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SUMMARY 1. Regional haemodynamic alterations caused by hypertonic NaCl solution (Hi-Salt; 10%, 10 μL) injected intracerebroventricularly (i.c.v.) were investigated by using radioactive microspheres in anaesthetized rats. 2. Intracerebroventricular injections of Hi-Salt increased regional vascular resistance of visceral organs, including the kidney, and elevated plasma levels of vasopressin. 3. Intracerebroventricular pretreatment with TCV-11974 (50 μg/10 μL/nat), an angiotensin AT1 receptor antagonist, attenuated the pressor response and vasopressin release to subsequently injected Hi-Salt, but did not affect regional haemodynamic effects of i.c.v. Hi-Salt on vascular resistance. 4. In contrast, i.c.v. pretreatment with atrial natriuretic polypeptide (ANP) or type-C natriuretic polypeptide (CNP) almost completely abolished the haemodynamic changes and vasopressin release caused by i.c.v. Hi-Salt. 5. The present findings indicate that a natriuretic family in the brain may be involved to a great degree in the central regulation of salt-induced hypertension in rats, while brain angiotensin II is likely to participate only in vasopressin release.

To investigate the role of human hepatocyte growth factor (hHGF) in vascular lesions associated with endothelial injury, we measured serum hHGF concentrations in subjects with retinal arteriosclerosis, coronary atherosclerosis, or arteriolitis due to Henoch-Schonlein pur- pura. Individuals with more advanced grades of retinal arterioscle- rosis showed higher serum hHGF concentrations (grade 0, 0.053 6 0.005 ng/mL (n 5 68); grade 1, 0.144 6 0.022 ng/mL (n 5 21; P , 0.01 vs. grade 0); grade 2, 0.338 6 0.036 ng/mL (n 5 20; P , 0.01 vs. grade 0 or 1); grade 3, 0.526 6 0.051 ng/mL (n 5 9; P , 0.01 vs. grade 0, 1, or 2)). Patients with active arteriolitis due to Henoch-Schonlein pur- pura showed higher (P , 0.01) serum hHGF concentrations (0.347 6 0.038 ng/mL; n 5 14) than those in the remission phase (0.097 6 0.017 ng/mL; n 5 19). Mean serum hHGF concentrations were higher in subjects with coronary atherosclerosis than in those without, but a significant overlap in serum hHGF concentrations was found between subjects with and those without coronary atherosclerosis. Serum hHGF may be an indicator of the presence or development of arte- riolar lesions. (J Clin Endocrinol Metab 84: 2475-2480, 1999)

Changes in the renin-angiotensin system (RAS) mRNAs in the brain and the kidney of rats after administration of DOCA and/or sodium chloride were assessed by use of a competitive PCR method. Benzamil, a blocker of amiloride-sensitive sodium channels, was infused intracerebroventricularly or intravenously for 7 days in DOCA-salt or renal hypertensive rats, and the effects of benzamil on the brain RAS mRNAs were determined. Renin and ANG I-converting enzyme (ACE) mRNAs were not downregulated in the brain of rats administered DOCA and/or salt; however, these mRNAs were decreased in the kidney. Intracerebroventricular infusion of benzamil decreased renin, ACE, and ANG II type 1 receptor mRNAs in the brain of DOCA-salt hypertensive rats but not in the brain of renal hypertensive rats. The gene expression of the brain RAS, particularly renin and ACE, is regulated differently between the brain and the kidney in DOCA-salt hypertensive rats, and benzamil-blockable brain sodium channels may participate in the regulation of the brain RAS mRNAs.

Human hepatocyte GF (hHGF) has strong neoangiogenesis activity. The present study was designed to investigate the possible involvement of hHGF in neovascularization in proliferative diabetic retinopathy (PDR) by measuring vitreous hHGF concentrations. The mean vitreous hHGF concentration was higher in subjects with PDR (5.70 ± 0.68 ng/mL, n = 33) than in nondiabetic control subjects (1.50 ± 0.20 ng/mL, n = 18, P < 0.01), nondiabetic subjects with proliferative vitreoretinopathy (3.31 ± 0.57 ng//mL, n = 10, P < 0.05), or diabetic subjects without PDR (1.29 ± 0.28 ng/mL, n = 8, P < 0.01). PDR subjects with neovascularization of iris, which suggests advanced retinal ischemia, showed a higher mean vitreous hHGF concentration than those without iridal neovascularization [7.33 ± 1.16 ng/mL (n = 14) vs. 4.49 ± 0.72 ng/mL (n = 19), P < 0.05]. The mean vitreous hHGF concentration was higher in PDR subjects with retinal neovascularization at the optic disc than in those with neovascularization elsewhere [7.3 ± 1.1 ng/mL (n = 15) vs. 4.4 ± 0.7 ng/mL (n = 18), P < 0.05]. Our results indicate that vitreous hHGF may play a role in retinal neovascularization in PDR.

The serum levels of hepatocyte growth factor (HGF) were determined in patients with various renal diseases. In patients with acute-phase acute renal failure (ARF) and chronic tubulointerstitial nephritis (chronic TIN), the serum HGF levels were 0.55 ± 0.24 and 0.44 ± 0.37 ng/ml (mean ± SD), respectively, and were significantly higher than that in the control group (0.12 ± 0.12 ng/ml). The serum HGF level tended to be high also in patients with active-phase steroid-sensitive nephrotic syndrome (SSNS). The serum levels of HGF were not elevated in patients with IgA nephropathy (IgAN), Henoch-Schönlein purpura nephritis (HSPN), membranoproliferative glomerulonephritis (MPGN), poststreptococcal acute glomerulonephritis (PSAGN), unilateral renal atrophy, unilateral nephrectomy, or proximal tubular dysfunction. These observations suggest that glomerular disorders cause no apparent elevation of the serum HGF level, and that elevation of the serum HGF level may be associated with tubulointerstitial damage in renal diseases.

The expression of CD44 V6, V7, and V10 in normal endometrium and endometrial cancer was compared.Using reverse transcription polymerase chain reaction (RT-PCR) blot analysis, the expression of mRNA containing CD44 V6, V7, and V10 was determined in 19 normal endometrium and 27 endometrial cancer samples. Immunohistochemical staining of CD44 V6 and V7 was performed in the same samples.In RT-PCR analysis, the CD44 variant forms containing V6 and V7 exons were expressed in 96 and 93% of endometrial cancer tissues, respectively. These proportions were significantly higher than those in normal endometrium (V6, 63%; V7, 58%) (P0.01). CD44 V10 was expressed in 96% of endometrial cancers and 89% of normal endometrial samples. In immunohistochemical staining, CD44 V6 and V7 were detected in 48 and 61% of endometrial cancers and in 26 and 42% of normal endometrial samples, respectively. Neither of these differences was significant. No correlation was found between the expression of CD44 variants and any clinicopathological features.CD44 V6 and V7 were expressed in a significantly larger proportion of endometrial cancers than normal endometrial samples. However, they were also expressed in a considerable proportion of normal endometria. These findings suggest that CD44 V6 and V7 play roles in normal endometrial function and overexpression of CD44 V6 and V7 is not related to the metastatic potential of endometrial cancer.

To investigate the possible involvement of endogenous nitric oxide (NO) in acute hypotension during maintenance hemodialysis, we measured the plasma concentration of the nitrate anion NO3-, a stable metabolite of NO, in 19 patients undergoing hemodialysis. We analyzed heart rate variability to estimate the relationship between autonomic nervous activity and NO production, low-frequency/high-frequency components (L/H) as a parameter of cardiac sympathetic activity, and high-frequency power as a parameter of cardiac vagal activity. Six patients developed severe hypotension (a change in mean blood pressure during dialysisor = 20 mm Hg), four patients developed mild hypotension (a change in mean blood pressureor = 19 mm Hg andor = 1 mm Hg), and nine patients did not develop hypotension. The plasma levels of NO3- before dialysis were markedly elevated in the severely hypotensive group compared with the patients who showed no hypotension (566+/-122 micromol/L v 133+/-38 micromol/L; P0.01), and this difference disappeared midhemodialysis and after hemodialysis. The plasma concentration of NO3- before dialysis was significantly associated with both the change in mean blood pressure during dialysis (r= -0.735; P = 0.003) and the mean blood pressure after dialysis (r = -0.675; P = 0.0015). The L/H ratio was inhibited before or after dialysis in the severely hypotensive group compared with the nonhypotensive group, and hypotension during dialysis was correlated with the inhibited L/H ratio before (r = 0.784; P = 0.001) or after (r = 0.822; P = 0.001) dialysis. Plasma NO3- concentrations were correlated with the L/H ratio before (r = -0.553; P = .014) or after (r = -0.546; P = 0.015) dialysis. These results suggest that inhibited sympathetic activity is one of the causes of acute hypotension during dialysis, and the enhanced production of NO is involved in this inhibition of the sympathetic activity in patients having a hypotensive episode during dialysis. The plasma concentration of NO3- before dialysis may be a predictor of the risk of hypotension during dialysis in patients with end-stage renal disease.

OBJECTIVE: To elucidate the role of brain nitric oxide produced by neuronal constitutive nitric oxide synthase in sodium-induced hypertension. DESIGN AND METHODS: Diets containing a high (8% NaCl), a medium (2% NaCl), and a low (0.2% NaCl) sodium content were administered to Wistar rats aged 12 weeks for 10 days or 8 weeks until they were killed. Male Wistar rats administered either deoxycorticosterone acetate, 1% NaCl or both and the respective controls were killed 2 weeks (during prehypertensive stage) or 6 weeks (during hypertensive stage) after the start of treatment. The hypothalamus and lower brainstem were excised for extraction of total RNA. Reverse transcription polymerase chain reactions of constitutive nitric oxide synthase messenger RNA and glyceraldehyde-3-phosphate dehydrogenase messenger RNA were performed, and constitutive nitric oxide synthase messenger RNA levels were expressed relative to glyceraldehyde-3-phosphate dehydrogenase messenger RNA levels. RESULTS: A high sodium intake for 10 days tended to decrease constitutive nitric oxide synthase messenger RNA levels in the hypothalamus, compared with effect of a low sodium intake. Constitutive nitric oxide synthase messenger RNA levels in the hypothalamus of deoxycorticosterone acetate-salt hypertensive rats were lower than those in the control sham-operated rats. Neither alteration of sodium intake nor administration of deoxycorticosterone with and without sodium affected constitutive nitric oxide synthase gene expression in the lower brainstem. CONCLUSIONS: Expression of neuronal constitutive nitric oxide synthase gene is downregulated in the hypothalamus of deoxycorticosterone acetate-salt hypertensive rats. This lower than normal expression of neuronal constitutive nitric oxide synthase gene in the hypothalamus could be an adaptive response to sodium-induced hypertension, and suggests that nitric oxide produced by hypothalamic constitutive nitric oxide synthase plays a role in maintenance of blood pressure in relation to sodium balance in rats.

To determine the possible involvement of brain amiloride-sensitive Na+channels in Na+-induced hypertension, we investigated the effects of benzamil hydrochloride, a specific blocker of these Na+channels, on the acute pressor mechanisms of intracerebroventricular infusion of hypertonic NaCl and the continuous pressor mechanisms of Na+-induced chronic hypertension, such as deoxycorticosterone acetate-salt hypertensive or stroke-prone spontaneous hypertensive rats, and of non-Na+-induced hypertension, such as renovascular hypertensive rats. Intracerebroventricular preinjection with benzamil (1 or 10 nmol/kg) abolished the increase in mean arterial pressure, heart rate, abdominal sympathetic discharge, and plasma vasopressin concentration induced by an acute increase in cerebrospinal Na+concentrations at intracerebroventricular infusion of 1.5 M hypertonic NaCl. Continuous intracerebroventricular infusion of benzamil (1 or 10 nmol ⋅ kg−1⋅ day−1) for 7 days attenuated Na+-induced chronic hypertension in both deoxycorticosterone acetate-salt and stroke-prone spontaneous hypertensive rats, accompanied by reduction of urinary excretion of vasopressin and norepinephrine but not in renovascular hypertensive rats. Intravenous infusion of benzamil (10 nmol ⋅ kg−1⋅ day−1) for 7 days affected neither arterial pressure nor urinary excretion of vasopressin and norepinephrine in either model of hypertension. Benzamil-blockable brain amiloride-sensitive Na+channels are expected to function as one of the Na+receptors in the brain and to be involved in the pressor mechanism of Na+-induced hypertension.

Prognostic factors in idiopathic sudden sensorineural hearing loss were analyzed statistically in 135 patients admitted to the Department of Otorhinolaryngology at Sumitomo Hospital between 1993 and 1996. Patients treated within 6 days after onset recovered significantly better than those treated 7 or more days after onset. The patients with hearing within 80 dBHL recovered significantly better than those over 80 dBHL. Moreover, the improvement rate was better in the low frequencies than in the high frequencies. Severity of vertigo was closely related to poor recovery of hearing loss in the group with hearing of less than 40 dBHL at onset, although this relationship was not evident in the group with hearing of more than 40 dBHL at onset. These results suggest that patients with acute endocochlear hydrops may be included in the group with vertigo and hearing of better than 40 dBHL at onset.

The effect of brain l -arginine on arterial pressure was investigated by injecting l - or d -arginine into the cerebral ventricles of male Wistar rats that were anesthetized with urethane. Intracerebroventricular (ICV) injection of 1 μ mol l -arginine reduced the arterial pressure and the abdominal sympathetic nervous activity (SNA), whereas the injection of 10 μ mol l -arginine induced a transient pressor response and reduced both the heart rate and SNA. Although ICV injection of 1 μ mol d -arginine had no effect on cardiovascular function or SNA, injection of 10 μ mol of this enantiomer elicited a transient pressor response, similar to that induced by 10 μ mol l -arginine, followed by a persistent increase in arterial pressure and a corresponding increase in SNA. ICV pretreatment with the nitric oxide synthase inhibitor N G -monomethyl l -arginine abolished the vasodepressor response and reduced the inhibition of SNA induced by ICV injection of 1 μ mol l -arginine; such pretreatment increased the arterial pressure, heart rate, and SNA measured 30 min after ICV injection of 10 μ mol l -arginine. ICV pretreatment with the angiotensin II type 1 receptor antagonist CV-11974 inhibited the pressor response to 10 μ mol l -arginine and the first phase of the pressor response to 10 μ mol d -arginine. Intravenous pretreatment with the α 1 -adrenoceptor blocker bunazosin hydrochloride abolished the pressor response to 10 μ mol l -arginine and both phases of the pressor response to 10 μ mol d -arginine. Brain l -arginine thus appears to exert pressor actions through stimulation of the brain renin-angiotensin system and peripheral SNA. However, these actions may be attenuated by l -arginine-derived nitric oxide.

To clarify the precise relationship between sodium and nitric oxide (NO), we studied the effects of altered sodium intake on NO production. Male Wistar rats were maintained on a low-sodium (0.2% NaCl), normal-sodium (2% NaCl), or high-sodium (8% NaCl) diet for 10 days or 8 weeks; 24-h urine was collected at those times for assay of nitrate ion (NO3-), a stable metabolite of NO, and of cyclic GMP. Urinary excretion of NO3- and cyclic GMP was increased on the 10th day in the low-sodium group, as compared with the normal- and high-sodium groups. The urinary excretion of cyclic GMP was increased at the 8th week, and NO3- showed a tendency to increase in the low-sodium group, as compared with the high-sodium group. An up- regulation of NO production may explain, at least in part, the antihypertensive effect of sodium restriction. (Hypertens Res 1997; 20: 57-60)

ヒスタミンH2受容体拮抗剤が心臓自律神経機能に与える影響を調べる目的で, 健常成人15名を対象にcimetidine, famotidine, roxatidineを静脈内投与し, 心拍変動スペクトル解析に於ける心臓迷走神経活動の指標である高周波成分域 (highfrequenoy, 0.15-0.40Hz) の変化率を測定したところ, cimetidine, famotidineでは投与後に―過性の上昇を認めたのに対しroxatidineでは有意な変化を認めなかった.cimetidine, famotidineの投与で認められた心臓迷走神経活動の亢進がヒスタミンH2受容体拮抗剤の心臓への影響である変時作用の機序の一つである可能性が示唆された.また心臓迷走神経機能への影響はヒスタミンH2受容体拮抗剤の種類によって差異が存在することが示唆され, 臨床的には病態によってヒスタミンH2受容体拮抗剤の選択を考慮する場合も必要であると考えられた.

Platelet-derived growth factor receptor alpha (PDGFRα) is believed to be associated with cell survival. We examined (i) whether PDGFRα blockade enhances the antitumor activity of taxanes in ovarian carcinoma and (ii) potential biomarkers of response to anti-PDGFRα therapy.PDGFRα expression in 176 ovarian carcinomas was evaluated with tissue microarray and correlated to survival outcome. Human-specific monoclonal antibody to PDGFRα (IMC-3G3) was used for in vitro and in vivo experiments with or without docetaxel. Gene microarrays and reverse-phase protein arrays with pathway analyses were performed to identify potential predictive biomarkers.When compared to low or no PDGFRα expression, increased PDGFRα expression was associated with significantly poorer overall survival of patients with ovarian cancer (P=0.014). Although treatment with IMC-3G3 alone did not affect cell viability or increase apoptosis, concurrent use of IMC-3G3 with docetaxel significantly enhanced sensitization to docetaxel and apoptosis. In an orthotopic mouse model, IMC-3G3 monotherapy had no significant antitumor effects in SKOV3-ip1 (low PDGFRα expression), but showed significant antitumor effects in HeyA8-MDR (high PDGFRα expression). Concurrent use of IMC-3G3 with docetaxel, compared with use of docetaxel alone, significantly reduced tumor weight in all tested cell lines. In protein ontology, the EGFR and AKT pathways were downregulated by IMC-3G3 therapy. MAPK and CCNB1 were downregulated only in the HeyA8-MDR model.These data identify IMC-3G3 as an attractive therapeutic strategy and identify potential predictive markers for further development.

Background/Aims: The assessment of myocardial fatty acid metabolism impairment by single-photon emission computed tomography (SPECT) using 123I-β-methyliodophenyl-pentadecanoic acid (BMIPP) might predict the risk of cardiac death in hemodialysis patients. We investigated the potential of oral nicorandil to improve myocardial fatty acid metabolism after percutaneous coronary intervention (PCI) in this population. Methods: We evaluated 128 hemodialysis patients who had obtained coronary revascularization by PCI (90 men and 38 women, 66 ± 9 years). Participants for the analysis were randomly assigned to either the nicorandil (n = 63) or control group (n = 65). BMIPP SPECT was performed every year after coronary revascularization by PCI. Uptake on SPECT was graded in 17 segments on a 5-point scale (0, normal; 4, absent) and assessed as BMIPP summed scores (SS). Results: The incidence of cardiac death was lower (p = 0.004) in the nicorandil group (7/63, 11.1%) than in the control group (21/65, 32.3%) during a mean follow-up of 2.7 ± 1.4 years. BMIPP SS reduction rates improved in the nicorandil group compared with the control group from 3 years of administration. In Kaplan-Meier analyses, free survival rate of cardiac death was higher in patients with a ≥20% BMIPP SS reduction rate as compared with those with a Conclusion: Long-term oral administration of nicorandil may improve impaired myocardial fatty acid metabolism after coronary revascularization by PCI in hemodialysis patients.

The vibration and the noise generated by the water jet electric boats are low compared with those of same sized internal combustion engine boats. However, an objective evaluation of the vibration and the noise from electric boats has not yet been conducted. In this research, an underwater noise from an electric boat and that from an internal combustion engine boat were measured and analyzed. From results of experiments and frequency analysis, maximum noise level of the electric boat was found to be lower than that of internal combustion engine boat. It was also shown that the impeller revolution was the main source of underwater noise from the electric boat.

Abstract The ATP-sensitive potassium channels (K ATP ) are activated either by a decrease in intracellular ATP content or by a lowering of the ATP-ADP ratio such as during stroke. We studied the role of cerebral K ATP on arterial pressure during acute reduction of cerebral blood flow in 12-week-old male Wistar rats anesthetized with urethane by recording arterial pressure and heart rate continuously. After bilateral ligation of the common carotid arteries, glibenclamide, a specific blocker of K ATP , was injected intracerebroventricularly into the cerebral lateral ventricle. Glibenclamide elicited a sustained vasopressor response in a dose-dependent manner in rats with bilateral carotid artery ligation (10 nmol, +15±2 mm Hg; 1 nmol, +5±1 mm Hg, P 1 -adrenoceptor antagonist, did not affect the pressor response of intracerebroventricular glibenclamide. To investigate the vasopressor mechanism further, we measured plasma and pituitary concentrations of arginine vasopressin and determined the effects of vasopressin receptor antagonists. The intracerebroventricular injections of glibenclamide significantly increased the plasma concentration of vasopressin ( P P 1 receptor antagonist OPC-21268 abolished the vasopressor response to intracerebroventricular glibenclamide (+16±2 versus +1±1 mm Hg, P ATP in the brain may inhibit an excess rise in arterial pressure in part by decreasing the release of vasopressin from the pituitary during bilateral carotid artery ligation.

In order to clarify the mechanism of hypertension induced by a nitric oxide (NO) synthase inhibitor, L-NG-nitro-L-arginine (LNNA), metabolites of NO, catecholamines, and hemodynamic parameters were measured during 7 days of oral administration of LNNA in rats. Control rats received either L-arginine (L-Arg) or the vehicle. Systolic blood pressure, measured by the tail-cuff method was elevated throughout the period of LNNA administration, but that in the two control groups was not influenced by treatment. Heart rate decreased on the second day only in LNNA-treated rats. Although L-Arg treatment had no influence, LNNA markedly decreased the plasma level and the urinary excretion of nitrate ions (NO3-). Urinary excretion of noradrenaline was significantly decreased on the second day of LNNA administration and returned to the control level thereafter. When hemodynamic changes were measured by using radioactive microspheres, LNNA was found to increase blood pressure by markedly increasing total peripheral resistance. Cardiac output was decreased by LNNA. L-Arg, again, did not influence the hemodynamic variables as compared with the vehicle control group. The regional vascular resistance index was increased by LNNA in many tissues and organs, except the brain and the heart. Regional blood flow, on the other hand, was significantly decreased only in the liver and skin by LNNA. The marked reduction in NO3- in urine by LNNA-treatments may indicate that the measured NO3- is exclusively of endogenous origin, and that inhibition of NO production causes elevation of blood pressure by constricting peripheral arteries. Sympatholytic responses by the baroreceptor reflex were thereby evident only on the second and the third days, which was indicated by bradycardia and suppression of noradrenaline excretion into urine. These results indicate that the inhibition of NO synthase actually decreases production of endogenous NO, and that the hypertension caused by decreases in NO production is due to elevation of total peripheral vascular resistance. (Hypertens Res 1995; 18: 319-324)

(99.9995%) and N2 (99.999%) or the pure Ar was used as sputtering gas. The total working gas pressure (Ptot) was 1.33 Pa, which was the sum of the partial pressure of N2 (PN2) and that of Ar. In order to change the composition of the film, the concentration of partial N2 gas pressure (cN2=100� PN2=Ptot) was changed. Transparent AlN film was obtained at cN2=12%N2. 7) Of course the pure Al film was formed without N2. Corning #7059 glass (0.7 mm in thickness) was used as a substrate. Film thickness was measured using a surface texture measurement instrument (Surfcom 200B, Tokyo Seimitu Ltd.). The deposition rates were estimated by using smooth films with the thickness less than 100 nm. The typical deposition rates at input power of 200 W were 0.18 and 0.13 nm/s at 0 and 12%N2, respectively. Then in this study each film (or layer) is named by its substance, deposition film thickness (d) which is estimated by deposition rate, and substrate temperature (Tsub), e.g., a notation of Al(d ,T sub) represents an aluminum film with a thickness of d deposited at Tsub. Surface morphology was observed using an atomic force microscope (AFM: Nanopics, NPX100AFM head, Seiko Instruments Inc.). Optical properties of the specimens were measured using an ultraviolet-visible-near infrared spectrometer (UV-3100PC, Shimadzu Co.) in the wavelength range of 0.24 to 2.60 mm. The specular reflectance (R0) was evaluated by measuring the reflectance at an incidence angle of 12 � . The diffusive reflectance (Rd) at normal incidence was also measured using an integrating sphere with a diameter of 60 mm. The color photograph of specimen is taken using a digital camera (Digital Revio KD-300Z, Konica Co.). 3. Results

SUMMARY 1. When carteolol, a β-adrenergic blocker, was administered to KK-Ay/Ta Jcl mice that are obese and develop spontaneously non-insulin dependent diabetes, their increase in bodyweight was arrested from the age of 16 weeks. Since their intake of food and water was not influenced by carteolol treatment, compared with the control KK-Ay/Ta Jcl mice, abolition of the weight gain might be attributed to increased energy metabolism. 2. Non-fasting serum glucose levels in carteolol-treated mice at the age of 17 weeks were within normal range (118±4 vs 186±12 mg/dL). An intraperitoneal glucose-tolerance test revealed that the carteolol treatment markedly restored glucose metabolism; fasting plasma glucose (88±6 mg/dL) was within normal range, and immunoreactive insulin (IRI; 5.8±0.8 vs 33.3 ± 10.5 ng/mL) and plasma glucose levels at 60 min post glucose (361±44 vs 541 ±32 mg/dL) were significantly lower in carteolol-treated mice than those in the control group at the age of 20 weeks. 3. From these findings, carteolol is considered to have little effect on the growth of mice but to correct the obesity that develops after age 16 weeks, when their growth terminates. In addition, the normalization of blood glucose and marked decrease in IRI levels suggests that carteolol improves glucose tolerance by increasing the insulin sensitivity. 4. Since brown adipose tissue (BAT) is closely associated with thermogenesis and energy consumption, we tested whether carteolol may affect BAT, When the regional blood flow was measured by radioactive microspheres in rats, blood flow in BAT and white adipose tissue was markedly increased by carteolol. 5. These findings indicate that carteolol blocks β1- and β2-adrenoceptors, but may stimulate β-receptors particularly in the adipose tissue to promote lipolysis and thermogenesis, and to consume excess energy in mice. Thus, carteolol does not influence mouse growth, but may prevent obesity leading to increases in insulin sensitivity.

Possible central actions of adrenomedullin were explored and compared with the peripheral effects by injecting it into the lateral ventricle, cisterna magna, and femoral vein in urethane-anesthetized rats. Adrenomedullin, 1.0 to 3.0 nmol/kg, injected intravenously (i.v.), caused a transient vasodepression of about 10 to 30 mm Hg, dose dependently, which lasted for15 min. On the other hand, intracerebroventricular (ICV) and intracisternal (IC) injections of adrenomedullin elicited sustained elevations of arterial pressure of gradual onset, dose dependently; the arterial pressure started to rise at about 3 min after the injection, and gained peak response after20 min. The pressor response lasted for2 h. Heart rate was not significantly influenced by these doses of adrenomedullin. The abdominal sympathetic outflow was markedly increased in relation to the blood pressure elevation. The time-course of the responses was quite similar with both ICV and IC injections. Hypotensive effects of i.v. injected adrenomedullin was partially attenuated, and the centrally induced vasopressor responses were abolished by the pretreatment with human calcitonin gene-related peptide (hCGRP)-receptor antagonist, hCGRP(8-37). These findings indicate that the receptors for adrenomedullin exist in the brain, and that the receptor site may be anatomically far from the surface of the brain and the ventricular system because the onset of the pressor response was delayed. Or, CGRP and adrenomedullin may share the same receptors, particularly in the brain.

Since it has been demonstrated that one of the endogenous digitalis-like factors (EDLF) is ouabain, searches for the EDLF are focused on the endogenous ouabain in the mammalian body. We have developed a monoclonal, anti-ouabain antibody which similarly cross-immunoreacts with other digitalis glycosides such as ouabain, digoxin, and digitoxin; the epitope of this antibody was confirmed to be the partial structure important for cardiac compounds and neutralizing their pharmacological activity, Na + /K + -ATPase inhibition, in a competitive mode against K + . By using this monoclonal antibody, we immunohistochemically examined the distribution of the digitalis-like substances in the adrenal glands and the hypothalamus. The immunoreactivity was diffusely distributed in the cytoplasm of endocrine cells of the adrenal medulla, but not in the adrenal cortex. Immunoreactive neuronal somata and their proximal processes were found in the hypothalamic paraventricular nucleus, and the intensity of the immunostaining in the proximal processes was greater than in the somata. In the neurons of the supraoptic nucleus very weak immunoreactivity was observed. No immunoreactive material was detected in the other areas of the hypothalamus examined in this study. Present findings with a monoclonal, ouabain antibody suggest that the ouabain-like immunoreactive substances are exclusively distributed in the neural tissues such as the hypothalamus and the adrenal medulla. Although the physiological role of the substance is still uncertain, this particular distribution suggests that it may be a neurotransmitter implicated in the cardiovascular and endocrine functions.

Regional vascular responses to NKY-722 (NKY), a novel dihydropyridine derivative calcium channel blocker, and the effects on the responses to endothelin (ET) were investigated using tracer microspheres with a reference sample method in anesthetized rats. Intravenous injections of NKY, 0.2 and 2mg/kg, decreased blood pressure and total peripheral resistance dose-dependently. Cardiac index significantly increased only with the high dose regardless of bradycardia. Regional blood flow significantly changed with NKY: It increased in the brain, brown adipose tissue (BAT), intestine, colon and skin, but decreased in the liver, spleen, kidneys, adrenals and skeletal muscle. NKY decreased the regional vascular resistance in the brain, heart, lungs, BAT, intestine, colon and skin, but increased it in the liver, spleen and skeletal muscle. ET significantly increased blood pressure, but this was abolished by pretreatment with the low and high doses of NKY. Cardiac index became significantly lower with ET, and was not affected by NKY. Total peripheral resistance after ET remained lower with NKY pretreatments. ET decreased the blood flow mainly in the liver, spleen, kidneys, adrenals, BAT, intestine, colon, and skeletal muscle. Pretreatments with NKY prevented the decrease of flow caused by ET in the kidneys, adrenals, BAT, intestine, colon and skeletal muscle. These findings indicate that NKY lowers blood pressure mainly by decreasing the peripheral vascular resistance, and that NKY blunts many, but not all, endothelin effects on vasculature. (Hypertens Res 1994; 17: 29-34)

Success of coronary stenting is limited by in-stent restenosis. We aimed to determine whether circulating levels of adiponectin could be associated with the occurrence of coronary in-stent restenosis in patients with end-stage renal disease (ESRD). We enrolled 71 consecutive ESRD patients undergoing hemodialysis (mean age: 64.9 +/- 8.9 years; 19 women, 52 men; mean hemodialysis duration: 78.2 +/- 87.5 months), who received stenting for a single coronary lesion. Plasma adiponectin concentrations were measured within one week before coronary stenting. Of 71 patients who had received stenting, in-stent restenosis occurred in 37 patients (52.1%) within 6 months after stenting. In univariate logistic analysis, homeostasis model assessment index of insulin resistance, blood hemoglobin, serum concentrations of high density lipoprotein cholesterol or triglycerides, and plasma concentrations of insulin or adiponectin were significantly associated with coronary in-stent restenosis. In multiple logistic regression analysis among these variables, however, only the plasma adiponectin concentration was associated with the coronary in-stent restenosis: the odds ratio of increase in 1 microg/ml of plasma adiponectin concentration for having restenosis was 0.651 (p = 0.001, 95% confidence interval: 0.506-0.839). Patients with restenosis had lower plasma adiponectin concentrations than those without [6.2 +/- 2.2 microg/ml (2.1-10.4 microg/ml; n=37) versus 27.2 +/- 10.8 microg/ml (17.9-79.8 microg/ml; n=34); p = 0.0001]. Circulating adiponectin concentrations may be associated with the occurrence of coronary in-stent restenosis in ESRD patients undergoing maintenance hemodialysis.

The central nervous system has a key role in regulating the circulatory system by modulating the sympathetic and parasympathetic nervous systems, pituitary hormone release, and the baroreceptor reflex. Digoxin- and ouabain-like immunoreactive materials were found >20 years ago in the hypothalamic nuclei. These factors appeared to localize to the paraventricular and supraoptic nuclei and the nerve fibers at the circumventricular organs and supposed to affect electrolyte balance and blood pressure. The turnover rate of these materials increases with increasing sodium intake. As intracerebroventricular injection of ouabain increases blood pressure via sympathetic activation, an endogenous digitalis-like factor (EDLF) was thought to regulate cardiovascular system-related functions in the brain, particularly after sodium loading. Experiments conducted mainly in rats revealed that the mechanism of action of ouabain in the brain involves sodium ions, epithelial sodium channels (ENaCs) and the renin–angiotensin–aldosterone system (RAAS), all of which are affected by sodium loading. Rats fed a high-sodium diet develop elevated sodium levels in their cerebrospinal fluid, which activates ENaCs. Activated ENaCs and/or increased intracellular sodium in neurons activate the RAAS; this releases EDLF in the brain, activating the sympathetic nervous system. The RAAS promotes oxidative stress in the brain, further activating the RAAS and augmenting sympathetic outflow. Angiotensin II and aldosterone of peripheral origin act in the brain to activate this cascade, increasing sympathetic outflow and leading to hypertension. Thus, the brain Na+–ENaC–RAAS–EDLF axis activates sympathetic outflow and has a crucial role in essential and secondary hypertension. This report provides an overview of the central mechanism underlying hypertension and discusses the use of antihypertensive agents.

Purpose: Mucinous ovarian carcinomas have a distinct clinical pattern compared with other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of Src kinase in preclinical models of mucinous ovarian carcinoma. Experimental Design: A total of 1,302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of Src kinase inhibition were tested using dasatinib-based therapy in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2). Results: Patients with advanced-stage mucinous ovarian cancer had significantly worse survival than those with serous histology: median overall survival, 1.67 versus 3.41 years, P = 0.002; median survival time after recurrence of 0.53 versus 1.66 years, P < 0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest Src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of Src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting Src with dasatinib in vivo showed significant antitumor effects in the RMUG-S-ip2 model but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further showed significant effects on reducing cell viability, increasing apoptosis, and in vivo antitumor effects in the RMUG-S-ip2 model. Conclusions: Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting Src kinase with a combination of dasatinib and oxaliplatin may be an attractive approach for this disease. Clin Cancer Res; 17(16); 5367–78. ©2011 AACR.

Summary Background and objectives S100A12 is an endogenous receptor ligand for advanced glycation end products. Cardiovascular disease remains a major cause of morbidity and mortality in patients with chronic kidney disease. In this study, we report cross-sectional data on 550 hemodialysis patients and assess the relationship between plasma S100A12 level and cardiovascular disease. Design, setting, participants, & measurements A cross-sectional study of 550 maintenance hemodialysis patients was conducted. We investigated the past history of cardiovascular disease and quantified the plasma level of S100A12 protein in all participants. Results Plasma S100A12 level was higher in hemodialysis patients with cardiovascular disease (n 197; 33.8 28.1 ng/ml) than in those without it (n 353; 20.2 16.1 ng/ml; P 0.001). In multivariate logistic regression analysis, the plasma S100A12 level (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.13 to 1.44; P 0.001) was identified as an independent factor associated with the prevalence of cardiovascular disease. The other factors associated with the prevalence of cardiovascular diseases were the presence of diabetes mellitus (OR, 2.81; 95% CI, 1.79 to 4.41; P 0.001) and high-sensitivity CRP level (OR, 1.02; 95% CI, 1.00 to 1.05; P 0.046). Furthermore, the plasma S100A12 level (OR, 1.30; 95% CI, 1.09 to 1.54; P 0.004) was significantly associated with cardiovascular disease even in hemodialysis patients without diabetes mellitus (n 348). Conclusions These results suggest that the plasma S100A12 protein level is strongly associated with the prevalence of cardiovascular disease in hemodialysis patients. Clin J Am Soc Nephrol 6: ●●● –●●● , 2011. doi: 10.2215/CJN.08310910

A new type of quick charging plug-in electric boat named "RAICHO-I" has been created by Tokyo University of Marine Science and Technology. "RAICHO-I" is the first electric boat adopted CHAdeMO standard which is the standard of quick charging method for electric vehicles in Japan. However, the operational time, speed and distance of electric boats are restricted since the loaded battery is limited because of cost, weight, etc. A Navigation Support System (NSS), which gives the remaining operational time, a possible cruising distance etc, is one of important technologies of electric boats from the view point of the operational safety. In this paper, algorithms to estimate the state of charge, the remaining operational time etc for NSS is proposed. The algorithm to obtain the recommended speed in order to cruise the desired distance is also proposed.

Background/Aims: We examined the potential of oral administration of nicorandil for protecting against cardiac death in hemodialysis patients without obstructive coronary artery disease. Methods: This study was based on a cohort study of 155 hemodialysis patients with angiographic absence of obstructive coronary lesions, with analysis performed in 100 propensity-matched patients (54 men and 46 women, 64 ± 10 years), including 50 who received oral administration of nicorandil (15 mg/day, nicorandil group) and 50 who did not (control). The efficacy of nicorandil in preventing cardiac death was investigated. Results: Over a mean follow-up period of 5.3 ± 1.9 years, we observed 25 cardiac deaths among 100 propensity-matched patients, including 6 due to acute myocardial infarction, 11 due to heart failure, and 8 due to sudden cardiac death. The incidence of cardiac death was lower (p < 0.001) in the nicorandil group (4/50, 8%) than in the control (21/50, 42%). On multivariate Cox hazard analysis, cardiac death was inversely associated with oral nicorandil (hazard ratio, 0.123; p = 0.0002). On Kaplan-Meier analysis, cardiac death-free survival rates at 5 years were higher in the nicorandil group than in the control group (91.4 vs. 66.4%). Conclusion: Oral nicorandil may inhibit cardiac death of hemodialysis patients without obstructive coronary artery disease.

To achieve effective delivery of siRNA into target cells in vivo, we have developed a novel approach of siRNA delivery by using local drug delivery systems.The chitosan hydrogel (CH-HG) displayed a liquid-solid phase transition in a temperature-dependent manner and formed an endothermic hydrogel in tumor tissue after intra-tumoral injection. Additionally, we tested the extent of in vivo delivery following a single intra-tumoral injection of Alexa555 siRNA/CH-HG into A375SM-bearing mice. The Alexa555 siRNA demonstrated higher localization into tumor cells compared to control. The Alexa555 siRNA delivery extends to tumor cells outside of CH-HG and some tumor cells also infiltrated into CH-HG. For therapeutic proof-of-concept studies, CH-HG including TG2-targeted siRNA significantly inhibited tumor growth in melanoma (A375SM) and breast (MDA-MB231) tumor models compared to control (A375SM: 72% reduction and MDA-MB231: 92% reduction, p0.001).we prepared a CH-HG system loaded with siRNA to enhance localized therapeutic efficacy without risk for systemic side effects. Delivery of siRNA into CH-HG was confirmed by fluorescence microscopy. Antitumor efficacy was examined in mouse models of melanoma (A375SM) and breast (MDA-MD231) cancer.This study developed a novel local delivery method for siRNA therapy using the CH-HG system. This approach could have broad applications for multiple localized diseases.

Purpose: Src is an attractive target because it is overexpressed in a number of malignancies, including ovarian cancer. However, the effect of Src silencing on other Src family kinases (SFKs) is not known. We hypothesized that other SFK members could compensate for the lack of Src activity. Experimental Design: Cell viability after either Src or Fgr silencing was examined in ovarian cancer cell lines by MTT assay. Expression of SFKs after Src silencing in ovarian cancer cells was examined by real-time reverse transcriptase (RT)-PCR. Therapeutic effect of in vivo Src and/or Fgr silencing was examined using siRNA incorporated into chitosan nanoparticles (siRNA/CH-NP). Microvessel density, cell proliferation, and apoptosis markers were determined by immunohistochemical staining in ovarian tumor tissues. Results: Src silencing enhanced cytotoxicity of docetaxel in both SKOV3ip1 and HeyA8 cells. In addition, Src silencing using siRNA/CH-NP in combination with docetaxel resulted in significant inhibition of tumor growth compared with control siRNA/CH-NP (81.8% reduction in SKOV3ip1, P = 0.017; 84.3% reduction in HeyA8, P < 0.005). These effects were mediated by decreased tumor cell proliferation and angiogenesis, and increased tumor cell apoptosis. Next, we assessed the effects of Src silencing on other SFK members in ovarian cancer cell lines. Src silencing resulted in significantly increased Fgr levels. Dual Src and Fgr silencing in vitro resulted in increased apoptosis that was mediated by increased caspase and AKT activity. In addition, dual silencing of Src and Fgr in vivo using siRNA/CH-NP resulted in the greatest reduction in tumor growth compared with silencing of either Src or Fgr alone in the HeyA8 model (68.8%, P < 0.05). Conclusions: This study demonstrates that, in addition to Src, Fgr plays a biologically significant role in ovarian cancer growth and might represent an important target. Clin Cancer Res; 17(7); 1713–21. ©2011 AACR.

A new dinucleating ligand 1,5-bis[bis(4-imidazolylmethyl)amino]-3-pentanol (Hbipl) has been synthesized. It forms the dicopper(II,II) and diiron(III,III) complexes, [Cu 2 (bipl)Cl](ClO 4 ) 2 ·H 2 O and [Fe 2 (bipl)(OAc) 2 ](ClO 4 ) 3 ·H 2 O, which are characterized by elemental analyses, magnetic susceptibility measurements, cyclic voltammetry, and IR and UV-Vis spectroscopies.

The effects of aprindine hydrochloride, an antiarrhythmic drug of the class IB, on heart rate variability were evaluated in 13 patients (eight men and five women), ages 76 ± 11 years, who showed a standard deviation of the R-R interval measured at 5-minute intervals (SDANN) of ⩽100 msec on 24-hour electrocardiograms. After 24-hour electrocardiograms were recorded during the control period, aprindine was administered at a dose of 60 mg/day. After 2 weeks of treatment 24-hour electrocardiograms were again recorded. The SDANN was ⩽100 msec (mean, 69.3 ± 17.0 msec) in all patients during the control period, but increased after aprindine administration (mean, 86.1 ± 31.5 msec, P

We evaluated the effects of tofisopam, a drug that modulates autonomic nerve function, on heart rate variability in 27 patients (12 men and 15 women; mean age, 71 ± 12 years) with a standard deviation of the R-R interval measured at 5-minute intervals (SDANN) of ⩽80 msec on 24-hour electrocardiograms (ECGs). After a control 24-hour ECG was recorded, patients were treated with tofisopam at a dosage of 150 mg/day. After 2 weeks of treatment, 24-hour ECGs were recorded again. The total cardiac rate and the number of ventricular extrasystoles on 24-hour ECGs did not differ between the control and treatment periods. The SDANN was ⩽80 msec (mean, 62.4 ± 14.7 msec) in all patients during the control period but increased significantly after tofisopam administration (84.8 ± 27.4 msec; P

The results of vestibular neurectomy (VN) were compared with those of streptomycin perfusion into the lateral semicircular canal (SM-perf). Three patients under 60 yearss of age, were treated with VN and three whose age was over 60, were treated with SM-perf. No vertigo spell occurred in any of the patients after treatment. Lateral canal function was abolished in all cases, which was confirmed by ice-water caloric tests. Hearing became better in two of the VN group, but worse in two of the SM-perf group. Tinnitus scores fell to less than half of the scores recorded before the operation in two patients in each group.

Ninety-eight patients with idiopathic sudden deafness were treated with a modified defibrinogenation (DF) therapy including batroxobin, low molecular dextran, vasodilators and vitamins. Hearing improvement was evaluated with two methods: categorical judgement and improvement rate (%). By categorical judgement, 60 patients (61% of the total) were classified into recovery or good improvement categories. The improvement rate was calculated for each of the 93 patients, and the average value was 64%. Modified DF therapy was effective especially for patients with severe hearing loss of 70-90 dB with flat audiogram. Although serum fibrinogen significantly decreased after batroxobin administration there was no correlation between the concentration of fibrinogen and hearing recovery. When prognostic factors were studied, the interval between the onset of hearing loss and start of treatment, initial hearing level, and the existence of vertigo all had significant correlation with the degree of hearing recovery.

Hydrophilic phosphine ligands possessing a carbohydrate side-chain, such as N -(4-diphenylphosphinophenyl)methyl gluconamide ( 9 ), N -[4-(2′-dicyclohexylphosphinobiphenyl)phenylmethyl] gluconamide ( 10 ), and N -[4-(2′-di- t -butylphosphinobiphenyl)]phenylmethyl gluconamide ( 11 ), were newly synthesized to carry out palladium-catalyzed biaryl coupling of arylboronic acids in a single aqueous medium. The catalyst prepared in situ from Pd(OAc) 2 and 10 exhibited a higher efficiency than that of 9 , 11 , Ph 2 P( m -C 6 H 4 SO 3 Na) (TPPMS) or P( m -C 6 H 4 SO 3 Na) 3 (TPPTS) for representative aryl bromides, chlorides, or triflates. The catalyst prepared in situ from Pd(OAc) 2 (0.001 mol%) and 10 (0.002 mol%) achieved 96,000 TON in the reaction of p -tolylboronic acid with 4-bromoacetophenone in water.

Recent evidence suggests an association between vasospastic angina and Brugada syndrome. Here we present two cases of coronary artery disease who presented with ECG abnormalities which might have been provoked or enhanced by ischemia of the conus branch of the right coronary artery. The 12-lead ECGs demonstrated normal sinus rhythm in these two cases. Interestingly, a saddle back or coved type ST segment elevation in leads V1-V3 was documented either in the percutaneous transluminal angioplasty procedure of the proximal right coronary artery or with an intracoronary acetylcholine (Ach) administration into the right coronary artery. These Brugada type ECG changes were restored to the baseline ECG waveform after improvement in the ischemia. In the second case, vasospasms of the conus branch of the right coronary artery were associated with a coved type ST segment elevation in leads V1 to V2. We discuss the possible interaction between ischemia caused by conus branch lesions and Brugada type electrocardiographic changes.

We examined the combined effects of nisoldipine, a calcium antagonist, and enalapril, an angiotensin converting enzyme (ACE) inhibitor, administered once daily on the control of blood pressure in hypertensive patients. Outpatients with essential hypertension whose untreated casual blood pressure on two separate occasions was greater than 160/95 mmHg were eligible for the trial. A total of 11 patients whose casual blood pressure remained above 160/95 mmHg after treatment with once-daily nisoldipine 5 mg or enalapril 5 mg for more than 4 weeks were enrolled in the study. Control 24-hour blood pressure data were recorded during monotherapy with once-daily morning administration of either nisoldipine 5 mg (three men, two women; mean age, 67 ± 9 years) or enalapril 5 mg (three men, three women; mean age, 69 ± 15 years). The drug that had not yet been taken, either enalapril 5 mg or nisoldipine 5 mg, was then added to the once-daily regimen. Two weeks later, 24-hour blood pressure monitoring was conducted to observe the effect of combined treatment on 24-hour blood pressure. Satisfactory antihypertensive effects were achieved both when nisoldipine was added to enalapril monotherapy and when enalapril was added to nisoldipine monotherapy. The circadian blood pressure rhythm profiles revealed that those patients in whom monotherapy was ineffective had high nocturnal blood pressures. However, a decrease of the blood pressure in the high blood pressure time period was achieved with combination therapy. Cumulative percentage analysis revealed that blood pressures in the high blood pressure range above the 90% value, as well as those in the low pressure range above the 10% value, decreased to an equal degree. These results indicate that combination therapy with a calcium antagonist and an ACE inhibitor is useful in the treatment of hypertension.

We have been examining diurnal blood pressure changes for various antihypertensive drugs to characterize their hypotensive effects on 24-hour blood pressure values. The present study evaluated blood pressure control using a combination of nitrendipine, a calcium antagonist, and cilazapril, an angiotensin converting enzyme inhibitor, administered once daily to 10 patients with essential hypertension who had casual blood pressure readings of 160/95 mmHg or higher measured on two different drug-free days. After receiving nitrendipine 10 mg or cilazapril 1 mg once daily in the morning for more than 4 weeks, none of the patients showed a sufficient reduction in blood pressure. A combination of nitrendipine 10 mg and cilazapril 1 mg was then administered once daily in the morning, and 24-hour blood pressure was recorded 2 weeks later. Satisfactory blood pressure reduction was achieved in the patients who did not respond adequately to cilazapril or nitrendipine alone. Analysis of diurnal blood pressure changes revealed that the patients who did not respond to a single drug had high nocturnal blood pressure values and a more severe type of hypertension. Analysis of cumulative percentages revealed that the decrease in the range of high values (the 90% value) was large but that the decrease in the range of low values (the 10% value) was small. These findings suggest that the combination of nitrendipine and cilazapril is an ideal therapy that reduces blood pressure in a manner similar to physiologic blood pressure changes.

The effects of various long-acting antihypertensive agents on 24-hour blood pressure were assessed by ambulatory blood pressure monitoring. Blood pressure (BP) was recorded in 56 patients with essential hypertension (34 men and 22 women; mean age, 64 ± 11 years). Each drug was administered once a day for 2 weeks. Beta-blockers (atenolol 50 mg/day and bisoprolol 5 mg/day) significantly reduced both blood pressure and heart rate throughout the 24-hour period, especially during the day. The beta-blockers had a similar hypotensive effect on both high and low BP ranges. An angiotensin converting enzyme inhibitor (enalapril 10 mg/day) significantly reduced both systolic and diastolic BP throughout the day, especially during the daytime, but heart rate was not altered. Cumulative percentage analysis revealed that enalapril decreased BP to a greater degree when baseline BP was higher. Calcium channel blockers (nitrendipine 10 mg/day, nisoldipine 5 mg/day, and manidipine 20 mg/day) significantly reduced blood pressure throughout the 24 hours, especially during the day, but heart rate was unaffected. Calcium channel blockers had a similar hypotensive effect on both the high and low BP ranges. These results show that oncedaily doses of long-acting antihypertensive drugs significantly reduce blood pressure throughout the day, especially in the daytime. Cumulative percentage analysis revealed that the pattern of blood pressure reduction by enalapril was similar to that of spontaneous and physiologic decreases in blood pressure.