than blood glucose of the pain threshold in acute physiological and flavone induced antinociception in mice

The present study investigated the cause effect relationship between glycemic and algesic states. The hypo- and hyperglycemic conditions were induced physiologically through exercise (3 min swim at room temperature 28 degrees - 30 degrees C) and external dextrose (2 g/kg, ip) administration respectively in mice. Besides, flavone (50 mg/kg, sc) a known antinociceptive drug was chosen to study such a cause effect relationship. The anti-nociception was assessed by acetic acid assay, blood glucose measured using glucometer (Ames) and serum insulin by radioimmunoassay. The findings revealed that irrespective of the glycemic state whether hypo-, hyper, or euglycemic induced by swim stress, dextrose or flavone per se respectively, significant antinociceptive response was recorded. Pretreatment with flavone (50 mg/kg, sc) always exhibited a tendency to reverse the hyperglycemia, if any, but enhanced the antinociceptive response either after swim stress or after dextrose. These data support the contention that changes in the glycemic state in acute condition is not responsible for antinociceptive response and thereby suggesting dissociation between these two parameters. Extended studies estimating serum insulin level after the above mentioned maneuvers showed a significant rise whenever antinociceptive response was recorded irrespective of the glycemic state. It is suggested that serum insulin level, a hormonal parameter rather than the blood glucose level, which is a metabolic parameter, appears more reliable. It appears that the changes in serum insulin level produced by various treatments may have a relationship with the antinociceptive response. However, this study has the limitation that the results can apply only for acute conditions and extrapolation to clinical conditions is debatable.     

Vitamin C lowers blood pressure and alters vascular responsiveness in salt-induced hypertension

The present study was undertaken to investigate the effect of vitamin C treatment on blood pressure and vascular reactivity in salt-induced hypertension. Male Sprague-Dawley rats were fed a normal rat diet, a high-sodium (8% NaCl) diet, a normal rat diet plus vitamin C treament (100 mg x kg(-1) x day(-1)), or a high-sodium diet plus vitamin C treatment for 6 weeks. Salt loading significantly increased blood pressure, which was attenuated by vitamin C treatment. Aortic rings from the different groups were suspended for isometric-tension recording. The contractile response to noradrenaline was significantly increased in the salt-loaded rats. Vitamin C reduced the sensitivity of aortic rings to noradrenaline in rats on normal and high-sodium diets. In noradrenaline-precontracted rings, the relaxation response to acetylcholine, which was attenuated in the salt-loaded rats, was restored by vitamin C treatment. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) abolished the enhanced response to acetylcholine caused by vitamin C. The results suggest that the antihypertensive effect of vitamin C is associated with a reduction in vascular sensitivity to noradrenaline and enhancement of endothelium-dependent relaxation due to increased nitric oxide bioavailability.     

Glucuronidated quercetin lowers blood pressure in spontaneously hypertensive rats via deconjugation

Background

Chronic oral quercetin reduces blood pressure and restores endothelial dysfunction in hypertensive animals. However, quercetin (aglycone) is usually not present in plasma, because it is rapidly metabolized into conjugated, mostly inactive, metabolites. The aim of the study is to analyze whether deconjugation of these metabolites is involved in the blood pressure lowering effect of quercetin.

Methodology/Principal Findings

We have analyzed the effects on blood pressure and vascular function in vitro of the conjugated metabolites of quercetin (quercetin-3-glucuronide, Q3GA; isorhamnetin-3-glucuronide, I3GA; and quercetin-3′-sulfate, Q3''S) in spontaneously hypertensive rats (SHR). Q3GA and I3GA (1 mg/kg i.v.), but not Q3''S, progressively reduced mean blood pressure (MBP), measured in conscious SHR. The hypotensive effect of Q3GA was abolished in SHR treated with the specific inhibitor of β-glucuronidase, saccharic acid 1,4-lactone (SAL, 10 mg/ml). In mesenteric arteries, unlike quercetin, Q3GA had no inhibitory effect in the contractile response to phenylephrine after 30 min of incubation. However, after 1 hour of incubation Q3GA strongly reduced this contractile response and this effect was prevented by SAL. Oral administration of quercetin (10 mg/Kg) induced a progressive decrease in MBP, which was also suppressed by SAL.

Conclusions

Conjugated metabolites are involved in the in vivo antihypertensive effect of quercetin, acting as molecules for the plasmatic transport of quercetin to the target tissues. Quercetin released from its glucuronidated metabolites could be responsible for its vasorelaxant and hypotensive effect.     

Dietary vitamin E supplementation lowers blood pressure in spontaneously hypertensive rats

Pre-eclampsia, is the most common, pregnancy-associated pathological syndrome accompanied by a significant increase in collagen and sulphated glycosaminoglycans (GAGs) contents in the umbilical cord arteries (UCAs). Insulin-like growth factor-I (IGF-I) is expressed in most foetal tissues and it is involved in anabolic effects. It stimulates protein (mainly collagen) and GAG biosynthesis, cell proliferation and differentiation. Previously, we have found that pre-eclampsia is associated with an increase of IGF-I concentration in the umbilical cord blood. A family of IGF-I-binding proteins (BPs) modulates the activity of IGF-I. We demonstrated qualitative differences between BPs of normal and pre-eclamptic human umbilical cord (UC) serum and UC-tissues (UCA-wall and Wharton's jelly) by Western immunoblot analysis. All examined sera and tissues contained BP-1 and BP-5 as well lower molecular weight materials. The BP-2 was recovered from both control and pre-eclamptic sera, while it was not detected in the UC-tissues. Instead, lower molecular weight forms of BP-2 were found as judged by the anti-BP-2 antibody. The BP-3 was detected in sera, UCA and Wharton's jelly. The most distinct expression of BP-3 was found in the UCA. The pre-eclamptic UCA and Wharton's jelly contained additional BP-3-reactive material of lower molecular weight. The BP-4 was strongly expressed in pre-eclamptic UC-serum and the expression was decreased in pre-eclamptic UC-tissues, compared to respective controls. Ligand binding assay revealed that most of IGF-I was bound to 46 kDa region (typical for BP-3) in both control and pre-eclamptic sera and tissues. However, distinctly less IGF-I was bound in pre-eclamptic serum, distinctly more in pre-eclamptic UCA and no differences were found in pre-eclamptic Wharton's jelly, compared to controls. We demonstrated that both normal and pre-eclamptic UC-sera and tissues are able to degrade 46 kDa IGF-I-BP. The degradation may result in a decrease of IGF-I binding, contributing to increase in free IGF-I that may stimulate the cells to produce extracellular matrix (ECM) components. The specific BPs and their proteolytic modification in UC tissues may be important modulators of IGF-I action during foetal development.     

Extra-cardiac BCAA catabolism lowers blood pressure and protects from heart failure

1. Download : Download high-res image (225KB)
2. Download : Download full-size image

     

Antioxidant activity and hypoglycemic effect of ferulic acid in STZ-induced diabetic mice and KK-Ay mice

Antioxidant activity and biological properties of ferulic acid (FA) are well recognized. This study was designed to estimate the potential utility of FA administered orally at low dosage for improvement of hyperglycemia in diabetes. With this aim we have evaluated the hypoglycemic effect of FA in two type diabetic animal models: (1) streptozotocin (STZ)-induced diabetic mice, a model of insulin-dependent diabetes mellitus (IDDM); (2) KK-Ay mice, a model of non-insulin dependent diabetes mellitus (NIDDM). In addition, we measured the production of thiobarbituric acid-reactive substances (TBARS) in brown adipose tissues of diabetic mice at the end of FA feeding experiment. FA at 0.01% and 0.1% of basal diet showed to suppress significantly blood glucose levels in STZ-induced diabetic mice. In KK-Ay mice 0.05% FA suppressed effectively blood glucose levels. In addition, FA inhibited the lipid peroxidation in brown adipose tissue of diabetic mice. Taken together, these findings suggest that dietary FA may be useful in alleviating oxidative stress and attenuating the hyperglycemic response associated with diabetes.     

Dietary vitamin C supplementation lowers blood pressure in spontaneously hypertensive rats

In spontaneously hypertensive rats (SHRs) excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca²⁺ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes. Vitamin C can increase tissue cysteine and glutathione levels. The aim of the present study was to investigate whether a dietary supplementation of vitamin C can lower tissue aldehydes and blood pressure and normalize associated biochemical and histopathological changes in SHRs. Starting at 12 weeks of age, animals were divided into 3 groups of 6 animals each. Animals in the WKY-control group and SHR-control group were given a normal diet and the SHR-vitamin C group a diet supplemented with vitamin C (1000 mg/kg feed) for the next 9 weeks. After nine weeks, systolic blood pressure, platelet [Ca²⁺]_i, plasma insulin and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared to WKY controls and the SHR-vitamin C group. SHR-controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin C supplementation in SHRs lowered the systolic blood pressure, tissue aldehyde conjugates and attenuated adverse renal vascular changes.     

Glial-specific ablation of angiotensinogen lowers arterial pressure in renin and angiotensinogen transgenic mice

Angiotensinogen (AGT) is mainly expressed in glial cells in close proximity to renin-expressing neurons in the brain. We previously reported that glial-specific overexpression of ANG II results in mild hypertension. Here, we tested the hypothesis that glial-derived AGT plays an important role in blood pressure regulation in hypertensive mice carrying human renin (hREN) and human AGT transgenes under the control of their own endogenous promoters. To perform a glial-specific deletion of AGT, we used an AGT transgene containing loxP sites (hAGT(flox)), so the gene can be permanently ablated in the presence of cre-recombinase expression, driven by the glial fibrillary acidic protein (GFAP) promoter. Triple transgenic mice (RAC) containing a: 1) systemically expressed hREN transgene, 2) systemically expressed hAGT(flox) transgene, and 3) GFAP-cre-recombinase were generated and compared with double transgenic mice (RA) lacking cre-recombinase. Liver and kidney hAGT mRNA levels were unaltered in RAC and RA mice, as was the level of hAGT in the systemic circulation, consistent with the absence of cre-recombinase expression in those tissues. Whereas hAGT mRNA was present in the brain of RA mice (lacking cre-recombinase), it was absent from the brain of RAC mice expressing cre-recombinase, confirming brain-specific elimination of AGT. Immunohistochemistry revealed a loss of AGT immunostaining glial cells throughout the brain in RAC mice. Arterial pressure measured by radiotelemetry was significantly lower in RAC than RA mice and unchanged from nontransgenic control mice. These data suggest that there is a major contribution of glial-AGT to the hypertensive state in mice carrying systemically expressed hREN and hAGT genes and confirm the importance of a glial source of ANG II substrate in the brain.     

阿魏酸对糖尿病小鼠心肌病变的影响及其机制

目的：研究阿魏酸对高脂饮食结合小剂量链脲佐菌素（STZ）诱导的2型糖尿病小鼠心肌病变的影响,探讨其可能的作用机制。方法：雄性ICR小鼠20只,高糖高脂饮食连续6周,STZ （30 mg/kg）腹腔注射连续5d后,隔9d测空腹血糖（FBG）,超过11.1 mmol/L视为糖尿病造模成功。将此20只小鼠随机分为模型组、阿魏酸组（200 mg/kg,i.g.）,每组10只;另取10只正常小鼠为对照组;连续给药8周。末次给药后,测定FBG、称体重、全心重和左心室重,计算心脏质量指数（HMI）和左室质量指数（LVMI）;测定超氧化物歧化酶（SOD）活力、丙二醛（MDA）含量;Masson染色观察左心室纤维增生情况;免疫组化法测定心肌组织转化生长因子-β1（TGF-β1）、Ⅲ型胶原蛋白表达。结果：与模型组小鼠比较,阿魏酸组小鼠HMI、LVMI减小（（P<0.01,P<0.05）,心肌组织SOD活力升高、MDA含量下降（P<0.05）;心肌胶原纤维沉积减少,间质纤维化改善;免疫组化显示心肌组织TGF-β1和Ⅲ型胶原蛋白表达减少（P<0.01,P<0.05）。结论：阿魏酸对糖尿病小鼠心肌病变具有保护作用,可能与抗氧化及抑制TGF-β1蛋白表达,减少Ⅲ型胶原蛋白沉积有关。     

Alpha-lactorphin lowers blood pressure measured by radiotelemetry in normotensive and spontaneously hypertensive rats

Cardiovascular effects of subcutaneous administration of synthetic alpha-lactorphin, a tetrapeptide (Tyr-Gly-Leu-Phe) originally derived from milk alpha-lactalbumin, were studied in conscious spontaneously hypertensive rats (SHR) and in normotensive Wistar Kyoto rats (WKY) with continuous radiotelemetric monitoring. Alpha-lactorphin dose-dependently lowered blood pressure (BP) without affecting heart rate in SHR and WKY. The lowest dose which reduced BP was 10 microg/kg, and the maximal reductions in systolic and diastolic BP (by 23+/-4 and 17+/-4 mm Hg, respectively) were observed at 100 microg/kg dose in SHR. No further reductions were obtained at a higher dose of 1 mg/kg. There were no significant differences in the BP responses to alpha-lactorphin between SHR and WKY. Naloxone (1 and 3 mg/kg s.c.), a specific opioid receptor antagonist, abolished the alpha-lactorphin-induced reduction in BP and reversed it into a pressor response, which provides evidence for an involvement of opioid receptors in the depressor action of the tetrapeptide.     

Origin of p-aminobenzoic acid from chorismic rather than iso-chorismic acid in Enterobacter aerogenes and Streptomyces species

Enzyme extracts from Enterobacter aerogenes (62-1), Streptomyces aminophilus, and Streptomyces coelicolor were used to investigate the biosynthesis of p-aminobenzoic acid. The enzyme preparations from E. aerogenes and S. aminophilus contained both p-aminobenzoate synthase and iso-chorismate synthase activity, and were able to convert both chorismic and iso-chorismic acid to p-aminobenzoic acid. The apparent KM for chorismic acid was, however, significantly lower than that for iso-chorismic acid, while the Vmax was identical for both substrates in both enzyme systems. The enzyme preparations from S. coelicolor did not contain iso-chorismate synthase activity and p-aminobenzoic acid synthesis took place in this system from chorismic acid only. It is concluded that iso-chorismic acid is not an obligatory intermediate in p-aminobenzoic acid biosynthesis in these organisms.     

LVV-hemorphin-7 lowers blood pressure in spontaneously hypertensive rats: radiotelemetry study

Cardiovascular effects of LVV-hemorphin-7, a member of the family of fragments from beta-chain of human or bovine hemoglobin, were studied in conscious spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats by radiotelemetry. Intraperitoneal injection of hemorphin in a dose of 100 microg/kg significantly decreased blood pressure in SHR, whereas negligible effect was seen in normotensive WKY rats. Blood pressure changes were accompanied by reduction of heart rate. In conclusion, a direct effect of LVV-hemorphin-7 on blood pressure was demonstrated in SHR. These biologically active peptides could be involved in blood pressure regulation especially in hypertensive rats, but the precise mechanism should be elucidated.     

A novel vasopressin peptide lowers blood pressure through decreases in cardiac output

The changes in blood pressure, cardiac output, and total peripheral conductance evoked by the novel hypotensive arginine vasopressin (AVP) - like peptide, d(CH2)5[D-Tyr(Et)2,Arg3,Val4,Arg7,Eda9]AVP (HYPO-AVP), were recorded in conscious unrestrained Sprague-Dawley rats implanted with radiotelemetry pressure transducers and ultrasonic transit-time flowprobes. Intravenous infusions of 0.6, 1.0, 2.0, and 4.0 microg x kg(-1) x min(-1) of HYPO-AVP evoked dose-related decreases in blood pressure. At the lowest dose of 0.6 microg x kg(-1) x min(-1), the fall in blood pressure was associated with a small but significant increase in total peripheral conductance. Cardiac output was unchanged. In contrast, at the three higher doses of 1.0, 2.0, and 4.0 microg x kg(-1) x min(-1), the fall in blood pressure was related to a dramatic fall in cardiac output. Indeed, total peripheral conductance decreased, preventing blood pressure from falling further. These hemodynamic findings should help to direct future research into the mechanism of the putative hypotensive property of vasopressin, a property that attenuates the well established blood pressure elevating actions of the peptide.     

Docosahexaenoic acid, but not eicosapentaenoic acid, lowers ambulatory blood pressure and shortens interval QT in spontaneously hypertensive rats in vivo

This study was designed to evaluate the effects of individual dietary long-chain n-3 polyunsaturated fatty acids (LCPUFA) on hypertension and cardiac consecutive disorders in spontaneously hypertensive rats (SHR) as compared to Wistar-Kyoto rats (WKY). Rats were fed for 2 months an eicosapentaenoic (EPA)- or docosahexaenoic acid (DHA)-rich diet (240 mg/day) or an n-3 PUFA-free diet. Male SHR (n=6), implanted with cardiovascular telemetry devices, were housed in individual cages for continuous measurements of cardiovascular parameters (blood pressure (BP) and heart rate (HR)) during either activity or rest periods, ECG were recorded during the quiet period. The n-6 PUFA upstream of arachidonic acid was affected in SHR tissues. The cardiac phospholipid fatty acid profile was significantly affected by dietary DHA supply, and EPA in a very lower extent, since DHA only was incorporated in the membranes instead of n-6 PUFAs. Endothelium n-6 PUFA content increased in all SHR groups. Compared to WKY, linoleic acid content decreased in both studied tissues. Cardiac noradrenalin decreased while the adrenal catecholamine stores decreased in SHR as compared to WKY. Both n-3 PUFA supply induced a decrease of adrenal catecholamine stores. Nevertheless after 6 weeks, DHA but not EPA induced a lowering-blood pressure effect and shortened the QT interval in SHR, most probably through its tissue enrichment and a specific effect on adrenergic function. Dietary DHA supply retards blood pressure development and has cardioprotective effect. These findings, showing the cardioprotective effects of DHA in living animals, were obtained in SHR, but may relate to essential hypertension in humans.     

三种突变GRK4转基因小鼠的血压动态分析

目的建立GRK4γ野生型和三种GRK4γ基因突变的转基因小鼠,并对其血压进行动态分析,建立高血压模型。方法把人GRK4γ野生型、GRK4γR 65L、GRK4γA142V和GRK4γA486V三个突变基因分别插入鸡β-肌动蛋白启动子下游,构建转基因表达载体,显微注射法建立C57BL/6J GRK4野生型和突变的转基因小鼠,PCR鉴定转基因小鼠基因型。采用Western Blot鉴定GRK4在心脏、肾脏和肾上腺中的表达筛选高表达转基因品系。用无创血压测量仪分析转基因小鼠动态血压。结果建立了在心脏、肾脏和肾上腺均高表达GRK4基因的转基因小鼠。转基因表达人GRK4γ野生型和GRK4γR 65L突变的小鼠血压正常,转基因表达人GRK4γA142V突变的小鼠在正常的钠盐摄入情况下即可发生高血压,而转基因表达人GRK4γA486V突变的小鼠只有在增加钠盐摄入情况下才发生高血压。结论 GRK4γA142V转基因小鼠可作为自发性高血压动物模型,GRK4γA486V转基因小鼠可作为盐敏感性高血压动物模型。