High incidence of coamplification of hst-1 and int-2 genes in human esophageal carcinomas.

We analyzed the alteration of the hst-1 and int-2 genes in 36 cases of esophageal squamous cell carcinoma, 42 cases of gastric adenocarcinoma, and 52 cases of colorectal adenocarcinoma. Coamplification of the hst-1 and int-2 genes was observed in 19 of 36 esophageal carcinomas (52%), 16 of 34 primary tumor tissues (47%), and 10 of 10 metastatic tumors (100%). The degree of amplification ranged from 4- to 8-fold. The incidence of hst-1 and int-2 gene coamplification was significantly higher in male patients than that in female patients (P less than 0.05). The coamplification of the hst-1 and int-2 genes had a tendency to correlate with clinical stage. The progesterone receptor gene, which is mapped to chromosome 11 at band q21-23, was not amplified in these esophageal carcinomas. Coamplification of the hst-1 and int-2 gene does not seem to imply increased numbers of chromosome 11, and the hst-1 and int-2 genes appear to be in same amplification unit on chromosome 11 at band q13. No coamplification of the hst-1 and int-2 genes was detected in gastric carcinomas and colorectal carcinomas. These results suggest that amplification of chromosomal locus of the hst-1 and int-2 genes might participate in carcinogenesis, in progression, and particularly in metastasis of esophageal carcinomas.

Telomerase activity in human liver tissues: comparison between chronic liver disease and hepatocellular carcinomas.

Telomerase activity was examined in 105 frozen samples from human normal liver tissues, chronic liver disease, and hepatocellular carcinoma (HCC). Telomerase activity was positive in 28 of 33 HCC tissues regardless of tumor stage or size. Telomerase was expressed in 15 of 18 differentiated HCC nodules smaller than 3 cm. HCC tissues from all eight hepatitis B virus-positive patients were telomerase positive, while telomerase activity was not detected in normal liver tissues (0 of 4). Weak telomerase activity was only detected in 1 of 22 nontumor liver tissues from HCC patients. Interestingly, in 19 of 38 hepatitis tissues and 6 of 8 cirrhotic liver tissues from apparently cancer-free patients, very weak telomerase activity was detected. These results indicate that the expression of telomerase may play a crucial role in hepatocarcinogenesis.

Frequent loss of heterozygosity on chromosomes 1q, 5q, and 17p in human gastric carcinomas.

Recently, loss or inactivation of genes at specific chromosomal loci has been considered to be one of the important mechanisms during the development of human tumors. In order to identify tumor suppressor genes for gastric carcinoma, we performed restriction fragment length polymorphism analysis on 48 human gastric carcinomas. Allele losses were investigated for 14 specific loci on chromosomes 1, 5, 6, 7, 10, 11, 12, and 17. Loss of heterozygosity on chromosome 17p13.1 (p53 locus) was detected in 13 (68%) of 19 informative cases. Well-differentiated adenocarcinoma showed high frequencies of allele losses on chromosomes 5q (60%) and 17p (67%) in early cancers and on chromosomes 1q (67%), 5q (36%), 7p (33%), 7q (39%), and 17p (73%) in advanced cancers. In poorly differentiated adenocarcinomas, loss of heterozygosity was detected on chromosomes 1p (38%), 12q (31%), and 17p (60%). Allele losses on chromosomes 1q, 5q, and 7p were not detected in poorly differentiated adenocarcinoma, their frequencies being significantly different between the two histological types. These results suggest that allele loss on chromosome 17p is a common event in gastric carcinoma, regardless of histological type, and that allele loss on chromosome 5q may play a role in the carcinogenesis of well-differentiated adenocarcinoma. Additionally, allele losses on chromosomes 1q and 7p may be involved in the progression of well-differentiated adenocarcinoma.

Immuno-histochemical detection of human telomerase reverse transcriptase in human liver tissues.

Although telomerase activity in hepatocellular carcinoma (HCC) increases in accordance with degree of histological undifferentiation, it is unknown whether the level of telomerase activity in HCC reflects of the degree of activity in individual cells or the frequency of telomerase-positive HCC cells. Non-cancerous liver tissues exhibit low but significant levels of telomerase activity, but the nature of telomerase-positive cells in these tissues is unclear. In this study, we performed immunohistochemical staining using specific antibody against telomerase reverse transcriptase (hTERT) protein in 15 HCC samples and 13 adjacent non-cancerous liver tissues. There were hTERT-positive hepatocytes, though very low frequency, in non-cancerous liver tissues. The frequencies in hTERT positive hepatocytes were very well correlated with clinicopathological parameters and telomerase activity levels: the average frequencies of chronic hepatitis was 0.2%, liver cirrhosis 0.2%, well-differentiated HCC 3.0%, moderately differentiated HCC 28%, and poorly differentiated HCC 95%. The intensity of staining varied among cells within a given specimen, and correlation with degree of histological undifferentiation was less obvious. Portions of migrating lymphocytes and biliary epithelial cells were also hTERT-positive. These findings indicate that the upregulation of telomerase activity with degree of undifferentiation of HCC is mainly due to the increase in frequency of hTERT positive HCC cells.

Mutations of a novel human RAD54 homologue, RAD54B, in primary cancer.

Association of breast tumor susceptibility gene products BRCA1 and BRCA2 with the RAD51 recombination protein suggested that cancer could arise through defects in recombination. The identification of NBS1, responsible for Nijmegen breakage syndrome, from the MRE11/RAD50 recombination protein complex also supports this hypothesis. However, our mutation analysis revealed that known members of the RAD52 epistasis group are rarely mutated in human primary cancer. Here we describe the isolation of a novel member of the SNF2 superfamily, characterized with sequence motifs similar to those in DNA and RNA helicases. The gene, designated RAD54B, is significantly homologous to the RAD54 recombination gene. The expression of RAD54B was high in testis and spleen, which are active in meiotic and mitotic recombination. These findings suggest that RAD54B may play an active role in recombination processes in concert with other members of the RAD52 epistasis group. RAD54B maps to human chromosome 8q21.3-q22 in a region associated with cancer-related chromosomal abnormalities. Homozygous mutations at highly conserved positions of RAD54B were observed in human primary lymphoma and colon cancer. These findings suggest that some cancers arise through alterations of the RAD54B function.

Apolipoprotein A-I stabilizes phospholipid lamellae and thus prolongs nucleation time in model bile systems: an ultrastructural study.

To explore the mechanisms whereby apolipoprotein A-I inhibits the nucleation of cholesterol crystals, we performed an ultrastructural study using supersaturated model bile systems. Vesicles, micelles and phospholipid lamellae were consistently separated by gel permeation chromatography either in the absence or presence of apolipoprotein A-I. Furthermore, apolipoprotein A-I coeluted with phospholipid lamellae. A sequential study using transmission electron microscopy revealed that phospholipid lamellae without apolipoprotein A-I showed a rapid transformation, with formation of multilamellae and fusion followed by microcrystal nucleation. In contrast, lamellae with apolipoprotein A-I showed little transformation. In conclusion, apolipoprotein A-I stabilizes the phospholipid lamellae, thereby inhibiting the nucleation of cholesterol crystals in supersaturated model bile systems.

Fatty acid composition of lecithin is a key factor in bile metastability in supersaturated model bile systems.

We studied the effect of fatty acid saturation of biliary lecithin on bile metastability, determined by nucleation time, using model bile solutions with identical lipid compositions except for the lecithin species (total lipid concentration, 9 g/dl; cholesterol, 12 mM; lecithin, 31 mM, bile salts, 116 mM). Gel permeation chromatographic studies revealed that nonmicellar cholesterol distribution was inversely related to the degree of unsaturation of the lecithin species. Differential interference contrast microscopy and cholesterol crystal growth assay showed that a lower degree of saturation of the lecithin species was associated with a faster nucleation time and crystal growth rate. These results suggest that vesicular lecithin containing more unsaturated fatty acyl chains binds less tightly to cholesterol as compared with lecithin containing predominantly saturated fatty acids and that the biliary lecithin species modulates cholesterol crystal nucleation in bile. Also, the high ratio of cholesterol to lecithin (more than 1.0) was found in the crystal forming model biles, although the vesicle aggregation was not always observed prior to the cholesterol crystal formation. These findings indicated that there are different processes in cholesterol crystal nucleation, with or without vesicle aggregation, and that such processes depend, in part, on lecithin species in vesicles.

Effect of CS-514, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, on cholesterol gallstone formation in hamsters.

Male golden hamsters fed a glucose diet as a model for cholesterol gallstone formation were used to investigate the effect of CS-514 on the lithogenicity of bile. Treatment with 0.05% (w/w) CS-514 in the diet for 1-4 weeks caused a decrease in plasma cholesterol and triacylglycerol levels. A marked increase in hepatic hydroxymethylglutaryl-CoA reductase activity in vitro and also an increased de novo cholesterol synthesis in the liver were induced by treatment with CS-514 for 1-4 weeks. The concentration of free cholesterol in liver microsomes and the cholesterol 7 alpha-hydroxylase activity were both decreased by treatment with CS-514 for 1 week, but were not affected by treatment for 4 weeks. The cholesterol output into bile and the lithogenic index of bile were double those of the control (glucose diet only) following treatment with CS-514 for 4 weeks, and the subsequent incidence of cholesterol gallstone formation was elevated. The content of free cholesterol and cholesterol ester in the liver was not affected by treatment with CS-514 for 4 weeks. These results suggest that long-term treatment with CS-514 causes a compensatory increase in the synthesis of hydroxymethylglutaryl-CoA reductase which leads to augmented hepatic de novo cholesterol synthesis and subsequent increased cholesterol output followed by an increase in the lithogenicity of bile. CS-514 apparently does not prevent cholesterol gallstone formation in those examples where the mechanism is thought to be due to augmented hepatic de novo cholesterol synthesis (type IV hyperlipidemia).

Metabolic changes in lipids of rat plasma and hepatocytes induced by 17 alpha-ethynylestradiol treatment.

Cultured hepatocytes isolated from livers of 17 alpha-ethynylestradiol-treated rats were used to investigate the change of lipid metabolism induced by administration of 17 alpha-ethynylestradiol. Treatment with 17 alpha-ethynylestradiol caused a decrease of rat plasma lipids (free cholesterol, cholesterol ester, triacylglycerol and phosphatidylcholine). No difference in the ability of urea nitrogen synthesis could be demonstrated between cultured hepatocytes isolated from livers of 17 alpha-ethynylestradiol-treated rats and propylene glycol-treated rats (control). Total cholesterol and cholesterol ester contents of cultured hepatocytes isolated from livers of 17 alpha-ethynylestradiol-treated rats were increased in comparison with those of the control. Triacylglycerol content of cultured hepatocytes was not affected by 17 alpha-ethynylestradiol treatment. There was no difference in the composition of lipid content between liver tissues and cultured hepatocytes. These results suggest that hepatocytes isolated from livers maintain the character of livers treated with 17 alpha-ethynylestradiol or livers treated with propylene glycol. Free cholesterol and cholesterol ester synthesis from [14C]acetic acid by cultured hepatocytes isolated from livers of 17 alpha-ethynylestradiol-treated rats were decreased to about 30% of the control. Triacylglycerol and polar lipid (phospholipid) synthesis from [14C]acetic acid were not affected by 17 alpha-ethynylestradiol treatment. Microsomal hydroxymethylglutaryl-CoA reductase activity of rat liver treated with 17 alpha-ethynylestradiol was decreased to about 50% of control. The secretions of free cholesterol, cholesterol ester, triacylglycerol, phosphatidylcholine, apolipoprotein BL and BS by cultured hepatocytes isolated from livers of 17 alpha-ethynylestradiol treated rats were not decreased when compared with the control. Because lipid and apolipoprotein secretions from cultured hepatocytes treated with 17 alpha-ethynylestradiol were not decreased and cholesterol contents of liver tissues and cultured hepatocytes treated with 17 alpha-ethynylestradiol were increased and hepatic microsomal hydroxymethylglutaryl-CoA reductase activity was decreased by 17 alpha-ethynylestradiol treatment, it is suggested that the liver plays an important role in hypolipidemia induced by 17 alpha-ethynylestradiol by increasing the plasma lipid uptake mediated by an increased amount of lipoprotein receptors of liver membranes.

Effect of fluvastatin sodium (XU62-320), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the induction of low-density lipoprotein receptor in HepG2 cells.

The effect of fluvastatin sodium (XU62-320), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A, on the induction of LDL receptor in the human liver-derived cell line HepG2 was investigated. Fluvastatin sodium produced marked inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and induction of LDL receptor on HepG2 cells at a concentration of 0.1-1.0 microM. These results suggest that fluvastatin sodium has potential for use as a strong plasma cholesterol-lowering drug.

High dose of fluvastatin sodium (XU62-320), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, lowers plasma cholesterol levels in homozygous Watanabe-heritable hyperlipidemic rabbits.

The effects of fluvastatin sodium (XU62-320), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on plasma cholesterol and triacylglycerol levels were investigated using homozygous Watanabe-heritable hyperlipidemic (WHHL) rabbit, an LDL-receptor-deficient animal which expresses a hepatic LDL receptor activity less than 5% that of control rabbits. Plasma levels of total, VLDL- and LDL-cholesterol were decreased profoundly after oral administration of fluvastatin at a dose of 50 mg/kg per day for 4 weeks. Plasma triacylglycerol levels were not affected by fluvastatin. Hepatic HMG-CoA reductase activity increased by 3-fold and hepatic LDL receptor activity increased by only 3.7-fold, as calculated by Scatchard plot analysis, with fluvastatin administration for 4 weeks, and the hepatic mRNA level for the rabbit LDL receptor was increased by 3-fold. Combined administration of fluvastatin (50 mg/kg per day) and cholestyramine, a bile acid sequestrant resin, at a level of 2% of the diet for 4 weeks more profoundly decreased plasma total, VLDL- and LDL-cholesterol levels with induction of hepatic cholesterol 7 alpha-hydroxylase and no further induction of the hepatic LDL receptor. Plasma triacylglycerol levels were increased by the combination treatment. These results suggest that high dose of fluvastatin sodium is effective in lowering plasma cholesterol levels in homozygous WHHL rabbits through the shared mechanisms involving decrease in production and secretion of cholesterol from the liver and the induction of hepatic LDL receptor. Additional effect of cholestyramine on decrease in plasma cholesterol levels seems to be due to the further decrease in hepatic cholesterol secretion by up-regulation of hepatic cholesterol 7 alpha-hydroxylase.

Potentiation of the intracellular Ca2+ response to arginine vasopressin by increased cytosolic-free Mg2+ in rat vascular smooth muscle cells.

Although the inhibitory effects of extracellular Mg2+ on Ca2+ influx are well established, little is known about the effects of intracellular Mg2+ on Ca2+ handling. In the present study, the effects of cytosolic-free Mg2+ concentration in the physiological (submillimolar) range on Ca2+ handling were investigated after stimulation of rat vascular smooth muscle cells with arginine vasopressin. Cytosolic Mg2+ was manipulated by culturing cells in medium containing different Mg2+ concentrations. Peak cytosolic-free Ca2+ concentration responses to arginine vasopressin (1 mumol/1) were measured in the presence and absence of external Ca2+. The results suggest that an increase in cytosolic-free Mg2+ concentration increases both Ca2+ discharge from intracellular stores and Ca2+ influx, whereas a decrease in intracellular Mg2+ attenuates Ca2+ influx.

Metabolic changes in LDL receptors and an appearance of scavenger receptors after phorbol ester-induced differentiation of U937 cells.

Metabolic changes in lipoprotein receptors after cell differentiation were investigated using U937 cells, a human tumor cell line with monoblastic characteristics. After inducing the differentiation of U937 cells into monocyte-macrophage-like cells using TPA (12-tetradecanoyl-phorbol-13-acetate), the incorpotation of [14C]oleate into cellular cholesteryl [14C]oleate was increased in comparison with U937 cells when incubated with r-beta VLDL, h-VLDL or h-LDL. A marked down-regulation of LDL receptors was observed in U937 cells upon addition of 25-hydroxycholesterol. However, this down-regulation of LDL receptors was poor in monocyte-macrophage-like cells that had been induced to differentiate from U937 cells with TPA. Acyl coenzyme A:cholesterol acyltransferase activity was increased after TPA-induced differentiation of U-937 cells. The incorporation of [14C]oleate into cellular cholesteryl [14C]oleate was also increased when incubated with acetylated h-LDL in monocyte-macrophage-like cells in comparison with U937 cells. These results suggest that a poor down-regulation of LDL receptors, which is attributable to increased acyl coenzyme A:cholesterol acyltransferase activity, and scavenger receptors are induced and that these metabolic changes in lipoprotein receptors and an increased acyl coenzyme A:cholesterol acyltransferase activity contribute to cholesterol ester accumulation in monocyte-macrophage-like cells.

Opposite effects on cholesterol metabolism and their mechanisms induced by dietary oleic acid and palmitic acid in hamsters.

The effects of dietary oleic acid on cholesterol metabolism were investigated and compared with those of palmitic acid in hamsters. Addition of 5% oleic acid to a 0.1% cholesterol-supplemented diet decreased plasma total cholesterol, very low density lipoprotein (VLDL) cholesterol, and low density lipoprotein (LDL) cholesterol, increased hepatic LDL receptor activity, and decreased plasma cholesteryl ester transfer protein (CETP) activity in comparison with 0.1% cholesterol alone. In contrast, addition of 5% palmitic acid to a 0.1% cholesterol-supplemented diet increased total cholesterol and LDL-cholesterol, increased plasma CETP activity, and suppressed hepatic LDL receptor activity to a greater extent than 0.1% cholesterol alone. Neither oleic acid nor palmitic acid altered hepatic microsomal 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity, but oleic acid increased hepatic microsomal cholesterol 7 alpha-hydroxylase activity. These results suggest that dietary oleic acid inhibits the increases in total, VLDL-, and LDL-cholesterol induced by dietary cholesterol by preventing both LDL receptor suppression and increased CETP activity, whereas dietary palmitic acid augments the cholesterol-induced increases in total and LDL-cholesterol by both further suppression of LDL receptor activity and further stimulation of CETP activity.

Lack of effect of transmembrane gradient of magnesium and sodium on regulation of cytosolic free magnesium concentration in rat lymphocytes.

The regulation of the intracellular concentration of Mg2+ ([Mg2+]i) is not fully understood. The level of Mg in lymphocytes is a good predictor of total body Mg status. We measured [Mg2+]i and total Mg in rat lymphocytes by using, respectively, the fluorescent Mg2+ indicator mag-fura-2 and atomic absorption spectrophotometry. The basal [Mg2+]i in rat lymphocytes was 328 +/- 23 micromol/l. An elevation to 5 mmol/l or the removal of extracellular Mg2+ did not affect [Mg2+]i. A reduction in extracellular Na+ did not influence [Mg2+]i for 60 min. The total Mg concentration in lymphocytes also remained stable. Results suggest that the permeability of the plasma membrane to Mg2+ is very low, and that Na+/Mg2+ exchange is not involved in the regulation of [Mg2+]i in rat lymphocytes.

Regular aerobic exercise augments endothelium-dependent vascular relaxation in normotensive as well as hypertensive subjects: role of endothelium-derived nitric oxide.

BACKGROUND: Several nonpharmacological interventions, including exercise, are recommended in primary prevention of hypertension and other cardiovascular diseases in which the pathogenetic role of endothelial dysfunction has been suggested. We studied the effects of long-term aerobic exercise on endothelial function in patients with essential hypertension. METHODS AND RESULTS: The forearm blood flow was measured by strain-gauge plethysmography. The responses of forearm vasculature to acetylcholine were smaller in the hypertensive patients than in the normotensive subjects. There was no significant difference in forearm vascular responses to isosorbide dinitrate in the normotensive and hypertensive subjects. We evaluated the effects of physical exercise for 12 weeks on forearm hemodynamics in untreated patients with mild essential hypertension who were divided randomly into an exercise group (n=10) and a control group (n=7). After 12 weeks, the forearm blood flow response to acetylcholine increased significantly, from 25.8+/-9.8 to 32.3+/-11.2 mL. min(-1). 100 mL tissue(-1) (P<0.05), in the exercise group but not in the control group. The increase in the forearm blood flow after isosorbide dinitrate was similar before and after 12 weeks of follow-up in both groups. The infusion of N(G)-monomethyl-L-arginine abolished the exercise-induced enhancement of forearm vasorelaxation evoked by acetylcholine in the exercising group. In normotensive subjects also, long-term aerobic exercise augmented acetylcholine-stimulated nitric oxide release. CONCLUSIONS: These findings suggest that long-term physical exercise improves endothelium-dependent vasorelaxation through an increase in the release of nitric oxide in normotensive as well as hypertensive subjects.

Flow-mediated vasodilation of human epicardial coronary arteries: effect of inhibition of nitric oxide synthesis.

OBJECTIVES: This study sought to investigate the role of nitric oxide, an endothelium-derived relaxing factor, in flow-mediated vasodilation in human epicardial coronary arteries. BACKGROUND: Endothelium-derived relaxing factors may be released from the coronary artery endothelium in response to increases in blood flow. METHODS: We studied the effect of the nitric oxide synthesis inhibitor NG-monomethyl-L-arginine (L-NMMA) on the flow-mediated vasodilation of epicardial coronary arteries in 12 patients, using quantitative angiographic and Doppler flow velocity measurements. Adenosine at 100 micrograms/min was infused into the left anterior descending coronary artery to test the dilator response of the proximal artery to increases in blood flow. Acetylcholine at 3 and 30 micrograms/min was infused into the left coronary ostium to determine endothelium-dependent vasodilation of the proximal left anterior descending artery. Adenosine and acetylcholine were infused before and after the intracoronary infusion of L-NMMA (25 mumol/min for 5 min). RESULTS: Infusion of L-NMMA caused a significant decrease in the baseline diameter of the proximal left anterior descending artery (from 2.90 +/- 0.14 to 2.74 +/- 0.13 mm [mean +/- SEM], p < 0.01). Adenosine increased coronary blood flow before and after L-NMMA (+399.5 +/- 27.5% and +511.9 +/- 33.3%, respectively). Flow-mediated vasodilation was observed in the proximal left anterior descending artery before and after L-NMMA (+9.2 +/- 1.5%, p < 0.01 and +8.6 +/- 2.1%, p < 0.01, respectively). A dose of 3 micrograms/min of acetylcholine significantly dilated the proximal left anterior descending artery before L-NMMA (+7.6 +/- 1.0%, p < 0.01), but acetylcholine-induced vasodilation was attenuated after L-NMMA (-1.8 +/- 1.0%). CONCLUSIONS: Our data suggest that nitric oxide modulates basal coronary artery tone but that mediators other than nitric oxide may be responsible for the flow-mediated vasodilation of human epicardial coronary arteries.

Effect of the angiotensin-converting enzyme inhibitor imidapril on reactive hyperemia in patients with essential hypertension: relationship between treatment periods and resistance artery endothelial function.

OBJECTIVES: The purpose of this study was to evaluate the effects of the angiotensin-converting enzyme (ACE) inhibitor imidapril and the calcium antagonist amlodipine on endothelial function before and after 2, 4, 8, 12, 24 and 48 weeks of treatment. BACKGROUND: There are limited data on whether and how long endothelial function is improved after initiation of ACE inhibitor treatment and how the grade of endothelial function further progresses after improvement of endothelial dysfunction in patients with essential hypertension. METHODS: The forearm blood flow (FBF) was measured in 25 patients with essential hypertension and in 25 normotensive subjects by using strain-gauge plethysmography during reactive hyperemia (RH) (280 mm Hg for 5 min) and after sublingual administration of nitroglycerin (NTG, 0.3 mg). RESULTS: The FBF of patients with essential hypertension during RH was significantly less than that of normotensive subjects. The increase in FBF after sublingual NTG was similar in both groups. Both imidapril (n = 13) and amlodipine (n = 12) significantly reduced systolic blood pressure and diastolic after eight weeks of treatment from the pretreatment values. Forearm vascular resistance was significantly decreased after two weeks of treatment. Imidapril significantly augmented RH after 12 weeks of treatment from the pretreatment values (31.6 +/- 5.7 to 38.2 +/- 6.0 m/min per 100 ml tissue, p < 0.05), whereas amlodipine did not alter RH for each treatment period. The ability of imidapril to improve RH was maintained throughout the 48-week treatment period. There was no significant difference in RH at 12, 24 and 48 weeks. The increase in FBF after sublingual administration of NTG was similar in all treatment periods for the two groups. The infusion of NG-monomethyl-L-arginine, a nitric oxide (NO) synthase inhibitor, abolished the enhancement of RH in hypertensive patients treated with imidapril. CONCLUSIONS: These findings suggest that the ACE inhibitor imidapril augments RH after 12 weeks of treatment in patients with essential hypertension and that this ACE inhibitor-induced augmentation of RH may be due to an increase in NO.

Abnormal systolic blood pressure response during exercise recovery in patients with angina pectoris.

OBJECTIVES: This study was conducted to clarify the mechanisms of the abnormal systolic blood pressure response after exercise in patients with angina pectoris. BACKGROUND: An abnormal systolic blood pressure response in patients with angina pectoris has been observed not only during exercise but also during the recovery period after exercise. However, the mechanisms of this abnormal response during recovery have not been elucidated. METHODS: Thirty-five patients with angina pectoris and 17 control subjects underwent bicycle ergometric studies after insertion of a Swan-Ganz catheter. RESULTS: In control subjects, all hemodynamic variables decreased rapidly after exercise. In 7 of the 35 patients, systolic blood pressure increased after exercise. The patients with angina were classified into two groups. In group I (17 patients), changes in systolic blood pressure during recovery were smaller than those in control subjects. In group II (18 patients) recovery of systolic blood pressure was normal. Changes in stroke index from rest to peak exercise were smaller in group I than in group II. Stroke index in both patient groups increased paradoxically during recovery. The increase in systemic vascular resistance index during recovery and the ratio of plasma norepinephrine concentration to cumulative work load were greater in group I than in group II. CONCLUSIONS: An abnormal systolic blood pressure response after physical exercise in patients with angina pectoris is indicative of severe myocardial ischemia during exercise and may be caused by an increase in stroke volume due to recovery from myocardial ischemia and increased systemic vascular resistance secondary to exaggerated sympathetic nervous activity.

A comparison of angiotensin-converting enzyme inhibitors, calcium antagonists, beta-blockers and diuretic agents on reactive hyperemia in patients with essential hypertension: a multicenter study.

OBJECTIVES: The purpose of this study was to compare the effect of different antihypertensive agents, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and diuretic agents on endothelial function. BACKGROUND: Endothelial dysfunction is a component of essential hypertension, and various antihypertensive drugs may be able to restore normal function. METHODS: Forearm blood flow (FBF) was measured in 296 patients with essential hypertension, including 46 untreated subjects using strain-gauge plethysmography during reactive hyperemia and after sublingual administration of nitroglycerin (NTG). Forty-seven normotensive subjects were similarly evaluated as control subjects. RESULTS: The FBF during reactive hyperemia in the 296 hypertensive patients was significantly less than that in age-matched normotensive subjects. The increase in FBF after administration of sublingual NTG was similar in both groups. Systolic and diastolic blood pressures and forearm vascular resistance were greater in the untreated group than in the four treated groups and did not differ with respect to the antihypertensive agent used. The maximal FBF response from reactive hyperemia was significantly greater in the ACE inhibitor-treated group than in the group treated with calcium antagonists, beta-blockers, diuretic agents, or nothing (40.5 +/- 5.2 vs. 32.9 +/- 5.8, 34.0 +/- 5.6, 32.1 +/- 5.9, and 31.9 +/- 5.8 ml/min per 100 ml tissue, p < 0.05, respectively). Reactive hyperemia was similar in the calcium antagonist, beta-blocker, diuretic and untreated groups, and changes in FBF after sublingual NTG administration were similar in all groups. The infusion of NG-monomethyl-L-arginine, a nitric oxide (NO) synthase inhibitor, abolished the enhancement of reactive hyperemia in hypertensive patients treated with ACE inhibitors. CONCLUSIONS: These findings suggest that ACE inhibitors augment reactive hyperemia, an index of endothelium-dependent vasorelaxation, in patients with essential hypertension. This augmentation may be due to increases in NO.