Biomedical subjects

M Ihara

Publications and source records attributed to M Ihara.

At least 73 records · Page 4Linked to original sources

PubMed1998

[A case of spontaneous intracranial hypotension successfully treated with an epidural blood patch].

A 76-year-old woman was admitted to our hospital with complaints of a three-day history of severe postural headache without any apparent cause. Neurological examination revealed nuchal rigidity, and right auditory nerve paresis. Lumbar puncture yielded a low opening pressure of 50mmH2O and an elevated total protein up to 77mg/dl. Cranial magnetic resonance imaging (MRI) using gadolinium revealed diffuse dural enhancement, and effacement of the prepontine cistern. Spontaneous intracranial hypotension was strongly suspected, and to ascertain the presence of a cerebrospinal fluid (CSF) leak, radionuclide cisternography (RNC) was performed, which demonstrated a spinal CSF leak along the nerve root at the level of the lower lumbar spine. Interestingly, computed tomography-myelography (CTM) did not detect these abnormalities. An epidural blood patch with 15 ml of autologous blood at the L3-L4 interspace brought a dramatic symptomatic relief. Follow-up MRI, RNC, and CSF analysis demonstrated that the abnormal findings had disappeared. It is speculated that RNC is more sensitive for detecting small dural tears and CTM for anatomical anomalies including meningeal diverticula and perineural (Tarlov) cysts. We wish to stress, however, that RNC and CTM are complementary and sometimes interchangeable diagnostic modalities, and should be actively employed for detecting CSF leakage in SIH and for appropriate treatment.

Aged↗

PubMed1998

[Hereditary spherocytosis associated with severe hypophosphatemia in patients recovering from aplastic crisis].

This is a report about two cases of hereditary spherocytosis complicated by severe hypophosphatemia, while recovering from aplastic crisis. Case #1: A 31-year-old male, who had jaundice and splenomegaly since the age of 15 and who has a son diagnosed with hemolytic anemia, was admitted because of fever lymphadenopathy, and jaundice. A diagnosis of hereditary spherocytosis was made based on microspherocytes observed in his peripheral blood smear. After admission, the anemia became more serious for a few days and he was considered suffering from bone marrow aplastic crisis. His serum phosphorus level fell to 0.5 mg/dl on the second day, but it rapidly returned to normal as reticulocyte counts rose. Case #2: A 29-year-old male with known transient jaundice and splenomegaly suffered from fever, anemia and jaundice, but recovered two weeks later. Laboratory examination revealed positive human Parvovirus B19 (HPV-B19) DNA, anti-HPV-19 IgM and IgG-antibody. His serum phosphorus level fell to 1.2 mg/dl on the eighth day, but it rose in the same manner as seen in case #1. The fall in serum phosphorus is probably due to its shift to the erythroblasts during erythroid hyperplasia.

Adult↗

PubMed1997

Coexpression studies with endothelin receptor subtypes indicate the existence of intracellular cross-talk between ET(A) and ET(B) receptors.

Human Girardi heart cells expressing endothelin ET(B) receptors (GH(B) cells) were transfected with human ET(A) cDNA, and coexpression of ET(A) and ET(B) in the ratio of 4:6 was demonstrated by Scatchard analysis. [125I]Endothelin (ET)-1 binding to ET(A)-transfected GH cells (GH(AB) cells) was displaced by an ET(A) antagonist, BQ-123, in a biphasic manner. An ET(B) agonist, BQ-3020, and an ET(B) antagonist, BQ-788, inhibited [125I]ET-1 binding to GH(AB) cells in a monophasic manner with low affinities (IC50 = 2,800 and 890 nM, respectively); IC50 values for ET(B) receptors seemed to be as weak as those for ET(A) receptors. However, BQ-3020 and BQ-788 had a high affinity for ET(B) receptors in a binding experiment using [125I]ET-1 in the presence of 1 microM BQ-123, where ET(A) receptors are masked (IC50 = 0.49 and 0.89 nM, respectively). The ET(B)-mediated increase in intracellular calcium concentrations in GH(AB) cells was not affected by 0.1 microM BQ-788 alone but was inhibited significantly by the same concentration of BQ-788 in combination with 10 microM BQ-123. ET-1 suppressed forskolin-stimulated accumulation of cAMP through the activation of ET(A) and ET(B) in GH(AB) cells; 1 microM BQ-123 or BQ-788 inhibited the suppression by only 20%, whereas a mixture of BQ-123 and BQ-788 (1 microM each) completely inhibited the cAMP decrease. These findings suggest that the stimulation of ET(A) receptors with ET-1 results in a lowering of the affinity of BQ-3020 and BQ-788 for ET(B) receptors in GH(AB) cells. We conclude that there is intracellular cross-talk between ET(A) and ET(B) receptors in GH(AB) cells.

Amino Acid Sequence↗

PubMed1996

p53 accumulation in the organs of low-dose X-ray-irradiated mice.

In order to search for the direct evidence of cellular response to low-dose radiation, we investigated wild-type p53 protein accumulation in several organs of mice after exposure to low doses of X-rays. Significant p53 accumulation within 24 h was observed in the mouse adrenal glands and pancreas after X-ray irradiation at 25 cGy and 50 cGy, but not at 100 cGy. In addition, differential p53 accumulation was also observed in the hypophysis, thymus, skin, lung, bone marrow and liver at different doses. In contrast, we observed no accumulation of p53 protein in the spleen, testis or kidney at any dose used in this experiment. The p53 accumulation induced by low-dose X-rays in mice was organ-specific. It is suggested that cell type and interactions with other signal transduction pathways of the hormone system, immune system and/or nervous system may contribute to the variable induction of p53 by low-dose X-ray irradiation. The association of organ-specific p53 response with radiosensitivity and cancer incidence by radiation in each organ was discussed.

Adrenal Glands↗

PubMed1996

Synthesis and structure-activity relationships of 2-substituted D-tryptophan-containing peptidic endothelin receptor antagonists: importance of the C-2 substituent of the D-tryptophan residue for endothelin A and B receptor subtype selectivity.

Continuing studies on modifications of potent cyclic pentapeptide endothelin (ET) receptor antagonists, represented by BQ-123, and potent linear tripeptide derivative ET receptor antagonists, represented by BQ-788, are described herein. The introduction of D-tryptophan analogues with C-2 substituents in these peptidic ET antagonists resulted in potent ET receptor antagonists with various ETA/ETB subtype selectivity. Combined ETA/ETB receptor antagonists were found in both cyclic pentapeptide and linear tripeptide series with 2-halo- and 2-methyl-D-tryptophans. In contrast, compounds with 2-cyano-D-tryptophan were ETB receptor-selective antagonists. The C-2 substituent of the D-tryptophanyl residue appeared to be very important for the discrimination of ETA/ETB subtype selectivity of the antagonists. The potent ET receptor antagonists with various ETA/ETB subtype selectivity synthesized in this study may be useful tools for elucidating the physiological and pathophysiological roles of ET and ET receptors.

Animals↗

PubMed1996

Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure. Marked increase in endothelin-1 production in the failing heart.

BACKGROUND: Although it was demonstrated that circulating endothelin-1 (ET-1) levels are elevated in congestive heart failure (CHF), the production and roles of ET-1 in the failing heart are not known. We investigated the production of ET-1 in the heart and the density of myocardial ET receptors in rats with CHF. We also investigated the effects of intravenously infused BQ-123, an endothelin(A) (ETA) receptor antagonist, on both heart and myocardial contractility in rats with CHF. METHODS AND RESULTS: We used the left coronary artery-ligated rat model of CHF (CHF rats). Three weeks after surgery, the rats developed CHF. Plasma ET-1 concentration was significantly higher in the CHF rats than in the sham-operated rats (P<.01). In the left ventricle, the expression prepro-ET-1 mRNA was markedly higher in the CHF rats than in the sham-operated rats. The peptide level of ET-1 in the left ventricle was also significantly higher in the CHF rats than in the sham-operated rats (500+/-41 versus 102+/-10 pg/g tissue, P<.01). Myocardial ET receptors were significantly higher in the CHF rats than in the sham-operated rats (243+/-20 versus 155+/-17 fmol/mg protein, P<.05). In the CHF rats, intravenous BQ-123 infusion (0.1 mg x kg(-1) x min(-1) for 120 minutes) significantly decreased both heart rate (P<.01) and LV+dP x dt(max) (P<.05) but not mean blood pressure. BQ-123 infusion did not affect these hemodynamic parameters in the sham-operated rats. CONCLUSIONS: In the present study, we demonstrated that the production of ET-1 in the heart is markedly increased and that the density of myocardial ET receptors is significantly elevated in the CHF rats. Intravenous BQ-123 infusion significantly reduced both heart rate and LV+dP/dt(max) in the CHF rats but not in the sham-operated rats. Therefore, the ET receptor-mediated signal transduction system in the heart appears to be markedly stimulated in the CHF rats, and endogenous ET-1 may be involved in the maintenance of the cardiac function in these rats.

Animals↗

PubMed1996

Necessity of dual blockade of endothelin ETA and ETB receptor subtypes for antagonism of endothelin-1-induced contraction in human bronchi.

1. Endothelin (ET)-1 has been postulated to be involved in the development of obstructive airway diseases in man. In the present study, we attempted to characterize ET receptor subtypes mediating ET-1-induced contraction in human isolated bronchi. The ET receptor antagonists used in the present study were BQ-123 (ETA receptor-selective), BQ-788 (ETB receptor-selective) and BQ-928 (ETA/ETB dual). Sarafotoxin S6c (S6c) was also used as an ETB receptor-selective agonist. 2. In human bronchi, ET-1 and S6c (10(-12)M to 10(-7) M) produced concentration-dependent contraction with almost equal potency (pD2: 8.88 +/- 0.16 for ET-1 and 9.42 +/- 0.15 for S6c). The contraction induced by S6c was competitively antagonized by BQ-788 alone (1 and 10 microM) with a pKB value of 7.49 +/- 0.21, suggesting that the stimulation of ETB receptors causes a contraction of human bronchi. However, contrary to expectation, the concentration-response curves for ET-1 were not affected by BQ-788. The ET-1- and S6c-induced contractions were not affected by BQ-123 (10 microM). Thus, ET-1-induced contraction of human bronchi is not antagonized by BQ-123 alone or by BQ-788 alone. 3. Combined treatment with 10 microM BQ-123 and 10 microM BQ-788 significantly antagonized the contraction induced by ET-1 with a dose-ratio of 11. BQ-928 also significantly antagonized ET-1-induced contraction with a pKB value of 6.32 +/- 0.24. 4. The specific binding of [125I]-ET-1 to human bronchial membrane preparations was inhibited by BQ-123 (100 pM to 1 microM) by approximately 40%. Combination treatment with BQ-788 (100 pM to 1 microM) completely inhibited the BQ-123-resistant component of [125I]-ET-1 specific binding. 5. In conclusion, the present study demonstrates that BQ-788 alone cannot inhibit ET-1-induced contractions in human bronchi, although human bronchial ETB receptors are BQ-788-sensitive. Furthermore, it was shown that blockade of both receptor subtypes antagonizes ET-1-induced contraction, and that both receptor subtypes co-exist in human bronchial smooth muscles. These findings suggest that ETA receptors as well as ETB receptors are involved in ET-1-induced contraction in human bronchi. If ET-1 is involved in human airway diseases, dual blockade of ETA and ETB receptors may be necessary to treat the diseases.

Adult↗

PubMed1996

Potent neuropeptide Y Y1 receptor antagonist, 1229U91: blockade of neuropeptide Y-induced and physiological food intake.

Neuropeptide Y (NPY) is thought to increase food intake through the action of Y1 (-like) receptors in the hypothalamus. To confirm the involvement of Y1 receptors in feeding behavior, selective and potent antagonists for Y1 receptors are required. In the present study, we showed that a peptide, 1229U91 [(Ile,Glu,Pro,Dpr,Tyr,Arg,Leu,Arg, Tyr-NH2)2 cyclic (2,4'),(2',4)-diamide], is a potent and selective antagonist for Y1 receptors. 1229U91 displaced [125I]peptide YY (PYY) binding to membranes of human neuroblastoma-derived SK-N-MC cells that predominantly express Y1 receptors with a K1 value 0.10 nM and inhibited the NPY-induced increase in intracellular calcium levels(IC50 = 0.27 nM). In contrast, the K1 values for [125I]PYY binding to Y2 receptors in membranes of human neuroblastoma-derived SK-N-BE2 cells and rat hypothalamus were 700 nM and more than 1 microM, respectively. Although [125I]PYY could not detect Y1 receptors in the rat hypothalamic membranes, [125I]1229U91 revealed binding sites with a high affinity (Kd = 18 pM), indicating the presence of Y1 receptors in the hypothalamus. Intracerebroventricular injection of 1229U91 (30 micrograms) into male Sprague-Dawley rats completely inhibited NPY (5 micrograms)-induced food intake without any other behavioral change. Furthermore, intracerebroventricular injection of 1229U91 significantly suppressed physiological feeding behavior after overnight fasting. These results indicate that Y1 receptors in the rat hypothalamus mediate NPY-induced food intake, and that physiological feeding behavior after overnight fasting may be largely regulated by NPY via Y1 receptors. 1229U91 may be useful for further elucidating the pathophysiological roles of NPY in feeding behavior.

Animals↗

PubMed1996

Cyclic pentapeptide endothelin A receptor antagonists with attenuated in vivo clearance.

A series of analogues of BQ-123 (1), a potent cyclic pentapeptide endothelin A receptor antagonist, with amino acids linked to the side-chain of the Pro residue via an ester linkage was synthesized. All analogues synthesized exhibited potent endothelin A receptor binding affinity similar to that of 1. Of the synthesized analogues, the Lys, Arg and N alpha,N epsilon-dimethyllysine analogues, 9d-f, exhibited about a three-fold attenuation of in vivo clearance compared with 1. In rats, these analogues exhibited a 3-fold-higher plasma concentration and a longer retention time in plasma as compared with those of 1. The attenuated in vivo clearance was thought to be a consequence of decreased extraction of the compounds from the blood via the hepatic anion transport system, which efficiently extracts 1 from the blood.

Amino Acid Sequence↗

PubMed1996

[Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with chronic renal failure: report of mother-child cases].

A 25-year-old man developed nausea, vomiting, severe headache, and confusion. He had a past history of hyperuricemia and mild renal dysfunction. On admission he had somatic growth retardation, hypertrichosis, and bilateral auditory impairment. A cranial CT scan showed a small area of low density in the left temporal lobe and cerebellar atrophy. Five days later, he developed right homonymous hemianopia, sensory aphasia, and sensory inattention, and a new, large area of low density in the left occipital lobe on a cranial CT scan. On laboratory examination, lactate, pyruvate, and the lactate-to-pyruvate ratio were elevated in both the serum and cerebrospinal fluid. The biopsied muscle showed ragged red fibers and strongly SDH-reactive blood vessels. Gene analysis revealed the presence of the A 3243 G point mutation of the mitochondrial tRNA(Leu) gene in his blood leucocytes and muscle. Serum concentrations of BUN and creatinine were elevated to 46 mg/dl and 2.2 mg/dl, respectively. Creatinine clearance was 14.1 ml/min. An abdominal CT scan disclosed atrophy of his left kidney with subcapsular calcification and the findings of his abdominal ultrasonography were compatible with chronic renal failure. His mother, who suffered from renal failure and became dialysis dependent in her late forties also bore the A 3243 G mutation of the mitochondrial tRNA(Leu) gene in her circulating leucocytes. Though the association between MELAS and renal dysfunction still remains obscure, we speculate that renal failure can be a manifestation of MELAS.

Adult↗

PubMed1995

ETB-mediated regulation of extracellular levels of endothelin-1 in cultured human endothelial cells.

Our previous report suggests the important role that ETB receptors play in the clearance of circulating endothelin (ET)-1. The present study confirmed this finding by measuring the extracellular levels of immunoreactive (ir) ET-1 and intracellular contents of prepro (pp) ET-1 mRNA in the presence and absence of ETA- and ETB-selective antagonists (i.e., BQ-123 and BQ-788, respectively) in cultured human umbilical vein endothelial cells (HUVECs). ET-1 was secreted into the culture medium of HUVECs in a time-dependent manner with a plateau reached after incubation for more than 36 hr. In the presence of 10 microM BQ-788, the irET-1 level was enhanced significantly (i.e., up to 180% of control at 48 hr) whereas BQ-123 had no such effect. Specific binding of [125I]ET-1 to HUVECs was inhibited strongly by BQ-788 (IC50 = 2.4 nM) but very weakly by BQ-123 (IC50 = 1.4 microM), indicating that BQ-788 has a potent affinity for ETB receptors in HUVECs. The expression of ppET-1 mRNA was not changed by BQ-788. Extracellular levels of ET-1 decreased gradually after cellular treatment with cycloheximide. This decrease was significantly inhibited by BQ-788 but not by BQ-123 and was non-existent when the cells were incubated at 4 degrees C (where internalization of the receptor protein is not likely). In conclusion, HUVECs secrete ET-1 which, in turn, is internalized after binding to ETB receptors on HUVECs.

Amino Acid Sequence↗

PubMed1995

[3H]BQ-123, a highly specific and reversible radioligand for the endothelin ETA receptor subtype.

The mode of binding of [3H]BQ-123 (cyclo(-D-Trp-D-Asp-[prolyl-3,4 (n)-[3H]]Pro-D-Val-Leu)), an endothelin receptor antagonist radioligand, was evaluated in the human neuroblastoma cell line SK-N-MC at 37 degrees C. Scatchard analysis indicated the presence of a single class of [3H]BQ-123 binding sites with a high affinity of 3.2 nM. [3H]BQ-123 binding achieved steady state within 7 min and dissociated with a half-time of 1.4 min, while [125I] endothelin-1 binding barely reached a steady state even after 6 h and showed little dissociation. [3H]BQ-123 binding was sensitive to endothelin-1 and endothelin-2 (Ki values = 0.058 and 0.10 nM, respectively) and the endothelin ETA receptor-selective antagonist BQ-123 (Ki = 3.3 nM), while showing low affinity for endothelin-3 (Ki = 50 nM), the endothelin ETB receptor-selective agonist BQ-3020 (Ki = 970 nM) and other bioactive peptides. Thus, [3H]BQ-123 is a specific and reversible radioligand for endothelin ETA receptors. The rapid reversibility of [3H]BQ-123 binding should provide a tool for estimating the equilibrium inhibition constants (Ki values) of various compounds for endothelin ETA receptors.

Amino Acid Sequence↗

PubMed1995

Analysis of genomic polymorphism among herpes simplex virus type 2 isolates from four areas of Japan and three other countries.

Genomic polymorphism of 307 epidemiologically unrelated strains of herpes simplex virus type 2 (HSV-2) from four areas of Japan and three other countries (Korea, Sweden and the U.S.A.) was analysed by using 16 variable markers selected from 97 restriction endonuclease (RE) sites with five REs. In addition to the 16 markers, 26 rare variable RE sites were found in 307 isolates. Five and four of 16 markers (RE sites) were found to differ in the frequency of isolates with the markers between isolates from Japan and Sweden and between those from Japan and the U.S.A., respectively, suggesting that they are genomically different from each other. In this manner, 307 HSV-2 isolates from four countries could be classified into 68 different genotypes (no. of isolates/no. of genotypes = 4.5). Some isolates from one country or more than two countries at times were classified into the same genotypes, which were referred to as predominant genotypes. The most predominant genotypes for isolates from Japan, Sweden and the U.S.A. were genotypes 30, 26 (32) and 3, respectively, indicating that they are different by the country. In genotypes 1 and 6, the frequency of isolates was found to be significantly different between Japan and Sweden and between Japan and the U.S.A., respectively. Nine out of 16 markers differed in the most genomically distant isolates, each of which was obtained in Sweden and Japan. In addition, high correlation coefficients (r) in the Japanese isolates were detected in different pairs of markers from those in the Swedish isolates, suggesting that isolates from these two countries are evolutionarily distant.

Biological Evolution↗

PubMed1995

Preferential inhibition of nucleosome assembly by ultraviolet-induced (6-4)photoproducts.

We reconstituted nucleosomes in vitro using two kinds of damaged pBR322 plasmid DNA carrying cyclobutane pyrimidine dimers (CPD) or (6-4)photoproducts. The results indicate that nucleosome assembly is inhibited preferentially by (6-4)photoproducts compared with CPD, suggesting that the regions carrying (6-4)photoproducts retain their nucleosome-free form, i.e. linker-like conformation until completion of the repair processes.

Animals↗

PubMed1995

Unique DNA repair property of an ultraviolet-sensitive (radC) mutant of Dictyostelium discoideum.

Dictyostelium discoideum is an organism that shows higher UV resistance than other organisms, such as Escherichia coli and human cultured cells. We examined the removal of cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts from DNA in the radC mutant and the wild-type strain using an enzyme-linked immunosorbent assay with monoclonal antibodies. Wild-type cells excised more than 90% of both CPD and 6-4 photoproducts within 4 h. Dictyostelium discoideum appeared to have a special repair system, because 6-4 photoproducts were repaired faster than CPD in E. coli and human cultured cells. In radC mutant cells, although only 50% of CPD were excised from DNA within 8 h, effective removal of 6-4 photoproducts (80% in 8 h) was observed. Excision repair-deficient mutants generally cannot remove both CPD and 6-4 photoproducts. Though the radC mutant shows deficient excision repair, it can remove 6-4 photoproducts to a moderate degree. These results suggest that D. discoideum has two kinds of repair systems, one mainly for CPD and the other for 6-4 photoproducts, and that the radC mutant has a defect mainly in the repair enzyme for CPD.

Animals↗

PubMed1995

Increased endothelin-1 binding sites in the cardiac membranes in rats with chronic heart failure.

The effects of experimental chronic heart failure (CHF) on the density and affinity for endothelin-1 (ET-1) binding was studied in the rat heart. Because it has been reported that ET-1 binding sites on cultured cardiocytes are downregulated by pretreatment with ET-1, we also studied the plasma concentrations of ET-1 in rats with CHF. Three weeks after ligation of the left coronary artery, rats developed chronic heart failure (CHF rats). The plasma concentrations of ET-1, as measured by a sandwich-enzyme immunoassay, were significantly higher in CHF rats than in sham-operated rats [4.80 +/- 0.33 vs. 0.91 +/- 0.11 (mean +/- SEM) pg/ml; p < 0.01]. [125I]ET-1 binding experiments on rat cardiac membranes revealed that the binding site density (Bmax) was significantly higher in the CHF rats than in the sham-operated rats (243.0 +/- 20.0 vs. 154.8 +/- 17.4 fmol/mg protein; p < 0.05), whereas the values for the dissociation constant (Kd) were not different between the two groups (28.7 +/- 7.0 vs. 29.8 +/- 1.9 pM). Therefore, in the CHF rats, although plasma concentrations of ET-1 were elevated, the density of myocardial ET receptors was increased. Because ET-1 has potent inotropic and hypertrophic effects on cardiac myocytes, it is suggested that the effects of endogenous ET-1 in the heart are different between the CHF rats and the sham-operated rats.

Animals↗

PubMed1994

Nonspecific regulatory mechanism of contact sensitivity: nonspecific suppressor factor suppresses the antigen-presenting activity of dendritic cells to induce contact sensitivity.

Nonspecific suppressor factor (NSF), which inhibits the passive transfer of contact sensitivity (CS), is produced from macrophage-like cells induced by oxazolone-conjugated spleen cells. NSF binds selectively to Ia-positive, cyclophosphamide-sensitive, and plastic-adherent non-T cells (named intermediate cells) present in the spleen. NSF-treated intermediate cells acquire the ability to suppress the passive transfer of CS nonspecifically. Because the phenotype of the intermediate cells is similar to that of antigen-presenting cells (APC) of macrophage lineage, we examined the effect of NSF on APC. NSF suppressed the APC activity of draining lymph node cells from mice sensitized with fluorescein isothiocyanate or picryl chloride (FITC-LNC or TNP-LNC) to induce CS. Suppressor molecules which suppress the passive transfer of CS and the APC activity were recovered in the same fraction around 43 kDa by dye-affinity and gel chromatography purification. The results that the suppressor activity of NSF was absorbed with lymph node cells or FITC-LNC, but not 33D1 or anti-Ia monoclonal antibody plus complement-treated FITC-LNC indicated that NSF reacts directly with antigen-bearing dendritic cells in the draining lymph node. In contrast with spleen cells, lymph node cells did not have the intermediate function, i.e., NSF-treated LNC could not suppress the passive transfer of CS nor the ability of FITC-LNC to induce CS (APC activity). NSF still blocks the ability of FITC-LNC to induce CS after treatment with cyclophosphamide. Thus, the lymph node and spleen include distinct functional cell populations which express Ia antigen and interact with NSF. APC in the draining lymph node are downregulated directly by NSF and the intermediate cells in the spleen play a modulatory role in the suppressor pathway of NSF.

Absorption↗

PubMed1994

Biochemical and pharmacological profile of a potent and selective endothelin B-receptor antagonist, BQ-788.

We describe the characteristics of a potent and selective endothelin (ET) B-receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1- methoxycarbonyltryptophanyl-D-norleucine]. In vitro, this compound potently and competitively inhibits 125I-labeled endothelin 1 (ET-1) binding to ETB receptors on human Girardi heart cells (IC50, 1.2 nM) but only poorly inhibits the binding to ETA receptors on human neuroblastoma cell line SK-N-MC cells (IC50, 1300 nM). In isolated rabbit pulmonary arteries, BQ-788 shows no agonist activity up to 10 microM and competitively antagonizes the vasoconstriction induced by an ETB-selective agonist, BQ-3020 (pA2, 8.4). In rat, an ETA-selective antagonist, BQ-123 (1 mg/kg, i.v.), does not affect transient depressor response to ET-1 (0.3 nmol/kg, i.v.) but potently inhibits following sustained pressor response; vice versa, BQ-788 (1 mg/kg, i.v.) abolishes the depressor response, resulting in a rapid onset of apparently enhanced pressor response. Thus, being a potent and selective ETB receptor antagonist, BQ-788 may be considered as a powerful tool for investigating the role of ET in physiological and pathological processes.

Amino Acid Sequence↗