Biomedical subjects

K Niwa

Publications and source records attributed to K Niwa.

At least 19 recordsLinked to original sources

PubMed2002

Capacitation status and in vitro fertility of boar spermatozoa: effects of seminal plasma, cumulus-oocyte-complexes-conditioned medium and hyaluronan.

In the present study, the effects of seminal plasma (SP), cumulus-oocyte-complexes (COCs) conditioned medium (CCM) and hyaluronan (HA) on functional changes and in vitro fertilizing ability of porcine spermatozoa were examined. In in vitro fertilization (IVF) experiments, 10% (v/v) of exogenous SP in the fertilization medium prevented sperm penetration (using fresh-extended and frozen-thawed ejaculated spermatozoa). Analysis of frozen-thawed CCM revealed a HA content to levels of 30 ng/mL per incubated COC. Presence of frozen-thawed CCM did not, however, prove effective to increase (furthermore decreasing) oocyte penetration in vitro, and neither did supplementation with exogenous HA at the same concentration as that present in the CCM (secreted by COCs). Analysis of sperm capacitation using the chlortetracycline (CTC) assay showed that frozen-thawed CCM had no elevating effect on 'B-pattern' spermatozoa (implying capacitation-like changes) and that addition of 10% (v/v) SP held spermatozoa in the 'F-pattern' (intact) status. Dose of 500 microg/mL HA and freshly prepared CCM increased, however, the frequency of capacitated spermatozoa (B-pattern) without resulting in increased rates of 'AR-pattern' (acrosome-reacted) spermatozoa, compared with controls. The present results confirm the decapacitating effect of SP and suggest capacitating actions of HA (dose-related) and CCM (freshly prepared) on boar spermatozoa in vitro. The unclear effects of frozen-thawed CCM and a low dose of HA on penetration rates of boar spermatozoa call for further researches of their function in vivo.

Animals↗

PubMed2001

Cell proliferation in cancer prevention; effects of preventive agents on estrogen-related endometrial carcinogenesis model and on an in vitro model in human colorectal cells.

Proto-oncogenes such as c-fos, c-jun and c-myc are known to relate to cell proliferation and differentiation. Some oriental herbal medicines like Glycyrrhizae radix or Juzen-taiho-to were found to suppress estradiol-17 beta (E2)-induced expression of c-fos/jun in uterine corpus and inhibited N-methyl-N-nitrosourea and E2-induced endometrial carcinogenesis in mice. It is suggested that the effects of such oriental drugs are exerted probably through suppression of estrogen-induced c-fos/jun expression and they are promising preventing agents for endometrial cancers. In the combined in vitro assay for cell proliferation (MTS assay) and apoptosis (DNA fragmentation) in human colorectal cancer cells (Colo 320), a number of naturally occurring chemopreventive agents such as curcumin, quercetin, auraptene, 1'-acetoxychavicol acetate (ACA) and indole-3-carbinol were shown to generate apoptosis as well as to inhibit cell proliferation. The results suggest a mode of action of these chemopreventive agents and also imply that such in vitro short term assay is useful for detection of new agents for cancer prevention.

Adenocarcinoma↗

PubMed2001

Alleviation of myocardial ischemia after Kawasaki disease by heparin and exercise therapy.

BACKGROUND: Heparin promotes angiogenesis. We evaluated the effects of combined treatment with heparin and exercise on myocardial ischemia in the chronic stage of Kawasaki disease. METHODS AND RESULTS: This study was conducted in 7 patients (aged 6 to 19 years) who had a totally occluded coronary artery and stress-induced myocardial ischemia in the collateral-dependent areas. Twice-daily exercise using a bicycle ergometer was performed with increments of 0.5 W/kg every 3 minutes up to maximal exertion for 10 days. Heparin, which immediately increased circulating hepatocyte growth factor, was given intravenously 10 minutes before each exercise period. Newly developed myocardial infarction, ventricular tachyarrhythmia, anginal attack, or hemorrhagic complication was not observed in any patient. Dipyridamole-loading single photon emission computed tomography documented improved myocardial perfusion in the collateral-dependent areas and a significant reduction in total defect scores in all patients after the completion of 20 sessions (P=0.01). In control patients who did not receive the heparin-exercise therapy, however, stress defect scores remained unchanged (n=1) or increased (n=2) during follow-up. Computerized quantitative coronary angiography provided evidence that the heparin-exercise therapy increased the diameter of the occluded artery to which collaterals terminated (P=0.001) but not that of the reference artery with which collaterals were not connected (P=0.96). CONCLUSIONS: The findings suggest that a series of heparin and exercise treatments over 10 days may have a dramatic effect on the alleviation of myocardial ischemia in collateral-dependent regions. This may be a safe, noninvasive revascularization therapy for patients with coronary artery occlusion in the chronic stage of Kawasaki disease.

Adolescent↗

PubMed2001

Impact of pulmonary valve replacement on arrhythmia propensity late after repair of tetralogy of Fallot.

BACKGROUND: Chronic pulmonary regurgitation after repair of tetralogy of Fallot (TOF) may lead to right ventricular dilatation, which may be accompanied by ventricular tachycardia and sudden death. We aimed to examine the effects of pulmonary valve replacement (PVR) on (1) certain electrocardiographic markers predictive of monomorphic ventricular arrhythmia and sudden death and (2) sustained atrial flutter/fibrillation and monomorphic ventricular tachycardia. METHODS AND RESULTS: We studied 70 patients who underwent PVR for pulmonary regurgitation and/or right ventricular outflow tract obstruction late after repair of TOF. Maximum QRS duration and QT dispersion were measured from standard ECGs before PVR and at the latest follow-up. Arrhythmia was defined as sustained atrial flutter/fibrillation or sustained monomorphic ventricular tachycardia. Concomitant intraoperative electrophysiological mapping and/or cryoablation were performed in 9 patients (60%) with preexisting ventricular tachycardia and 6 patients (50%) with preexisting atrial flutter. QRS duration remained unchanged in the study group (P=0.46), but it was significantly prolonged (P<0.001) in a comparable group of patients with repaired TOF who did not undergo PVR. At a mean follow-up of 4.7 years, the incidence of ventricular tachycardia diminished from 22% to 9% (P<0.001), and atrial flutter/fibrillation decreased from 17% to 12% (P=0.32). Intraoperative ablation prevented recurrence of preexisting tachyarrhythmia (0 of 15 patients). CONCLUSIONS: PVR in patients with previous TOF repair and chronic pulmonary regurgitation leads to stabilization of QRS duration and, in conjunction with intraoperative cryoablation, to a decrease in the incidence of preexisting atrial and ventricular tachyarrhythmia. When applicable, this combined approach should be used in patients late after repair of TOF.

Adolescent↗

PubMed2001

Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation.

Cyclooxygenase (COX) is a prostanoid-synthesizing enzyme present in 2 isoforms: COX-1 and COX-2. Although it has long been hypothesized that prostanoids participate in cerebrovascular regulation, the lack of adequate pharmacological tools has led to conflicting results and has not permitted investigators to define the relative contribution of COX-1 and COX-2. We used the COX-1 inhibitor SC-560 and COX-1-null (COX-1(-/-)) mice to investigate whether COX-1 plays a role in cerebrovascular regulation. Mice were anesthetized (urethane and chloralose) and equipped with a cranial window. Cerebral blood flow (CBF) was measured by laser Doppler flowmetry or by the (14)C-iodoantipyrine technique with quantitative autoradiography. In wild-type mice, SC-560 (25 micromol/L) reduced resting CBF by 21+/-4% and attenuated the CBF increase produced by topical application of bradykinin (-59%) or calcium ionophore A23187 (-49%) and by systemic hypercapnia (-58%) (P<0.05 to 0.01). However, SC-560 did not reduce responses to acetylcholine or the increase in somatosensory cortex blood flow produced by vibrissal stimulation. In COX-1(-/-) mice, resting CBF assessed by (14)C-iodoantipyrine was reduced (-13% to -20%) in cerebral cortex and other telencephalic regions (P<0.05). The CBF increase produced by bradykinin, A23187, and hypercapnia, but not acetylcholine or vibrissal stimulation, were attenuated (P<0.05 to 0.01). The free radical scavenger superoxide dismutase attenuated responses to bradykinin and A23187 in wild-type mice but not in COX-1(-/-) mice, suggesting that COX-1 is the source of the reactive oxygen species known to mediate these responses. The data provide evidence for a critical role of COX-1 in maintaining resting vascular tone and in selected vasodilator responses of the cerebral microcirculation.

Acetylcholine↗

PubMed2001

Fertile and diploid nuclear transplants derived from embryonic cells of a small laboratory fish, medaka (Oryzias latipes).

Fertile and diploid nuclear transplants were successfully generated by using embryonic cells as donors in a small laboratory fish, medaka (Oryzias latipes). Embryonic cell nuclei from transgenic fish carrying the green fluorescent protein (GFP) gene were transplanted into unfertilized eggs enucleated by x-ray irradiation. In this study, 1 out of 588 eggs transplanted in the first experiment and 5 out of 298 eggs transplanted in the second experiment reached the adult stage. All of these nuclear transplants were fertile and diploid, and the natural and GFP markers of the donor nuclei were transmitted to the F(1) and F(2) offspring in a Mendelian fashion. This systematic study proves the feasibility of generating nuclear transplants by using embryonic cells from fish as donors, and it is supported by convincing evidence.

Animals↗

PubMed2001

Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice.

Cyclooxygenase-2 (COX-2), a prostanoid-synthesizing enzyme that contributes to the toxicity associated with inflammation, has recently emerged as a promising therapeutic target for several illnesses, ranging from osteoarthritis to Alzheimer's disease. Although COX-2 has also been linked to ischemic stroke, its role in the mechanisms of ischemic brain injury remains controversial. We demonstrate that COX-2-deficient mice have a significant reduction in the brain injury produced by occlusion of the middle cerebral artery. The protection can be attributed to attenuation of glutamate neurotoxicity, a critical factor in the initiation of ischemic brain injury, and to abrogation of the deleterious effects of postischemic inflammation, a process contributing to the secondary progression of the damage. Thus, COX-2 is involved in pathogenic events occurring in both the early and late stages of cerebral ischemia and may be a valuable therapeutic target for treatment of human stroke.

Animals↗

PubMed2001

Structural abnormalities of great arterial walls in congenital heart disease: light and electron microscopic analyses.

BACKGROUND: Great arteries in congenital heart disease (CHD) may dilate, become aneurysmal, or rupture. Little is known about medial abnormalities in these arterial walls. Accordingly, we studied 18 types of CHD in patients from neonates to older adults. METHODS AND RESULTS: Intraoperative biopsies from ascending aorta, paracoarctation aorta, truncus arteriosus, and pulmonary trunk in 86 patients were supplemented by 16 necropsy specimens. The 102 patients were 3 weeks to 81 years old (average, 32+/-6 years). Biopsies were examined by light (LM) and electron (EM) microscopy; necropsy specimens by LM. Positive aortic controls were from 15 Marfan patients. Negative aortic controls were from 11 coronary artery disease patients and 1 transplant donor. Nine biopsies from acquired trileaflet aortic stenosis were compared with biopsies from bicuspid aortic stenosis. Negative pulmonary trunk controls were from 7 coronary artery disease patients. A grading system consisted of negative controls and grades 1, 2, and 3 (positive controls) based on LM and EM examination of medial constituents. CONCLUSIONS: Medial abnormalities in ascending aorta, paracoarctation aorta, truncus arteriosus, and pulmonary trunk were prevalent in patients with a variety of forms of CHD encompassing a wide age range. Aortic abnormalities may predispose to dilatation, aneurysm, and rupture. Pulmonary trunk abnormalities may predispose to dilatation and aneurysm; hypertensive aneurysms may rupture. Pivotal questions are whether these abnormalities are inherent or acquired, whether CHD plays a causal or facilitating role, and whether genetic determinants are operative.

Adolescent↗

PubMed2001

Patterns of pelvic invasion are prognostic in the treatment of locally recurrent rectal cancer.

BACKGROUND: Local recurrence of rectal cancer after curative resection remains a difficult clinical problem. The aim of this study was to elucidate prognostic risk factors after resection of recurrent cancer. METHODS: Between January 1983 and December 1999, 83 patients with locally recurrent rectal cancer were studied retrospectively for survival benefit by re-resection. Sixty patients underwent resection for recurrent cancer, including total pelvic exenteration in 30 patients and sacrectomy in 23 patients. The extent of locally recurrent tumour was classified by the pattern of pelvic invasion as follows: localized, sacral invasion and lateral invasion. RESULTS: Multivariate analysis showed that the pattern of pelvic invasion was a significant prognostic factor which independently influenced survival after resection of recurrent cancer (P < 0.001). The 5-year survival rates were 38 per cent in the localized type (n = 27), 10 per cent in the sacral invasive type (n = 16) and zero in the lateral invasive type (n = 17). CONCLUSION: Resection for locally recurrent rectal cancer is potentially curative in patients with localized or sacral invasive patterns of recurrence. Alternatives should be explored in patients with recurrence involving the lateral pelvic wall.

Adult↗

PubMed2001

p38 MAPK and Ca2+ contribute to hydrogen peroxide-induced increase of permeability in vascular endothelial cells but ERK does not.

To examine the involvement of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK) in the oxidative stress-induced increase of permeability in endothelial cells, the effects of a p38 MAPK inhibitor (SB203580) and ERK inhibitor (PD90859) on the H2O2-induced increase of permeability in bovine pulmonary artery endothelial cells (BPAEC) were investigated using a two-compartment system partitioned by a semi-permeable filter. H2O2 at 1 mM caused an increase of the permeation rate of fluorescein isothiocyanate (FITC)-labeled dextran 40 through BPAEC monolayers. SB203580 inhibited the H2O2-induced increase of permeability but PD98059 did not, though activation (phosphorylation) of both p38 MAPK and ERK was observed in H2O2-treated cells in Western blot analysis. An H2O2-induced increase of the intracellular Ca2+ concentration ([Ca2+]i) was also observed and an intracellular Ca2+ chelator (BAPTA-AM) significantly inhibited the H2O2-induced increase of permeability. However, it showed no inhibitory effects on the H2O2-induced phosphorylation of p38 MAPK and ERK. The H2O2-induced increase of [Ca2+]i was not influenced by SB203580 and PD98059. These results indicate that the activation of p38 MAPK and the increase of [Ca2+]i are essential for the H2O2-induced increase of endothelial permeability and that ERK is not.

Animals↗

PubMed2001

Superoxide generation from human polymorphonuclear leukocytes by liposome-encapsulated hemoglobin.

We investigated the interactions between liposome-encapsulated hemoglobin (Neo Red Cells: NRC) and human polymorphonuclear leukocytes as assessed by superoxide generation. NRC triggered superoxide generation from neutrophils in a dose-dependent manner. Empty liposomes also induced superoxide production of neutrophils. Superoxide generation of neutrophils induced by phorbol myristate acetate (PMA) was delayed but intensified both by NRC and empty liposomes. The intensity of superoxide generation induced by NRC was smaller than that by the empty liposomes. As NRC contained superoxide dismutase (SOD) that was copurified with hemoglobin from red blood cells and its activity remained, SOD contained in NRC may partially eliminate superoxide.

Blood Substitutes↗

PubMed2001

Nuclear transfer of blastomeres expressing EGFP-reporter gene may improve the efficiency of transgenic cattle.

The effect of timing of microinjection of DNA constructs on the efficiency of transgenic embryo production and improved efficiency and quality through combining EGFP as a reporter gene with nuclear transfer techniques were examined. From 12 to 24 h after insemination, constructs of pCXNeo-EGFP were microinjected into a pronucleus of bovine IVM-IVF zygotes. Due to the difficulty in visualizing pronuclei, the incidence of successful injection of linear DNA was higher when zygotes were injected between 20 and 24 h, as compared with an early period between 12 and 16 h after insemination. However, developmental competence of DNA-injected zygotes and the EGFP expression rate were not affected by the injection time. A majority of the embryos expressing EGFP signal were mosaic. Following nuclear transfer of blastomeres expressing EGFP, 4.5% of morulae that developed from the NT eggs had a strong EGFP signal in all live blastomeres. In other embryos, EGFP signal had been lost. When cells derived from the EGFP-positive NT morulae were subcultured, all the cells expressed strong EGFP signal at the second passage and demonstrated neomycin resistance. These results show that transient expression of nonintegrated EGFP appears frequently in EGFP-positive bovine embryos and that additional selection of EGFP-positive morulae after nuclear transfer of EGFP-positive blastomeres would facilitate selection of transgenic embryos.

Animals↗

PubMed2001

Preventive effects of Juzen-taiho-to on N-methyl-N-nitrosourea and estradiol-17beta-induced endometrial carcinogenesis in mice.

Two experiments were conducted to determine effects of Juzen-taiho-to on endometrial carcinogenesis in mice. In the first experiment, Juzen-taiho-to treatment (2 weeks) decreased the levels of estradiol-17beta (E(2))-stimulated expression of c-fos/jun mRNA and their oncoproteins, determined by reverse transcription-polymerase chain reaction and Southern blot analysis, and the immunohistochemical method, in the uteri of ovarectomized mice. For the second experiment, 93 female ICR mice were given N-methyl-N-nitrosourea (MNU) solution (1 mg/100 g body weight) and normal saline (as controls) into their left and right uterine corpora, respectively, and were divided into four groups. Group 1 was given a diet containing 0.2% Juzen-taiho-to and 5 p.p.m. E(2). Group 2 was given a diet containing 5 p.p.m. E(2) alone. Group 3 was given a diet containing 0.2% Juzen-taiho-to alone. Group 4 was kept on the basal diet alone and treated as a control. Juzen-taiho-to treatment significantly decreased incidences of the uterine endometrial atypical (P<0.01), complex (P<0.05) and simple hyperplasias (P<0.01), under estrogenic stimulation. It is suggested that Juzen-taiho-to has an inhibitory effect on E2-related endometrial carcinogenesis in mice, relevantly through suppression of estrogen-induced c-fos/jun-expression.

Animals↗

PubMed2001

Induction of anesthesia with ketamine reduces the magnitude of redistribution hypothermia.

UNLABELLED: Hypothermia after induction of general anesthesia results largely from core-to-peripheral redistribution of body heat. Both central inhibition of tonic thermoregulatory vasoconstriction in arteriovenous shunts and anesthetic-induced arteriolar and venous dilation contribute to this redistribution. Ketamine, unique among anesthetics, increases peripheral arteriolar resistance; in contrast, propofol causes profound venodilation that other anesthetics do not. We therefore tested the hypothesis that induction of anesthesia with ketamine causes less core hypothermia than induction with propofol. Twenty patients undergoing elective surgery were randomly assigned to anesthetic induction with either 1.5 mg/kg ketamine (n = 10) or 2.5 mg/kg propofol (n = 10). Anesthesia in both groups was subsequently maintained with sevoflurane and 60% nitrous oxide in oxygen. Forearm minus finger, skin-temperature gradients <0 degrees C were considered indicative of significant arteriovenous shunt vasodilation. Ketamine did not cause vasodilation just after induction, whereas propofol rapidly induced vasodilation. Core temperatures in the patients given ketamine remained significantly greater than those in the patients induced with propofol. These data suggest that maintaining vasoconstriction during induction of anesthesia reduces the magnitude of redistribution hypothermia. IMPLICATIONS: Core hypothermia during the first hour of anesthesia was less after induction of anesthesia with ketamine than propofol. Maintaining arteriovenous shunt vasoconstriction during induction of anesthesia reduces the magnitude of redistribution hypothermia.

Adult↗

PubMed2001

Increased susceptibility to ischemic brain injury in cyclooxygenase-1-deficient mice.

Cyclooxygenase-1 (COX-1), a rate-limiting enzyme in the synthesis of prostanoids, is involved in selected vasodilatatory responses of the cerebral circulation. Cyclooxygenase-1-null mice were used to determine whether COX-1 influences cerebral ischemic damage. The middle cerebral artery was occluded in COX-1 -/- and +/+ mice (n = 9/group), and lesion volume was determined in thionin-stained sections 24 or 96 hours later. Middle cerebral artery occlusion produced larger infarcts in COX-1 -/- mice, both at 24 (35 +/- 17%; P < 0.05) and 96 hours (41 +/- 16%; P < 0.05) after ischemia. The enlargement was not due to increased susceptibility to glutamate excitotoxicity, because microinjection of N-methyl-D-aspartate or kainate in the parietal cortex produced comparable lesions in COX-1 +/+ and -/- mice ( P > 0.05; n = 8/group). To examine the contribution of hemodynamic factors to the enlargement of the infarct, cerebral blood flow was monitored by laser-Doppler flowmetry in the ischemic territory (n = 6/group). Although the reduction in cerebral blood flow was comparable in the ischemic core ( P > 0.05), at the periphery of the ischemic territory the reduction was greater in COX-1 -/- mice (-58 +/- 4%) than in COX-1 +/+ mice (-34 +/- 5%; P < 0.05). It is concluded that mice lacking COX-1 are more susceptible to focal cerebral ischemia, an effect that can be attributed to a more severe cerebral blood flow reduction in vulnerable regions at the periphery of the ischemic territory. Thus, the vascular effects of COX-1 may contribute to maintain cerebral blood flow in the postischemic brain and, as such, play a protective role in ischemic brain injury.

Animals↗

PubMed2001

Preventive effects of isoflavones, genistein and daidzein, on estradiol-17beta-related endometrial carcinogenesis in mice.

The effects of isoflavones (genistein and daidzein) on endometrial carcinogenesis in mice were investigated in two experiments. In the short-term experiment (2 weeks), single subcutaneous (s.c.) administration of genistein [1 mg / 30 g body weight (b.w.)] significantly decreased the levels of estradiol-17beta (E(2)) (5 ppm in diet)-induced expression of c-jun, interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) mRNAs in the uteri of ovariectomized mice (P < 0.005, P < 0.05 and P < 0.01, respectively). Daidzein significantly inhibited E(2)-induced expression of c-fos and IL-1alpha (P < 0.01, P < 0.01 respectively). In the long-term experiment (30 weeks), 140 female ICR mice were given N-methyl-N-nitrosourea-containing solution (1 mg / 100 g b.w.) and normal saline (as controls) into their left and right uterine corpora, respectively. They were divided into six groups; group 1 was given E(2) (in diet) alone. Group 2 was given E(2) and genistein (1 mg / 30 g b.w., s.c., every four weeks). Group 3 was exposed to E(2) and daidzein (1 mg / 30 g b.w., s.c., every four weeks). Groups 4 and 5 respectively received genistein and daidzein, and were kept on the basal diet. Group 6 was kept on the basal diet and served as a control. At the termination of the experiment, incidences of endometrial adenocarcinoma and atypical endometrial hyperplasia of the group given E(2) and genistein or daidzein were significantly lower than of the group with E(2) alone (P < 0.01 and P < 0.05, respectively). It is suggested that both genistein and daidzein have an inhibitory effect on estrogen-related endometrial carcinogenesis in mice, possibly by suppressing expression of estrogen-induced estrogen-related genes c-fos and c-jun, and internal cytokines IL-1alpha and TNF-alpha through a cytokine and estrogen receptor-mediated pathway.

Adenocarcinoma↗

PubMed2001

Moxibustion treatment of breech presentation.

Breech presentation was successfully corrected by stimulating acupuncture points with moxibustion or low-frequency electrical current. Only patients with breech pregnancies at the 28th week or later were entered into the study. With moxibustion treatment, the control group had a spontaneous correction rate of 165/224 (73.66%), and the treatment group had a correction rate of 123/133 (92.48%) (P<0.0001, x2 test). With low-frequency percutaneous electrical stimulation, the correction rate was 20/941 (83.87%) in the control group and 171/191 (89.52%) in the treatment group (P=0.094, x2 test). The controls in the moxibustion study did no exercises and received no external manipulation to correct breech presentation whereas those in the electrical stimulation study experienced both. Acupuncture stimulation, especially with moxibustion, is expected to serve as a safe and effective modality in the management of breech presentation in a clinical setting.

Acupuncture Points↗

PubMed2001

A beta-peptides enhance vasoconstriction in cerebral circulation.

Amyloid-beta (A beta)-peptides are involved in the pathophysiology of Alzheimer's dementia. We studied the effects of A beta on selected constrictor responses of cerebral circulation. Mice were anesthetized (by using urethane-chloralose) and equipped with a cranial window. Arterial pressure and blood gases were monitored and controlled. Cerebral blood flow (CBF) was monitored by a laser Doppler probe. Topical superfusion with A beta 1-40 (0.1-10 microM), but not with the reverse peptide A beta 40-1, reduced resting CBF (-29 +/- 4% at 5 microM; P < 0.05) and augmented the reduction in CBF produced by the thromboxane analog U-46619 (+45 +/- 3% at 5 microM; P < 0.05). A beta 1-40 or A beta 1-42 did not affect the reduction in CBF produced by hypocapnia. The reduction in resting CBF and the enhancement of vasoconstriction were reversed by treatment with the free radical scavengers superoxide dismutase or manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin. Substitution of the methionine residue in position 35 with norleucine, a mutation that abolishes the ability of A beta to produce free radicals, abolished its vascular effects. Nanomolar concentrations of A beta 1-40 constricted isolated pressurized middle cerebral artery segments with intrinsic tone (-16 +/- 3% at 100 nM; P < 0.05). We conclude that A beta acts directly on cerebral arteries to produce vasoconstriction and to enhance selected constrictor responses. The evidence supports the idea that A beta-induced production of reactive oxygen species plays a role in this effect. The vascular actions of A beta may contribute to the deleterious effects resulting from accumulation of this peptide in Alzheimer's dementia.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗