TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer.

The existence of tumor-suppressor genes was originally demonstrated by functional complementation through whole-cell and microcell fusion. Transfer of chromosome 11 into a human non-small-cell lung cancer (NSCLC) cell line, A549, suppresses tumorigenicity. Loss of heterozygosity (LOH) on the long arm of chromosome 11 has been reported in NSCLC and other cancers. Several independent studies indicate that multiple tumor-suppressor genes are found in this region, including the gene PPP2R1B at 11q23-24 (ref. 7). Linkage studies of NSCLC are precluded because no hereditary forms are known. We previously identified a region of 700 kb on 11q23.2 that completely suppresses tumorigenicity of A549 human NSCLC cells. Most of this tumor-suppressor activity localizes to a 100-kb segment by functional complementation. Here we report that this region contains a single confirmed gene, TSLC1, whose expression is reduced or absent in A549 and several other NSCLC, hepatocellular carcinoma (HCC) and pancreatic cancer (PaC) cell lines. TSLC1 expression or suppression is correlated with promoter methylation state in these cell lines. Restoration of TSLC1 expression to normal or higher levels suppresses tumor formation by A549 cells in nude mice. Only 2 inactivating mutations of TSLC1 were discovered in 161 tumors and tumor cell lines, both among the 20 primary tumors with LOH for 11q23.2. Promoter methylation was observed in 15 of the other 18 primary NSCLC, HCC and PaC tumors with LOH for 11q23.2. Thus, attenuation of TSLC1 expression occurred in 85% of primary tumors with LOH. Hypermethylation of the TSLC1 promoter would seem to represent the 'second hit' in NSCLC with LOH.

Structural basis for the coiled-coil architecture of human CtIP.

The DNA repair factor CtIP has a critical function in double-strand break (DSB) repair by homologous recombination, promoting the assembly of the repair apparatus at DNA ends and participating in DNA-end resection. However, the molecular mechanisms of CtIP function in DSB repair remain unclear. Here, we present an atomic model for the three-dimensional architecture of human CtIP, derived from a multi-disciplinary approach that includes X-ray crystallography, small-angle X-ray scattering (SAXS) and diffracted X-ray tracking (DXT). Our data show that CtIP adopts an extended dimer-of-dimers structure, in agreement with a role in bridging distant sites on chromosomal DNA during the recombinational repair. The zinc-binding motif in the CtIP N-terminus alters dynamically the coiled-coil structure, with functional implications for the long-range interactions of CtIP with DNA. Our results provide a structural basis for the three-dimensional arrangement of chains in the CtIP tetramer, a key aspect of CtIP function in DNA DSB repair.

Minimum stable structure of the receptor for advanced glycation end product possesses multi ligand binding ability.

The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor involved in the development of diabetic complications. Although the soluble form of the extracellular domain maintains the ability to bind multi-ligands, it is unstable and degrades into several peptide species during storage. Proteolysis with thrombin or factor Xa revealed several protease sensitive sites. Most sensitive site is located between Arg228 and Val229, and peptide bond next to Arg216, Arg116, Arg114 and Trp271 are also cleaved. Seven truncated extracellular domains of RAGE were engineered in order to obtain a stable soluble fragment. RAGE 143 (Ala23-Thr143) is not only protease resistant but also shows the same ligand-binding ability as that of the full-length extracellular domain. The resultant minimum RAGE 143 works as a stable recognition devise to detect advanced glycation end products (AGEs).

Superior: a novel repetitive DNA element dispersed in the rye genome.

A new class of rye-specific repetitive DNA elements designated Superior has been identified. The rye genome library was constructed by cleavage with EcoO109I, the recognition sites of which consisted of 5'-PuGGNCCPy-3' multi-sequences and were present with high frequency in the rye repetitive families. A novel 495-bp segment enriched in the rye genome was successfully identified. Southern blot hybridization and fluorescence in situ hybridization using the repetitive element showed a dispersed array through all 7 chromosomes of rye. The repetitive DNA element did not share identity with known class I or class II transposable elements or known repetitive elements. Only several DNA segments in BACs and ESTs of barley showed partial similarity to the repetitive DNA element in all DNA databases of living species. The new class of dispersed repetitive elements was designated Superior. The entire structure of Superior was determined by using a rye genomic library of lambda FIXII screened by the 495-bp probe. The Superior family consisted of 1,292-bp, 1,324-bp, and 1,432-bp elements in which the 5' regions had been destroyed, indicating the presence of considerable structural diversity. Superior might be a useful tool for studying genomic organization and differentiation.

Effect of Gadolinium on the Estimation of Myelin and Brain Tissue Volumes Based on Quantitative Synthetic MRI.

BACKGROUND AND PURPOSE: The effect of gadolinium on the estimation of myelin has not been reported. The aim of the current study was to investigate the effects of gadolinium on automatic myelin and brain tissue volumetry via quantitative synthetic MR imaging. MATERIALS AND METHODS: The study included 36 patients who were referred for brain metastases screening, and quantitative synthetic MR imaging data before and after gadolinium-based contrast agent administration were analyzed retrospectively. Brain metastases were detected in 17 patients. WM volume, GM volume, CSF volume, non-WM/GM/CSF volume, myelin volume, brain parenchymal volume, myelin fraction (myelin volume/brain parenchymal volume), and intracranial volume were estimated. T1 and T2 relaxation times, proton density, and myelin partial volume per voxel averaged across the brain parenchyma were also analyzed. RESULTS: In patients with and without metastases after gadolinium-based contrast agent administration, measurements of WM and myelin volumes, and myelin fraction were significantly increased (+26.65 and +29.42 mL, +10.14 and +12.46 mL, +0.88% and +1.09%, respectively), whereas measurements of GM, CSF, brain parenchymal, and intracranial volumes were significantly decreased (-36.23 and -34.49 mL, -20.77 and -18.94 mL, -6.76 and -2.84 mL, -27.41 and -21.84 mL, respectively). Non-WM/GM/CSF volume did not show a significant change. T1, T2, and proton density were significantly decreased (-51.34 and -46.84 ms, -2.67 and -4.70 ms, -1.05%, and -1.28%, respectively) after gadolinium-based contrast agent administration, whereas measurements of myelin partial volume were significantly increased (+0.78% and +0.75%, respectively). CONCLUSIONS: Gadolinium had a significant effect on the automatic calculation of myelin and brain tissue volumes using quantitative synthetic MR imaging, which can be explained by decreases in T1, T2, and proton density.

Young adult-specific hyperphagia in diabetic Goto-kakizaki rats is associated with leptin resistance and elevation of neuropeptide Y mRNA in the arcuate nucleus.

The present study aimed to examine whether hyperphagia, which is frequently observed in type 1 diabetic patients and model animals, also occurs in type 2 diabetic Goto-Kakizaki (GK) rats and, if so, to explore underlying abnormalities in the hypothalamus. GK rats at postnatal weeks 6-12, compared to control Wistar rats, exhibited hyperphagia, hyperglycaemia, hyperleptinemia and increased visceral fat accumulation, whereas body weight was unaltered. The ability of leptin to suppress feeding was reduced in GK rats compared to Wistar rats of these ages. In GK rats, leptin-induced phosphorylation of signal transducer and activator of transcription 3 was significantly reduced in the cells of the hypothalamic arcuate nucleus (ARC), but not of the ventromedial hypothalamus, whereas the mRNA level of functional leptin receptor was unaltered. By real-time polymerase chain reaction and in situ hybridisation, mRNA levels of neuropeptide Y, but not pro-opiomelanocortin and galanin-like peptide, were significantly increased in the ARC of GK rats at 11 weeks, but not 26 weeks. Following i.c.v. injection of a NPY Y1 antagonist, 1229U91, the amount of food intake in GK rats was indistinguishable from that in Wistar rats, thus eliminating the hyperphagia of GK rats. These results demonstrate that young adult GK rats display hyperphagia in association with leptin resistance and increased NPY mRNA level in the ARC.

Isolation of the TSLL1 and TSLL2 genes, members of the tumor suppressor TSLC1 gene family encoding transmembrane proteins.

We have recently identified the TSLC1 gene as a novel tumor suppressor in human non-small cell lung cancers. TSLC1 encodes a membrane glycoprotein with an extracellular domain homologous to those of immunoglobulin superfamily proteins. Truncation of TSLC1 in the cytoplasmic domain in a primary human tumor suggests that this domain is important for tumor suppressor activity. Here, we report the isolation of two TSLC1-like genes, TSLL1 and TSLL2, based on their structural homology with the sequences corresponding to the cytoplasmic domain of TSLC1. Significant similarity was also observed in the extracellular domain as well as in the overall gene structure, indicating that these three genes form a unique subfamily (the TSLC1-gene family) in the immunoglobulin superfamily genes. In contrast to the ubiquitous expression of TSLC1, TSLL1 is expressed exclusively in adult and fetal human brain, while TSLL2 is expressed in several specific tissues including prostate, brain, kidney and some other organs. Expression of TSLL1 and TSLL2 was lost or markedly reduced in many human glioma cell lines or some prostate cancer cell lines, suggesting that loss of expression of these genes might be involved in some human cancers.

Measurement of left atrial systolic time intervals in hypertensive patients using Doppler echocardiography: relation to fourth heart sound and left ventricular wall thickness.

The concept of left atrial systolic time intervals and Doppler echocardiography were used in a quantitative assessment of left atrial function in relation to the presence or absence of a fourth heart sound and to left ventricular hypertrophy in 47 patients with hypertension. Left atrial systolic time interval indexes included atrial pre-ejection period (the time between the onset of an electrocardiographic P wave and the onset of left ventricular inflow during atrial systole [A wave]), corrected atrial pre-ejection period (the atrial pre-ejection period divided by the duration of the P wave), and atrial ejection time (the time between the onset and cessation of the A wave). Twenty-one patients with a fourth heart sound on the phonocardiogram had a shorter atrial pre-ejection period (81 +/- 10 versus 89 +/- 14 ms p less than 0.05) and a corrected atrial pre-ejection period (66 +/- 17 versus 83 +/- 18 ms, p less than 0.01), as well as a longer atrial ejection time (147 +/- 15 versus 126 +/- 13 ms, p less than 0.001) than did 26 patients without a fourth heart sound. The ratio of atrial pre-ejection period to atrial ejection time and that of corrected atrial pre-ejection period to atrial ejection time was smaller in patients with than in patients without a fourth heart sound (0.56 +/- 0.08 versus 0.71 +/- 0.11, p less than 0.001; 0.46 +/- 0.16 ms-1 versus 0.67 +/- 0.17 ms-1, p less than 0.001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased sodium-calcium exchange in arterial smooth muscle of spontaneously hypertensive rats.

We compared sodium-calcium (Na-Ca) exchange in vascular smooth muscle between spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Aortic rings of 11 SHR and 11 WKY rats aged 11-12 weeks were superfused with physiological saline, and isometric tension was measured. Systolic blood pressure was higher in SHR (174 +/- 12 mm Hg) than in WKY rats (132 +/- 4 mm Hg): 1) In the presence of 10 microM phentolamine, 10 microM verapamil, and 5 mM caffeine, reduction of ionized extracellular sodium concentration [( Na+]o) from normal (139.2 mM) to 1.2 mM (replaced by N-methyl-D-glucamine) caused an external Ca2+-dependent increase in tonic tension (calcium entry by Na-Ca exchange). The rate of increase was higher in SHR (35.4 +/- 3.9 mg/min) than in WKY rats (17.9 +/- 1.3 mg/min) (p less than 0.01). 2) In the presence of phentolamine, verapamil, and caffeine, relaxation from low-Na+ contraction was promoted by external calcium removal. The rate of relaxation was directly related to [Na+]o. The rates of relaxation at normal (139.2 mM) [Na+]o were higher in SHR than in WKY rats (p less than 0.05). The rates of relaxation at 1.2 mM [Na+]o (calcium extrusion by adenosine triphosphate-driven calcium pump) were not different between SHR (11.6 +/- 2.8 mg/min) and WKY rats (8.9 +/- 2.5 mg/min). The increase in the rates of relaxation from 1.2 mM to normal (139.2 mM) [Na+]o (calcium extrusion by Na-Ca exchange) was greater in SHR (34.9 +/- 6.6 mg/min) than in WKY rats (17.1 +/- 4.5 mg/min) (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum hepatocyte growth factor in patients with peripheral arterial occlusive disease.

Hepatocyte growth factor (HGF) is a multifunctional protein implicated in tissue regeneration, wound healing, and angiogenesis. We measured serum HGF concentrations in 37 patients with peripheral arterial occlusive disease (PAOD). Among them, 36 patients underwent arteriography. Serum HGF concentrations were also measured in 40 control subjects who remained free of vascular, liver, kidney, or lung disease. Patients with PAOD showed elevated serum HGF concentrations compared with control subjects (0.40+/-0.02 vs. 0.19+/-0.01 ng/mL; P<0.001). Serum HGF concentrations were significantly higher in smokers compared with nonsmokers (0.45+/-0.03 vs. 0.35+/-0.02 ng/mL; P = 0.003). The serum HGF concentrations in patients with collaterals tended to be higher than those in patients without collaterals (0.43+/-0.03 vs. 0.35+/-0.02 ng/mL; P = 0.06). Moreover, in patients who underwent bypass surgery or angioplasty, serum HGF concentrations decreased from 0.41+/-0.03 to 0.21+/-0.04 ng/mL after treatment (P<0.001). Serum HGF may be an useful marker for the diagnosis of PAOD. HGF may play an important role in angiogenesis and collateral vessel growth in PAOD.

Effect of synthetic human atrial natriuretic peptide on aldosterone secretion by dispersed aldosterone-producing adenoma cells in vitro.

The effect of synthetic alpha-human atrial natriuretic peptide (alpha hANP), a potent natriuretic and vasorelaxant polypeptide recently isolated from human atria, on aldosterone secretion was studied in vitro in collagenase-dispersed adrenal adenoma cells from a patient with primary aldosteronism. alpha hANP (3.2 X 10(-7) M) significantly inhibited both basal and potassium (16 mM)-stimulated aldosterone secretion, whereas it had little or no effect on aldosterone secretion submaximally or maximally stimulated by ACTH (3.4 X 10(-10)-3.4 X 10(-9) M) or angiotensin II (10(-8)-10(-9) M). The less potent effect of alpha hANP on aldosterone secretion by dispersed human adrenal tumor cells compared to that in in vitro animal studies may reflect decreased affinity and/or number of specific receptors for ANP on the tumor cells. Whether ANP plays a physiological role in regulation of aldosterone secretion in humans in vivo remains to be determined.

Acute depressor effect of alcohol in patients with essential hypertension.

To investigate the time course of the effects of alcohol on blood pressure, we studied the response of ambulatory blood pressure, neurohumoral variables, and hemodynamics to a single moderate dose of alcohol in hypertensive patients. Sixteen Japanese men (22-70 years old) with essential hypertension who were habitual drinkers were examined under standardized conditions. On the alcohol intake day, they ingested 1 ml/kg ethanol (vodka) at dinner, and on the control day they consumed a nonalcoholic beverage. The order of the two periods was randomized. Mean ambulatory blood pressure was lower in the alcohol intake period than in the control period (125 +/- 3/74 +/- 2 versus 132 +/- 4/78 +/- 2 mm Hg, p less than 0.05), and the significant depressor effect of alcohol lasted for up to 8 hours after drinking. Blood pressure on the next day did not differ with or without alcohol intake. The acute hypotensive effect of alcohol was associated with an increase in heart rate and cardiac output and with a decrease in systemic vascular resistance as determined by echocardiography. Plasma catecholamine levels and renin activity rose significantly at 2 hours after dinner, whereas vasopressin and potassium levels fell on the alcohol day. Blood glucose and serum insulin levels were comparable between the two periods. Three patients with marked alcohol-induced flush had greater hypotensive and tachycardiac responses than those who did not show an alcohol-induced flush. The change in mean blood pressure induced by alcohol was negatively correlated with age, the baseline blood pressure, and the change in plasma norepinephrine. These results indicate that the major effect of acute alcohol intake is to lower blood pressure through systemic vasodilatation in hypertensive subjects. Ambulatory blood pressure monitoring may be useful for assessing blood pressure in habitual drinkers.

Renal function curve in patients with secondary forms of hypertension.

The causative mechanisms of hypertension were investigated by studying the renal function (pressure-natriuresis) curve in patients with primary aldosteronism (n = 6) and renovascular hypertension (n = 6). Before and after radical operation (removal of adenoma in primary aldosteronism and percutaneous transluminal angioplasty in renovascular hypertension), dietary NaCl intake was altered from 10 to 13 g/day in Week 1 to 1 to 3 g/day in Week 2. Mean arterial pressure (MAP) and urinary sodium excretion were measured on the last 3 days of each week. By restricting sodium intake before operation, MAP was reduced from 122 +/- 7 to 113 +/- 7 mm Hg (p less than 0.025) in primary aldosteronism but not in renovascular hypertension (130 +/- 6 to 128 +/- 5 mm Hg). The renal function curve was drawn by plotting urinary sodium excretion on the ordinate and MAP on the abscissa before and after operation. The slope of the curve was analyzed between the plotted points, and each curve was extrapolated to zero sodium excretion as an estimate of the degree of shift of the curve along the MAP axis. Before, as compared with after operation, the extrapolated x-intercept of the curve was shifted rightward in both primary aldosteronism (111 +/- 7 vs 87 +/- 4 mm Hg; p less than 0.025) and renovascular hypertension (128 +/- 5 vs 95 +/- 2 mm Hg; p less than 0.025) and the slope was depressed in primary aldosteronism (16 +/- 1 vs 40 +/- 17 [mEq/day]/mm Hg; p less than 0.025) but not in renovascular hypertension (130 +/- 75 vs 40 +/- 13 [mEq/day]/mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin lowers blood pressure in patients with renovascular hypertension.

To clarify the role of renal prostanoid in hyperreninemia and high blood pressure in human renovascular hypertension, we measured prostaglandin E2 and renin activity in renal venous and abdominal aortic plasma before and after the intravenous administration of the cyclooxygenase inhibitor, aspirin DL-lysine. Subjects were six patients with unilateral renovascular hypertension and six with essential hypertension. In patients with renovascular hypertension, prostaglandin E2 concentration in renal venous plasma from the stenotic kidney was 9.25 +/- 1.48 pg/ml, which was significantly higher (p less than 0.01) than the concentration in the renal venous plasma from the normal kidney (4.97 +/- 1.02 pg/ml) or in the aortic plasma (2.59 +/- 0.15 pg/ml). Plasma renin activity was also higher in the renal vein of the stenotic kidney than in the other two sites. The stenotic side/normal side ratio of the renal venous prostaglandin E2 correlated significantly with a renin ratio greater than 1.5 (r = 0.8211, p less than 0.05). Intravenous injection of aspirin DL-lysine (18 mg/kg) 30 minutes later markedly suppressed prostaglandin E2 and renin levels at all sites and clearly lowered arterial blood pressure (mean: from 120 +/- 6 to 110 +/- 5 mm Hg, p less than 0.01). The reduction in blood pressure correlated significantly with the suppression of plasma renin activity in the aorta (p less than 0.05) and in the renal vein of the stenotic kidney (p less than 0.01). Conversely, in patients with essential hypertension, aspirin had little effect on renin levels and increased mean blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of changes in cardiac structure after treatment in secondary hypertension.

To investigate the role of aldosterone and the renin-angiotensin system in cardiac structure, we performed echocardiography in patients with secondary hypertension. The relation between blood pressure or hormonal influences and left ventricular hypertrophy has not been well established in secondary hypertension. Sixteen patients with primary aldosteronism and 11 with unilateral renovascular hypertension who had completely normalized blood pressure after operation or percutaneous transluminal angioplasty were evaluated by echocardiography before and after surgery or other interventional treatment. Blood pressure was not statistically different between the groups before treatment and was normalized after treatment in both groups. Left ventricular hypertrophy was mild in both groups before treatment, and its degree was not statistically different between the groups. At the end of the follow-up period, all parameters of primary aldosteronism and left ventricular mass index in patients with unilateral renovascular hypertension were significantly reduced. In patients with primary aldosteronism, changes in end-diastolic left ventricular internal dimension correlated positively with changes in left ventricular mass index (r=.58,P<.01). In patients with unilateral renovascular hypertension, changes in mean blood pressure and left ventricular mass index were significantly correlated (r=.77,P<.01). The expanded plasma volume induced by an excess of aldosterone and high blood pressure may play an important role in the increase of left ventricular mass in primary aldosteronism. In unilateral renovascular hypertension, high blood pressure mainly contributes significantly to increased left ventricular mass. Therefore, different factors may modulate the development of left ventricular hypertrophy in patients with secondary hypertension.

Effect of dietary sodium on platelet alpha 2-adrenergic receptors in essential hypertension.

To study the aggregation, adhesion, and specific binding of an alpha 2-antagonist, [3H]rauwolscine, to the platelet membrane fractions, platelets were obtained from 30 patients with essential hypertension and nine normotensive subjects fed a high sodium diet (NaCl, 16-18 g/day) for 7 days and thereafter a low sodium diet (NaCl, 1-3 g/day) for 7 days. The patients with essential hypertension were classified as either salt responders (all those who had greater than 7% decrease in mean arterial pressure from the high to low sodium period) or salt nonresponders (all others). In salt responders, the number of alpha 2-adrenergic receptors on platelet membrane fraction was increased from 523.4 +/- 55.4 fmol/mg of protein in the high sodium period to 669.4 +/- 84.0 fmol/mg of protein in the low sodium period (p less than 0.01), whereas it did not change in salt nonresponders. In contrast, the epinephrine-induced platelet aggregation through alpha 2-adrenergic receptors was decreased in nonresponders, from 47.3 +/- 7.4% in the high sodium period to 24.5 +/- 9.3% in the low sodium period (p less than 0.05), while it did not change in responders. No significant change in the number of alpha 2-adrenergic receptors or epinephrine-induced platelet aggregation was observed in the normotensive subjects.

Identification of tumor suppressor candidate genes by physical and sequence mapping of the TSLC1 region of human chromosome 11q23.

Loss of heterozygosity for a locus on human chromosome 11q22-23 is observed at high frequency in non-small cell lung carcinoma (NSCLC). Introduction of a 1.1 Mb fragmented yeast artificial chromosome (YAC) mapping to this region completely suppresses the tumorigenic properties of a human NSCLC cell line, A549. Smaller fragmented YACs give partial but not complete suppression. To further localize the gene(s) responsible for this partial suppression, a bacterial artificial chromosome (BAC) and P1-based artificial chromosome (PAC) contig was constructed, completely spanning the candidate region. End sequence generated in the construction of the BAC/PAC contig identified a previously unmapped EST and served to order genomic sequence contigs from the publicly available Celera Genomics (CG) and Human Genome Project (HGP) efforts. Comparison showed that CG provided larger contigs, while HGP provided more coverage. Neither CG nor HGP provided complete sequence coverage, alone or in combination. The sequence was used to map 110 ESTs and to predict new genes, including two GenScan gene predictions that overlapped ESTs and were shown to be differentially expressed in tumorigenic and suppressed A549 cell lines.

Effects of dietary salt on sodium-calcium exchange and ATP-driven calcium pump in arterial smooth muscle of Dahl rats.

AIM: To compare the effects of dietary salt on sodium-calcium exchange and the ATP-driven calcium pump in arterial smooth muscle between Dahl salt-sensitive (DS) and salt-resistant (DR) rats. METHODS: Aortic rings freshly excised from 16 DS rats and 16 DR rats on a low- (0.3%) or high- (8%) NaCl diet for 4 weeks were superfused with physiological saline and isometric tension was measured. In the presence of 10 mumol/l phentolamine, 10 mumol/l verapamil and 5 mmol/l caffeine, relaxation of a low-Na+ contraction was promoted by external calcium removal. RESULTS: On the high-salt diet, the rate of relaxation at 1.2 mmol/l extracellular sodium (calcium extrusion by calcium ATPase) was significantly lower in aortic rings from DS rats than from DR rats. The increase in the rates of relaxation from 1.2 mmol/l to normal (139.2 mmol/l) extracellular sodium (calcium extrusion by sodium-calcium exchange) was significantly greater with the high-salt diet than with the low-salt diet in rings from DR rats, but it was not different between the high- and low-salt diets in DS rats. The rate of increase in tonic tension by reducing extracellular Na+ from normal to 1.2 mmol/l in the presence of verapamil, caffeine and phentolamine (calcium entry by sodium-calcium exchange) was significantly lower in rings from DS rats than in those from DR rats on the high-salt diet. CONCLUSIONS: These observations suggest that the effects of dietary salt on the sodium-calcium exchange system in arterial smooth muscle differ between DS and DR rats and that calcium extrusion by the calcium pump is decreased in DS rats compared with DR rats. The lack of an increase in sodium-calcium exchange in salt-fed DS rats might lead to an elevation in cellular calcium and contribute to the mechanism of hypertension.

Effects of intracerebroventricular atrial natriuretic factor on angiotensin II- or sodium-induced blood pressure elevation and natriuresis.

We examined the effects of intracerebroventricular (i.c.v.) administration of atrial natriuretic factor (ANF) on pressor and natriuretic responses induced by i.c.v. angiotensin II (Ang II) or hypertonic NaCl. Conscious male Wistar rats were given one of the following solutions into the lateral ventricle: artificial cerebrospinal fluid (CSF); rat ANF (99-126) 1.0 microgram/kg per min; Ang II 100 ng/kg per min; 0.6 mol/l NaCl; Ang II plus ANF, and 0.6 mol/l NaCl plus ANF. The i.c.v. infusion of artificial CSF or ANF alone did not cause significant changes in mean blood pressure, urinary volume or sodium excretion (UNaV). The i.c.v. infusion of Ang II or 0.6 mol/l NaCl raised mean blood pressure, decreased urinary volume and increased UNaV. When ANF was administered with Ang II, the Ang II-induced responses were diminished significantly (delta mean blood pressure, +10 +/- 3 versus +20 +/- 4 mmHg; delta urinary volume, -38 +/- 9 versus -78 +/- 5 microliters/min; delta UNaV, +0.49 +/- 0.51 versus +2.28 +/- 0.58 mumol/min). The centrally administered ANF opposed the effects of 0.6 mol/l NaCl, though the effect was significant only in respect of blood pressure. Our results indicate that the brain ANF may have an antinatriuretic role in some conditions.

Increases in renal angiotensin II content and tubular angiotensin II receptors in prehypertensive spontaneously hypertensive rats.

To examine the role of the intrarenal renin-angiotensin system in the development of hypertension in spontaneously hypertensive rats (SHR), we measured angiotensin II contents and tubular 125I-angiotensin II binding sites in the kidney of SHR and age-matched Wistar-Kyoto rats (WKY). In prehypertensive (4-week-old) SHR, not only the kidney angiotensin II content but also the angiotensin II receptor density in brush border membranes were significantly higher than in the WKY. In contrast, angiotensin II levels in the 20-week-old SHR kidneys were significantly lower than in the WKY. Acceleration of the intrarenal renin-angiotensin system and the increased density of tubular angiotensin II receptors in young SHR may therefore play an important role in the development of high blood pressure in SHR.