Biomedical subjects

Koji Fujii

Publications and source records attributed to Koji Fujii.

At least 19 recordsLinked to original sources

PubMed2006

Overt diabetes mellitus in a patient with combined primary aldosteronism and Cushing's syndrome.

Although there are some case reports of combined aldosterone and cortisol producing adrenal tumor, overt diabetes mellitus has been rarely described. A 55-year-old hypertensive woman had hypokalemia and overt hyperglycemia without Cushingoid clinical features. The body mass index was 18.2 kg/m2, fasting blood glucose was 302 mg/dl and hemoglobin A1c was 11.6%. Endogenous insulin secretion was well preserved, whereas insulin sensitivity measured by short insulin tolerance test was markedly impaired. A solitary left aldosterone- and cortisol-producing adrenal tumor was diagnosed. We described a rare case of overt diabetes mellitus in a patient with combined primary aldosteronism and Cushing's syndrome.

Adrenal Gland Neoplasms↗

PubMed2006

Primary liposarcoma of gallbladder diagnosed by preoperative imagings: a case report and review of literature.

A 49-year-old Japanese woman was referred to our department because of high fever and a huge abdominal mass. Computed tomography (CT) and magnetic resonance (MR) imagings revealed a tumor, about 30 cm in diameter,occupied the right hepatic lobe and the peritoneal cavity. Abdominal angiography showed that the tumor was fed mainly by the cystic artery. We preoperatively diagnosed angiosarcoma of the gallbladder and performed tumor resection with cholecystectomy because the tumor was almost capsulated,however the posterior wall of the gallbladder attached to the tumor firmly. Histologically,the tumor was composed of spindle cells including lipoblasts with cellular pleomorphism, which were also detected in the muscular layer of the gallbladder. We finally diagnosed pleomorphic liposarcoma of the gallbladder. At 10 mo and 29 mo after the first operation, she underwent two more operations because of recurrence. Now she has a good quality of life 3 yr and 6 mo after the first operation.

Angiography↗

PubMed2006

Role of aldosterone in left ventricular hypertrophy in hypertension.

BACKGROUND: Aldosterone induces cardiac fibrosis in experimental animal models, but only limited information is available on the association between aldosterone and left ventricular (LV) hypertrophy in human beings. The aim of the present study was to determine the role of aldosterone in LV geometry and to investigate other types of target organ damage in hypertensive patients. METHODS: A total of 25 patients with primary aldosteronism caused by Conn's adenoma, 29 patients with renovascular hypertension, and 29 patients with essential hypertension (EHT) were included in the present study. Echocardiographic examinations and 24-h ambulatory blood pressure (BP) monitoring were conducted in all subjects. RESULTS: The mean 24-h systolic and diastolic BP in primary aldosteronism and renovascular hypertension were found to be comparable to those in EHT. However, LV mass index adjusted by age, sex, mean 24-h systolic BP, mean 24-h pulse rate, body mass index, and duration of hypertension was significantly increased in the patients with primary aldosteronism and renovascular hypertension compared with values in patients with EHT (150.2 +/- 7.7, 142.3 +/- 7.2, and 115.2 +/- 7.2 g/m(2), respectively). Hypertensive organ damages, such as proteinuria and hypertensive retinopathy, were more pronounced in the patients with renovascular hypertension; however, LV hypertrophy was especially exaggerated in patients with primary aldosteronism. CONCLUSIONS: These results indicate that aldosterone may induce LV hypertrophy in human beings as well as in experimental animals, and that angiotensin II and aldosterone may differentially participate in causing hypertensive target organ damage.

Adrenergic beta-Antagonists↗

PubMed2006

Effects of angiotensin II receptor antagonist on impaired endothelium-dependent and endothelium-independent relaxations in type II diabetic rats.

BACKGROUND: Diabetes mellitus is an important risk factor for cardiovascular diseases, and vasodilator dysfunction may contribute to vascular complications in diabetes. We previously demonstrated that the angiotensin II receptor blocker (ARB) corrected the impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated arterial hyperpolarization and relaxation associated with hypertension or aging, partially independently of blood pressure. OBJECTIVE: To test whether EDHF-mediated, as well as endothelium-independent, relaxations would be altered in arteries from type II diabetic Goto-Kakizaki rats, and whether ARB would correct these alterations. METHODS: Goto-Kakizaki rats were treated with either the ARB candesartan or a combination of hydralazine and hydrochlorothiazide for 8 weeks, beginning at 10 weeks of age. Membrane potentials and contractile responses were recorded from the isolated mesenteric arteries. RESULTS: The two treatments lowered blood pressure comparably. Acetylcholine-induced, EDHF-mediated hyperpolarization and relaxation in mesenteric arteries were markedly impaired in untreated Goto-Kakizaki rats compared with age-matched Wistar rats, and neither ARB nor the combination therapy improved these responses. On the other hand, relaxations to endothelium-derived nitric oxide, assessed in rings precontracted with high potassium solution, were similar among the four groups. Relaxation to the nitric oxide donor sodium nitroprusside and that to levcromakalim, an ATP-sensitive K-channel opener, were also impaired in untreated Goto-Kakizaki rats, and the response to sodium nitroprusside was partially improved in treated Goto-Kakizaki rats. CONCLUSIONS: These findings suggest that EDHF-mediated hyperpolarization and relaxation and endothelium-independent relaxations are both impaired in arteries of type II diabetic rats, and antihypertensive treatment with or without ARB partially corrects endothelium-independent relaxations to the nitric oxide donor but not EDHF-mediated responses.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2006

Chronic fluvastatin treatment alters vascular contraction by inhibiting the Rho/Rho-kinase pathway.

1. In the present study, we investigated the effects of chronic treatment of stroke-prone spontaneously hypertensive rats (SHRSP) with the statin fluvastatin on vascular Rho/Rho-kinase pathway mediated contraction, which has been shown to be upregulated in hypertension. 2. Contribution of the Rho/Rho-kinase pathway to noradrenaline-induced contraction of arteries from SHRSP was assessed by the inhibitory effect of Y-27632, a Rho/Rho-kinase inhibitor. Stroke-prone spontaneously hypertensive rats were treated with fluvastatin (10 mg/kg per day) for 1 month. 3. Treatment with fluvastatin tended to attenuate the contraction to noradrenaline and significantly decreased the Y-27632-sensitive component of the contraction in controls compared with fluvastatin-treated rats. 4. RhoA, as assessed by western blotting, was also reduced by fluvastatin treatment. 5. These findings suggest that chronic treatment with fluvastatin reduces the contractile response associated with Rho/Rho-kinase in arteries of hypertensive rats.

Amides↗

PubMed2006

Prediction of cognitive function by arterial stiffness in the very elderly.

BACKGROUND: Cognitive function is impaired in elderly subjects, so the aim of the present study was to determine the role of arterial stiffness on cognitive function. METHODS AND RESULTS: Cognitive function and arterial stiffness were assessed by the Mini-Mental State Examination (MMSE) and measurement of the brachial-ankle pulse wave velocity (PWV), respectively. The cross-sectional association of the MMSE score and PWV was studied in 203 subjects (87 men, 116 women), all of whom were 85 years old. Sex distribution, systolic and diastolic blood pressures did not differ between the normal (MMSE score >or=24, n=128) and impaired MMSE groups (MMSE score <24, n=75). In contrast, the PWV was significantly increased in the impaired MMSE group than in the normal MMSE group (25.0+/-0.8 vs 22.9+/-0.5 m/s, p<0.05). In multiple regression analysis, the PWV was also independently and significantly associated with the MMSE score. CONCLUSIONS: These results suggest that cognitive function could be predicted by arterial stiffness, as assessed by the PWV, in the very old. Preventing atherosclerosis may play an important role in preserving normal cognitive function until very old age.

Aged, 80 and over↗

PubMed2006

Gender-related association of serum uric acid and left ventricular hypertrophy in hypertension.

BACKGROUND: The aim of the present study was to determine whether sex differences contribute to the association of serum uric acid and left ventricular hypertrophy in individuals with hypertension. METHODS AND RESULTS: Seventy participants with essential hypertension (34 men, 36 women; 54.4 +/- 1.6 years old) were enrolled to undergo echocardiography to calculate the left ventricular mass index (LVMI). Twenty-four-hour ambulatory blood pressure monitoring was done to assess blood pressure level precisely. The LVMI was significantly correlated with serum uric acid (r = 0.295, p = 0.013) in all participants. After controlling for factors such as age, sex, mean 24-h systolic blood pressure, creatinine clearance, and duration of hypertension, serum uric acid was still found to be significantly and independently associated with LVMI. Because serum uric acid was significantly higher in men than in women (6.8 +/- 0.3 and 5.1 +/- 0.2 mg/dl, respectively), subsequent analysis was performed by gender. Multiple regression analysis revealed that the LVMI was significantly and independently associated with serum uric acid in women, but not in men. CONCLUSIONS: The potential effect of uric acid on LV hypertrophy is more pronounced in female than in males with essential hypertension.

Age Factors↗

PubMed2005

Chronic administration of olmesartan attenuates the exaggerated pressor response to glutamate in the rostral ventrolateral medulla of SHR.

It has been shown that the pressor responses to microinjection of L-glutamate in the rostral ventrolateral medulla (RVLM) are augmented in spontaneously hypertensive rats (SHR), and that these augmented responses are not altered by chronic conventional antihypertensive treatment. The aim of the present study was to determine the effect of chronic oral treatment with a new angiotensin II type 1 (AT(1)) receptor antagonist, RNH-6270 (the active form of olmesartan medoxomil), on cardiovascular responses to excitatory amino acids in the RVLM of SHR. SHR (12 weeks old) were treated with RNH-6270 (30 mg/kg/day) or vehicle for 4 weeks. At 16 weeks of age, L-glutamate (2 nmol), N-methyl-D-aspartate (NMDA; an ionotropic glutamate receptor agonist (20 pmol)), or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD; a metabotropic glutamate receptor agonist (1 nmol)) was microinjected into the RVLM of rats. The pressor responses to microinjection of L-glutamate or NMDA in the RNH-6270-treated SHR (+28.3 +/- 1.0 and +48.3 +/- 2.5 mm Hg, respectively) were significantly smaller than those in untreated SHR (+45.7 +/- 2.2 and +69.4 +/- 7.0 mm Hg, respectively, P < 0.05 each); however, they were still greater than those in the Wistar-Kyoto rats (+21.7 +/- 1.0 and +28.6 +/- 3.3 mm Hg, respectively, P < 0.05 each). In contrast, the augmented pressor responses to microinjection of (1S,3R)-ACPD in SHR were not affected by the RNH-6270 treatment. These results demonstrated that chronic oral treatment with RNH-6270, an AT(1) receptor antagonist, partly normalizes the pressor responses to L-glutamate or NMDA, but not (1S,3R)-ACPD, in the RVLM of SHR, suggesting that endogenous angiotensin II may be involved in the exaggerated pressor response to l-glutamate, probably through its ionotropic glutamate receptors.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2005

Central and peripheral cardiovascular actions of apelin in conscious rats.

APJ was cloned as an orphan G protein-coupled receptor and shares a close identity with angiotensin II type 1 receptor (AT1R). Apelin is a peptide that has recently been identified as an endogenous ligand of the APJ. Apelin and APJ mRNA are expressed in peripheral tissue and the central nervous system. However, little is known about the effects of apelin in cardiovascular regulation. To examine the central and peripheral role of apelin, we injected the active fragment of apelin [(Pyr1)apelin-13] intracerebroventricularly (ICV, 5 and 20 nmol, n=6) or intravenously (IV, 20 and 50 nmol, n=4 or 5) in conscious rats. ICV injection of (Pyr1)apelin-13 dose-dependently increased mean arterial pressure (MAP) and heart rate (HR) (19+/-3 mm Hg and 162+/-26 bpm at 20 nmol). Pretreatment with ICV injection of the AT1R antagonist (CV-11974, 20 nmol) did not alter the apelin-induced increase in MAP and HR. IV injection of (Pyr1)apelin-13 also dose-dependently increased MAP and HR (13+/-2 mm Hg and 103+/-18 bpm at 50 nmol); however, the peripheral effects of apelin were relatively weak compared to its central effects. Expression of c-fos in the paraventricular nucleus (PVN) of hypothalamus was increased in the rat that received ICV injection of (Pyr1)apelin-13 but not in the rat that received IV injection of (Pyr1)apelin-13. These results suggest that apelin plays a role in both central and peripheral cardiovascular regulation in conscious rats, and that the cardiovascular effects of apelin are not mediated by the AT1R.

Animals↗

PubMed2005

Impact of portal venous pressure on regeneration and graft damage after living-donor liver transplantation.

Several reports claim that portal hypertension after living-donor liver transplantation (LDLT) adversely affects graft function, but few have assessed the impact of portal venous pressure (PVP) on graft regeneration. We divided 32 adult LDLT recipients based on mean PVP during the 1st 3 days after LDLT into a group with a PVP > or = 20 mm of Hg (H Group; n = 17), and a group with a PVP < 20 mm of Hg (L Group; n = 15). Outcome in the H Group was poorer than in the L Group (58.8 vs. 92.9% at 1 year). Peak peripheral hepatocyte growth factor (HGF) during the 1st 2 weeks was higher in the H Group (L: 1,730 pg/mL, H: 3,696 pg/mL; P < .01), whereas peak portal vascular endothelial growth factor (VEGF) level during the 1st week was higher in the L Group (L: 433 pg/mL, H: 92 pg/mL; P < .05). Graft volume (GV) / standard liver volume (SLV) was higher in the H Group (L / H, at 2, 3, and 4 weeks, and at 3 months: 1.02 / 1.24, .916 / 1.16, .98 / 1.27, and .94 / 1.29, respectively; P < .05). Peak serum aspartate aminotransferase, bilirubin levels, and international normalized ratio after LDLT were significantly higher in the H Group, as was mean ascitic fluid volume. In conclusion, early postoperative PVP elevation to 20 mm of Hg or more was associated with rapid graft hypertrophy, higher peripheral blood HGF levels, and lower portal VEGF levels; and with a poor outcome, graft dysfunction with hyperbilirubinemia, coagulopathy, and severe ascites. Adequate liver regeneration requires an adequate increase in portal venous pressure and flow reflected by clearance of HGF and elevated VEGF levels.

Adult↗

PubMed2005

DNA typing of bone specimens--the potential use of the profiler test as a tool for bone identification.

Twenty-six bone DNA identification cases are described. The postmortem periods of the studied remains ranged from three days to over 30 years, and the locations where the remains were found varied resulting in a variety of postmortem conditions. Nuclear DNA typing using an AmpFLSTR Profiler kit and mitochondrial DNA (mtDNA) typing of hypervariable regions 1 and 2 (HV1 and HV2) in a control region were performed both with decalcified and non-treated bone powder samples. Decalcification was shown to improve the success of DNA typing. The nucleotide sequences of the HV1 and HV2 regions were successfully determined in all cases examined. Nuclear DNA typing was very successful, more than half of the loci were typed during multiple amplifications (10 loci in one reaction) in 23 cases. Polymerase chain reaction (PCR) inhibition was observed in five cases including three samples that were found buried in soil. This inhibitory effect was identified as the result of unbalanced multiple PCR during the profiler test. These results revealed that DNA typing targeting nuclear DNA is a potentially powerful tool for bone identification.

Adult↗

PubMed2005

Increased renal resistive index in atherosclerosis and diabetic nephropathy assessed by Doppler sonography.

OBJECTIVE: The renal resistive index (RI) and pulsatility index (PI), measured using Doppler ultrasonography, reflect intrarenal vascular resistance. We evaluated the relationship between these indices and pulse wave velocity (PWV), a measure of arterial stiffness, which reflects atherosclerosis, and determined whether renal RI and PI differ depending on the underlying renal disease. METHODS: A total of 245 inpatients with or without renal impairment who underwent ultrasonographic assessment of the renal artery were enrolled in the study. Patients with renal artery stenosis or severe renal failure (serum creatinine>or=6 mg/dl) were excluded from the study. RESULTS: In univariate analysis, the RI and PI of the main renal arteries and the interlobar arteries were significantly correlated with PWV. Multivariate analyses showed that PWV was independently associated with the RI of the main renal arteries (P<0.01, R=0.256). Patients with a creatinine level less than 3 mg/dl were divided into a control group without renal diseases and three groups with different underlying renal diseases: diabetic nephropathy, chronic glomerulonephritis, and nephrosclerosis. The RI and PI of the main renal arteries and the interlobar arteries were significantly higher in patients with diabetic nephropathy than in the other three groups, even after adjusting for multiple variables, including creatinine clearance. CONCLUSION: These results suggest that the increased RI of the renal arteries is associated with the severity of systemic atherosclerosis. Furthermore, the intrarenal vascular resistance differs depending on the underlying renal disease, and appears to increase to a greater extent in diabetic nephropathy.

Adult↗

PubMed2005

[Bi-weekly chemotherapy with medium-dose docetaxel for advanced and recurrent breast cancers (The 15th study of Keiji Breast Cancer Study Group)].

The efficacy and safety of bi-weekly administration of medium-dose docetaxel (TXT) were evaluated in patients with advanced and recurrent breast cancers. The additional effect of 5'-DFUR for non-responders was also evaluated. Forty patients with advanced and recurrent breast cancers were treated and 38 cases of 40 were evaluated (34 with recurrent cases and 4 with advanced cases). All cases were female, and their mean age was 56.0 (38-74). TXT of 60 mg/body, which was equivalent to 30-50 mg/m2 for standard-sized Japanese women, was administered every two weeks. 5'-DFUR of 800 mg/body was added for non-responders after 5 weeks. The response rate was calculated from the data of 32 cases with measurable lesions, and side effects were evaluated in about 34 cases with exact records. Two hundred seventy-one courses were performed for 38 patients (4-24 courses per person, average 7.13 courses). The mean dosage per course of TXT was 58.4 mg/body (38.3 mg/ m2). Three complete and 7 partial responses were observed (overall response rate: 31.3%). Ten non-responders were evaluated for the additional effect of 5' DFUR, and one case reached PR. Grade 3/4 bone marrow suppression occurred in 9 patients, and Grade 3/4 general malaise was observed in two patient. According to the results, bi-weekly administration of medium dose TXT is an active and safe regimen in patients with advanced and recurrent breast cancers. The additional effect of 5'-DFUR was observed in one of 10 non-responders of bi-weekly chemotherapy with medium-dose TXT.

Adult↗

PubMed2004

Angiotensin II receptor blockade corrects altered expression of gap junctions in vascular endothelial cells from hypertensive rats.

Blockade of the renin-angiotensin system improves the impaired endothelium-dependent relaxations associated with hypertension and aging, partly through amelioration of endothelium-derived hyperpolarizing factor (EDHF)-mediated responses. Although the nature of EDHF is still controversial, recent studies have suggested the involvement of gap junctions in EDHF-mediated responses. Gap junctions consist of connexins (Cx), and we therefore tested whether the expression of Cx in vascular endothelial cells would be altered by hypertension and antihypertensive treatment. Spontaneously hypertensive rats (SHR) were treated with either the angiotensin II type 1 receptor antagonist candesartan or the combination of hydralazine and hydrochlorothiazide for 3 mo from 5 to 8 mo of age. Confocal laser scanning microscopy after immunofluorescent labeling with antibodies against Cx37, Cx40, and Cx43 revealed that the expression of Cx37 and Cx40 in endothelial cells of the mesenteric artery was significantly lower in SHR than in WKY. Treatment with candesartan, but not the combination of hydralazine and hydrochlorothiazide, significantly increased the expression of Cx37 and Cx40, although blood pressure decreased similarly. On the other hand, the expression of Cx43, though scarce and heterogeneous, was increased in SHR compared with WKY, and candesartan treatment lowered the expression of Cx43. These findings suggest that renin-angiotensin system blockade corrects the decreased expression of Cx37 and Cx40 in arterial endothelial cells of hypertensive rats, partly independently of blood pressure, whereas the expression of Cx43 changed in the opposite direction. It remains to be clarified whether these changes in Cx37 and Cx40 are related to endothelial function, particularly that attributable to EDHF.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2004

Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in rats.

Ghrelin is an orexigenic peptide originally isolated from the stomach. Intracerebroventricular administration of ghrelin has been shown to elicit decreases in arterial pressure and renal sympathetic nerve activity in conscious rabbits. The aim of the present study was to determine the role of ghrelin in the brain stem in cardiovascular responses in rats. Unilateral microinjection of ghrelin into the nucleus of the solitary tract significantly decreased the mean arterial pressure and heart rate (-17.3+/-0.8 mm Hg and -13.6+/-3.5 bpm by 20 pmol). The microinjection of ghrelin into the nucleus of the solitary tract also suppressed the renal sympathetic nerve activity (-29.5+/-3.4%; P<0.0001). Pretreatment with intravenous injection of pentolinium (5 mg/kg), a ganglion-blocking agent, eliminated these cardiovascular responses induced by the microinjection of ghrelin (20 pmol) into the nucleus of the solitary tract; however, pretreatment with intravenous injection of atropine sulfate (0.1 mg/kg), an antagonist of muscarinic acetylcholine receptors, failed to prevent them. In contrast, unilateral microinjection of ghrelin into the area postrema, rostral, and caudal ventrolateral medulla caused no significant changes in the mean arterial pressure and heart rate. On the other hand, immunohistochemical study revealed that the receptor for ghrelin, the growth hormone secretagogue receptor, was expressed in the neuronal cells of the nucleus of the solitary tract and the dorsal motor nucleus of the vagus, but not in the cells of the area postrema. These results suggest that ghrelin acts at the nucleus of the solitary tract to suppress sympathetic activity and to decrease arterial pressure in rats.

Animals↗

PubMed2004

A new sequenced allelic ladder marker for D1S80 typing.

A sequenced allelic ladder marker that contains 32 alleles consisting of alleles 13-44 was developed for D1S80 ( MCT118) typing. Each allele, after amplification with D1S80 primers, was cloned to the pT7Blue T-Vector. The plasmid DNAs of these clones were mixed and amplified with D1S80 primers to construct the allelic ladder marker. All the alleles prepared in this study were sequenced in both directions, using two types of forward primers and one reverse primer. The sequencing results revealed that all the alleles in our allelic ladder marker had the correct length corresponding to the allele number. This marker can be used for more effectively typing D1S80.

Alleles↗

PubMed2004

Role of ERK and Rho kinase pathways in central pressor action of urotensin II.

BACKGROUND: It has been shown that central urotensin II acts on the central nervous system to increase arterial pressure in conscious rats. OBJECTIVE: To investigate the intracellular signal transduction mechanisms of the central cardiovascular action of urotensin II. METHODS: The effects of intracerebroventricular (i.c.v.) administration of the extracellular signal-regulated protein kinase (ERK) inhibitor, PD 98059 (20 nmol), the phosphatidylinositol 3 (PI3) kinase inhibitor, wortmannin (20 nmol), or the Rho kinase inhibitor, Y-27632 (20 nmol), on cardiovascular responses to i.c.v. urotensin II (10 nmol) were determined in conscious rats. RESULTS: I.c.v. injection of urotensin II increased both arterial pressure and heart rate (14.9 +/-1.5 mmHg and 94.6 +/-12.8 beats/min, respectively; P < 0.05 for each). Pretreatment with PD 98059 or Y-27632 significantly (P < 0.01 and P < 0.05, respectively) attenuated the pressor response induced by i.c.v. urotensin II (6.6 +/-1.4 and 6.9 +/-1.2 mmHg, respectively). Pretreatment with a mixed solution of PD 98059 and Y-27632 failed to cause further suppression of the urotensin II-induced pressor responses (4.5 +/-0.9 mmHg). In contrast, pretreatment with i.c.v. wortmannin failed to influence the pressor response induced by i.c.v. urotensin II (12.6 +/-1.3 mmHg). The tachycardiac response induced by i.c.v. urotensin II was not influenced by pretreatment with PD 98059, Y-27632 or wortmannin. CONCLUSIONS: These findings suggest that the ERK and Rho kinase pathways, but not the PI3 pathway, may be involved in the central pressor action of urotensin II in conscious rats.

Amides↗

PubMed2004

Changes in endothelium-derived hyperpolarizing factor in hypertension and ageing: response to chronic treatment with renin-angiotensin system inhibitors.

1. Endothelial function is impaired in hypertension and ageing and this may be associated with an increase in cardiovascular disease. Several clinical studies have shown that blocking the renin-angiotensin system (RAS) improves endothelial function not only in hypertensive patients, but also in normotensive patients with cardiovascular disease. 2. The aim of the present study was to test whether endothelium-derived hyperpolarizing factor (EDHF)-mediated smooth muscle hyperpolarization and relaxation are altered in hypertension and ageing and, if so, whether chronic treatment with RAS inhibitors (the angiotensin-converting enzyme inhibitor enalapril and the angiotensin AT1 receptor antagonist candesartan) would correct such changes. 3. Endothelium-derived hyperpolarizing factor-mediated responses were examined in mesenteric arteries from 12-month-old spontaneously hypertensive rats (SHR) and 3-, 6-, 12- and 24-month-old normotensive Wistar-Kyoto (WKY) rats. Furthermore, both strains were treated for 3 months with either RAS blockers or a conventional therapy with hydralazine and hydrochlorothiazide from 9 to 12 months of age. 4. In arteries of 12-month-old SHR, EDHF-mediated responses were impaired compared with age-matched WKY rats. In SHR, all antihypertensive treatments improved the impairment of EDHF-mediated responses; however, RAS inhibitors tended to improve these responses to a greater extent compared with conventional therapy with hydralazine and hydrochlorothiazide. 5. In arteries of WKY rats, EDHF-mediated responses were impaired at the age of 12 and 24 months compared with 3- and 6-month-old rats, with the response tending to be impaired to a greater extent in 24-month-old rats. 6. Three months of treatment of WKY rats, until 12 months of age, with RAS inhibitors, but not with conventional therapy with hydralazine and hydrochlorothiazide, improved the age-related impairment of EDHF-mediated responses, despite a similar reduction in blood pressure by both treatments. 7. These findings suggest that: (i) EDHF-mediated hyperpolarization and relaxation decline with hypertension and ageing in rat mesenteric arteries; (ii) antihypertensive treatment restores the impaired EDHF-mediated responses in hypertension; (iii) RAS inhibitors may be more efficacious in improving endothelial dysfunction associated with hypertension; and (iv) chronic treatment with RAS inhibitors improves the age-related impairment of EDHF-mediated responses, presumably through the blockade of RAS but not blood pressure lowering alone.

Aging↗