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PubMed1994

Maturation enhances the sensitivity of ovine cerebral arteries to the ATP-sensitive potassium channel activator lemakalim.

A wide variety of previous studies have demonstrated that arterial reactivity and contractility change dramatically during maturation. In light of recent findings that binding sites for glibenclamide, a ligand for ATP-sensitive potassium (KATP) channels, become more abundant with age in many tissues, the present studies examine the hypothesis that maturational changes in vascular reactivity involve changes in arterial electrophysiologic characteristics. To test this hypothesis, we determined the dose-response relation to lemakalim, a selective activator of KATP channels, in isolated endothelium-denuded segments of the second (2B, internal diameter approximately 200 microns) and fourth (4B, internal diameter approximately 125 microns) branches of middle cerebral arteries taken from newborn (3-7 d old) and adult sheep. At 100 microM, lemakalim completely relaxed serotonin-induced tone in all arteries. However, -log ED50 values were 29 to 43 times greater in adult (2B, 7.15 +/- 0.38; 4B, 6.61 +/- 0.42) than in newborn (2B, 5.52 +/- 0.25; 4B, 5.15 +/- 0.24) segments. Correspondingly, Hill values were significantly smaller in adults (2B, 0.47 +/- 0.17; 4B, 0.71 +/- 0.30) than in newborns (2B, 1.40 +/- 0.35; 4B, 3.30 +/- 0.92). These findings demonstrate that KATP channels are less sensitive to activation in newborn than in adult cerebral arteries. Given the important influence of KATP channels on vascular tone, and their possible role in many cardiovascular responses, the present data suggest that maturational increases in the activity of KATP channels contribute significantly to age-related changes in cerebrovascular contractility.

Adenosine Triphosphate↗
PubMed1983

Increased sensitivity of insulin-sensitive phosphodiesterase to insulin in fat cells from streptozotocin diabetic rats.

The effects of insulin on insulin-sensitive phosphodiesterase were investigated in fat cells from control and streptozotocin diabetic rats. Isolated cells were incubated at 37 C for 10 min, with and without insulin. A crude microsomal fraction prepared by differential centrifugation was assayed for phosphodiesterase activity. The enzyme activities in diabetic rats were higher at 0-1 nM insulin than in control rats. The dose-response curve of insulin was biphasic and of the convex type in both groups. In diabetic rats, the curve shifted to the left, and half-maximal stimulation was obtained at 0.06 nM insulin compared with 0.16 nM insulin in control rats. Kinetic analyses of the enzyme from diabetic rats revealed much the same findings as obtained in the controls. Specific binding of insulin in fat cells from control and diabetic rats was 3% and 4.9%/2 X 10(5) cells, respectively, at 24 C for 60-min incubation. Scatchard analysis indicates that the overall binding affinity in diabetic cells was greater than that in the control cells. These results suggest that the insulin effector system related to phosphodiesterase activation is intact and has an increased sensitivity in fat cells from streptozotocin diabetic rats; there is also a good correlation with alteration of insulin binding to its receptors.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

Low insulin sensitivity measured by both quantitative insulin sensitivity check index and homeostasis model assessment method as a risk factor of increased intima-media thickness of the carotid artery.

The present study evaluated the association of ultrasonographic manifestations of carotid atherosclerosis with glucose status, various components of the insulin resistance syndrome, and insulin sensitivity measured by a novel quantitative insulin sensitivity check index (QUICKI = 1/[log(I0) + log (G0)]). Carotid ultrasonographic measurements were performed on 54 diabetic subjects, 97 subjects with impaired glucose tolerance and 57 normoglycemic subjects. QUICKI and insulin resistance measured by a HOMA (homeostasis model assessment) method had a high negative correlation (r = -0.995, P < 0.001). QUICKI was lower in diabetic subjects (0.319 +/- 0.022) than in subjects with impaired glucose tolerance (0.334 +/- 0.027) or normoglycemia (0.335 +/- 0.022, P = 0.002). There was an increasing trend in the mean and maximal intima-media thickness (IMT) of the common carotid artery (CCA) with worsening of glucose status. The maximal IMT of the CCA correlated inversely with QUICKI (r = -0.158, P = 0.027). The prevalence of severe CCA atherosclerosis (maximal IMT of the CCA > or = 1.2 mm) was 41% in men and 16% in women (P < 0.001). It was also associated with a long (> or =26 yr) smoking history. The prevalence of severe CCA atherosclerosis was 11% in the highest QUICKI tertile, 36% in the middle tertile, and 33% in the lowest tertile (P = 0.002). Systolic blood pressure was higher and high-density lipoprotein cholesterol lower in subjects with severe CCA atherosclerosis, compared with those without it. In multiple regression analysis, the adjusted odds ratio for severe CCA atherosclerosis was 5.7 (95% confidence interval, 2.2-15.1) in subjects in the two lowest tertiles of QUICKI, compared with those in the highest tertile.

Blood Glucose↗
PubMed2005

Eyeshine and spectral tuning of long wavelength-sensitive rhodopsins: no evidence for red-sensitive photoreceptors among five Nymphalini butterfly species.

Spectral tuning of rhodopsins commonly refers to the effects of opsin amino acid substitutions on the wavelength for peak sensitivity of the rhodopsin absorption spectrum. Nymphalini butterflies provide an opportunity for identifying some of the amino acid substitutions responsible for insect rhodopsin spectral tuning because the majority of photoreceptor cells (R3-9) in the adult retina express only a single long wavelength-sensitive (LWS) opsin mRNA transcript. Therefore, the opsin genotype can be directly correlated with its phenotype. We determined the LWS opsin gene sequence from cDNA of the mourning cloak Nymphalis antiopa, and from genomic DNA of the malachite Siproeta stelenes and the peacock Inachis io. Using an epi-microspectrophotometer we examined each butterfly's eyeshine for photochemical evidence of multiple LWS rhodopsins and found only one. We then performed partial-bleaching experiments to obtain absorbance spectra for the LWS rhodopsins of all three species as well as from another nymphalid, the buckeye Junonia coenia. The isolated LWS opsin gene sequences varied in length from 1437-1612 bp and encode rhodopsins R522 (S. stelenes), R530 (I. io), R534 (N. antiopa) and, together with a previously published sequence, R510 (J. coenia). Comparative sequence analysis indicates that the S. stelenes rhodopsin is slightly blue-shifted compared to the typical 530 nm lepidopteran rhodopsin because of the presence of a S138A substitution at a homologous site that in mammalian MWS/LWS rhodopsins causes a 5 nm blue-shift. The difference in peak absorption between R522 of S. stelenes and R530 of Inachis io is therefore largely accounted for by this substitution. This suggests that spectral tuning mechanisms employing the S138A may have evolved in parallel in mammalian and butterfly MWS/LWS rhodopsins across 500 million years of evolution.

Amino Acid Sequence↗
PubMed1993

Neuropharmacological characterization of voltage-sensitive calcium channels: possible existence of neomycin-sensitive, omega-conotoxin GVIA- and dihydropyridines-resistant calcium channels in the rat brain.

We attempted to characterize the functional roles of subtypes of voltage-sensitive calcium channels in the brain. The maximal number of [125I]omega-conotoxin GVIA (omega-CTX) binding sites in rat brain associated with N-type calcium channels (N-channels) was approximately 10 times more than that of [3H]-PN200-110 associated with L-type calcium channels (L-channels). [125I]omega-CTX binding was inhibited by aminoglycoside antibiotics, neomycin and dynorphin A(1-13), but not by various classes of L-channel antagonists. A 6-hydroxydopamine-induced lesion of the striatum resulted in a marked reduction of both [125I]-omega-CTX and [3H]PN200-110 binding. Kainic acid-induced lesion of the striatum reduced [3H]PN200-110 binding by 57%, but did not reduce [125I]omega-CTX binding. Omega-CTX produced a small (18%) but significant reduction of potassium-stimulated Ca2+ influx into rat brain synaptosomes, although it produced a concentration-dependent inhibition in chick brain synaptosomes. Neomycin inhibited Ca2+ influx in both preparations in a concentration-dependent manner. Both omega-CTX and neomycin inhibited potassium-stimulated [3H]dopamine (DA) release from rat striatal slices. The L-channel antagonists had no effect on either Ca2+ influx or [3H]DA release. These results suggest that DA release in the striatum is regulated by Ca2+ influx through N-channels located in presynaptic nerve terminals, and that the most of the Ca2+ influx in rat brain appears to be governed by neomycin-sensitive, omega-CTX- and DHP-resistant calcium channels.

Animals↗
PubMed1983

Changes in prostaglandin levels in the sensitized and non-sensitized uterus of the mouse after the intrauterine instillation of oil or saline.

Intrauterine instillation of oil, but not saline, induced both a decidual cell reaction and a marked elevation in the uterine PGF-alpha content of suitably sensitized ovariectomized mice. Uterine PGF-alpha concentrations were elevated within 5 min of the oil instillation, reached maximal levels within 30-60 min and then declined to near baseline levels again by 3 h. A similar increase in uterine PGF-alpha content in response to oil instillation was seen in non-sensitized females, although no decidual cell reaction developed. No significant changes in PGE or 6-oxo-PGF-1 content were observed. These results suggest that although the increase in uterine PGF-alpha content is not solely due to the distension of the uterus after intrauterine injection, the increase is not necessarily sufficient to induce a decidual cell reaction.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Intraluminally injected oil induces changes in vascular permeability in the 'sensitized' and 'non-sensitized' uterus of the mouse.

After suitable sensitization of ovariectomized mice with progesterone and oestradiol, the intrauterine instillation of oil produces a massive decidual cell reaction. Vascular permeability, as reflected by the extra-vascular accumulation of 125I-labelled human serum albumin, increased after oil instillation and was maintained at 2-3 times control values for at least the next 3 days. Although oil instillation did not produce a decidual response in females treated with progesterone alone, an increase in vascular permeability (about 2 times control levels) still occurred. This response peaked 8 h after oil instillation and was not maintained. These results indicate that the progesterone-dominated uterus which has not been sensitized with oestradiol cannot be viewed as completely unresponsive to the stimulus of oil and demonstrate that a marked increase in vascular permeability is not itself sufficient to induce decidualization of progesterone-dominated uterine stromal cells. The uterine extravascular accumulation of 125I-labelled albumin was increased both in association with tribromoethanol anaesthesia and after oestradiol treatment of progesterone-primed animals. In pregnant mice, the appearance of Pontamine Sky Blue spots provided an earlier indication of implantation than did determination of total uterine extravascular 125I-labelled albumin accumulation.

Animals↗
PubMed2004

Comparison of the homeostasis model assessment and quantitative insulin sensitivity check index with data from forearm metabolic studies for the in vivo assessment of insulin sensitivity.

The present study was designed to compare the homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) with data from forearm metabolic studies of healthy individuals and of subjects in various pathological states. Fifty-five healthy individuals and 112 patients in various pathological states, including type 2 diabetes mellitus, essential hypertension and others, were studied after an overnight fast and for 3 h after ingestion of 75 g of glucose, by HOMA, QUICKI and the forearm technique to estimate muscle uptake of glucose combined with indirect calorimetry (oxidative and non-oxidative glucose metabolism). The patients showed increased HOMA (1.88 +/- 0.14 vs 1.13 +/- 0.10 pmol/l x mmol/l) and insulin/glucose (I/G) index (1.058.9 +/- 340.9 vs 518.6 +/- 70.7 pmol/l x (mg/100 ml forearm)-1), and decreased QUICKI (0.36 +/- 0.004 vs 0.39 +/- 0.006 ( microU/ml + mg/dl)-1) compared with the healthy individuals. Analysis of the data for the group as a whole (patients and healthy individuals) showed that the estimate of insulin resistance by HOMA was correlated with data obtained in the forearm metabolic studies (glucose uptake: r = -0.16, P = 0.04; non-oxidative glucose metabolism: r = -0.20. P = 0.01, and I/G index: r = 0.17, P = 0.03). The comparison of QUICKI with data of the forearm metabolic studies showed significant correlation between QUICKI and non-oxidative glucose metabolism (r = 0.17, P = 0.03) or I/G index (r = -0.37, P < 0.0001). The HOMA and QUICKI are good estimates of insulin sensitivity as data derived from forearm metabolic studies involving direct measurements of insulin action on muscle glucose metabolism.

Blood Glucose↗
PubMed1983

Statistics for diagnostic procedures. I. How sensitive is "sensitivity"; how specific is "specificity"?

The terms of medical decision making (i.e., accuracy, sensitivity, specificity, predictive value, false positive/negative rates) are often seen in the radiologic literature. The interrelationships among these terms are explained, with special emphasis on the following: (1) How useful a procedure is for detecting/excluding disease depends on sensitivity, specificity, and prevalence of disease, and thus varies from practice to practice, and (2) "Accuracy" is often very misleading.

Decision Making↗
PubMed1993

Glucose sensitivity of ATP-sensitive K+ channels is impaired in beta-cells of the GK rat. A new genetic model of NIDDM.

In the Goto-Kakizaki rat, a new genetic model of NIDDM, insulin response to glucose is selectively impaired. To elucidate the mechanism of this abnormality, we studied the properties of ATP-sensitive K+ channels, the inhibition of which is a key step of insulin secretion induced by fuel substrates, using the patch-clamp technique. The glucose-sensitivity of KATP channels was considerably reduced in GK rats. However, the inhibitory effects of ATP on channel activity and unitary conductance were not significantly different between control and GK rats. Thus, it appears that the impaired insulinotropic action of glucose in beta-cells of GK rats is attributable to insufficient closure of the KATP channels, probably because of deficient ATP production by impaired glucose metabolism. KATP-channel activities in both control and diabetic beta-cells were found to be equally suppressed by glyceraldehyde and 2-ketoisocaproate. These results strongly suggest that the step responsible for the metabolic dysfunction of diabetic beta-cells is located within the glycolytic pathway before glyceraldehyde-3-phosphate or in the glycerol phosphate shuttle.

Adenosine Triphosphate↗
PubMed1999

An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats.

Recently there has been growing interest in the effects of antioxidants on insulin activity. In the present study, we investigated the effect of metformin on free radical activity and insulin sensitivity in high fructose-fed rats, a diet that leads to insulin resistance. The animals were divided into four groups (n = 16 per group; experiment duration = 6 weeks): the control (C) group received a standard diet; the control metformin (CM) group was fed a control diet and received metformin (200 mg x kg(-1) x day(-1) in water); the fructose control (FT) group was fed a diet in which fructose composed 56.8% of the total carbohydrates; and the fructose metformin (FM) group received high-fructose diet and metformin (200 mg x kg(-1) x day(-1) in water). The glucose clamp technique was used to determine insulin sensitivity in eight animals per group. Metabolic and oxidative stress parameters were measured in the remaining rats. In the FT rats, insulin resistance, lower red cell CuZn superoxide dismutase activity and lower blood reduced glutathione were observed. Metformin treatment improved both the insulin activity and the antioxidant defense system. In the CM group, metformin had no effect on metabolic parameters, but improved red cell antioxidant enzyme activities and the blood GSH level, which suggests that it has an antioxidant activity independent of its effect on insulin activity.

Animals↗
PubMed2002

Nucleotide sensitivity of pancreatic ATP-sensitive potassium channels and type 2 diabetes.

Type 2 diabetes is generally perceived as a polygenic disorder, with disease development being influenced by both hereditary and environmental factors. However, despite intensive investigations, little progress has been made in identifying the genes that impart susceptibility to the common late-onset forms of the disease. E23K, a common single nucleotide polymorphism in K(IR)6.2, the pore-forming subunit of pancreatic beta-cell ATP-sensitive K(+) (K(ATP)) channels, significantly enhances the spontaneous open probability of these channels, and thus modulates sensitivities toward inhibitory and activatory adenine nucleotides. Based on previous association studies, we present evidence that with an estimated attributable proportion of 15% in Caucasians, E23K in K(IR)6.2 appears to be the most important genetic risk factor for type 2 diabetes yet identified.

Adenosine Triphosphate↗
PubMed2002

The common single nucleotide polymorphism E23K in K(IR)6.2 sensitizes pancreatic beta-cell ATP-sensitive potassium channels toward activation through nucleoside diphosphates.

E23K, a common polymorphism in the pore-forming subunit K(IR)6.2 of pancreatic beta-cell ATP-sensitive K(+) (K(ATP)) channels, is functionally relevant and thus might play a major role in the pathophysiology of common type 2 diabetes. In this study, we show that in the simultaneous presence of activatory and inhibitory nucleotides, the polymorphism exerts opposite effects on the potencies of these modulators: channel opening through nucleoside diphosphates is facilitated, whereas sensitivity toward inhibition through ATP is slightly decreased. The results support the conclusion that E23K predisposes to type 2 diabetes by changing the channel's response to physiological variation of cytosolic nucleotides, resulting in K(ATP) overactivity and discrete inhibition of insulin release.

Adenosine Diphosphate↗
PubMed2002

Carriers of an inactivating beta-cell ATP-sensitive K(+) channel mutation have normal glucose tolerance and insulin sensitivity and appropriate insulin secretion.

OBJECTIVE: Insulin release from the pancreatic beta-cells is controlled by ATP-sensitive K(+) (K(ATP)) channels, which consist of a hetero-octameric complex of four sulfonylurea receptor 1 (SUR1) and four Kir6.2 proteins. Mutations in the SUR1 gene are the major cause of congenital hyperinsulinemia (CHI). Despite the hereditary nature of CHI, studies of glucose homeostasis in heterozygous relatives of CHI patients are lacking. Theoretically, in the heterozygous state of the SUR1 gene mutation, only 1 of 16 K(ATP) channels consists of entirely normal subunits. The aim of our study was to investigate in vivo the glucose homeostasis of heterozygous SUR1 mutation carriers. RESEARCH DESIGN AND METHODS: We studied 8 parents of CHI patients, all 8 of whom were heterozygous for the inactivating SUR1 mutation V187D, and 10 matched control subjects. We evaluated glucose tolerance and insulin secretory capacity with oral and intravenous glucose tests, rates of whole-body glucose uptake with hyperinsulinemic-euglycemic clamps, C-peptide response to hypoglycemia during hyperinsulinemic-hypoglycemic clamp, and function of the K(ATP) channels with intravenous tolbutamide test. RESULTS: Carriers of the V187D substitution had normal glucose tolerance, normal tissue sensitivity to insulin, and no signs of inappropriate insulin secretion. The normal insulin response to tolbutamide indicated that heterozygosity for the V187D mutation did not impair K(ATP) channel function. CONCLUSIONS: We conclude that the heterozygous carriers of the SUR1 mutation had normal glucose metabolism and insulin secretion, indicating that carriers of recessive K(ATP) channel mutations are unlikely to be at an increased risk of hypoglycemia or other disturbances in glucose metabolism.

ATP-Binding Cassette Transporters↗
PubMed1995

Squamous cell carcinoma is highly sensitive to taxol, a possible new radiation sensitizer.

We studied the sensitivity of seven cell lines established from laryngeal carcinoma to the cytotoxic drug paclitaxel (Taxol) in vitro. In all four cell lines tested for growth inhibition, paclitaxel reduced growth at low concentrations, and in two cell lines growth was completely inhibited at a paclitaxel concentration of only 1 x 10(-8) M. Flow cytometric data showed a G2/M block in all seven cell lines after exposure to paclitaxel for 24 h at a concentration of 1 x 10(-8) M. This concentration is about one-one hundredth fold smaller than those measured in serum after a single intravenous dose of about 200 mg/m2. The high in vitro sensitivity of laryngeal cancer cell lines to paclitaxel,and the G2/M block suggest that the drug may potentially be used in conjunction with radiotherapy.

Carcinoma, Squamous Cell↗
PubMed1993

Two different histamine-sensitizing activities of pertussis vaccine observed in mice on the 4th and 12th days of sensitization.

The histamine-sensitizing (HS) activities of commercial precipitated diphtheria-tetanus-purified pertussis combined vaccines (DTP) submitted to the national quality control tests during the period from 1980 to 1991 were measured in mice on days 4 (EHS) and 12 (LHS) of sensitization. Annual averages of the EHS activity of the vaccines showed continuous decline during the period, while the LHS activity stayed unchanged except for 1990 and 1991. Correlation analysis between these two HS activities revealed that the vaccines could be differentiated into two groups, those showing a significant correlation and those lacking it, depending on their source manufacturers. When the vaccine was incubated at 37 C for four weeks, both the HS activities increased for the first couple of weeks at different rates, reaching their peaks after different periods; three weeks for the EHS activity and two weeks for the LHS activity. Treating the reference pertussis vaccine (for toxicity tests) with anti-pertussis toxin horse serum neutralized completely the EHS activity but the LHS activity resisted the serum. These findings suggest a possible difference between the two HS activities in their mode of action, therefore, in their roles in possible reactogenicity of the vaccine, and a necessity for separate controls of the two activities.

Animals↗
PubMed1976

[Study of temperature-sensitive mutations in the virilis group of Drosophila. 4. Phenogenetics of a temperature-sensitive mutation affecting the development of imaginal discs in Drosophila virilis Sturt].

The phenogenetics of a new temperature-sensitive mutation diskless-ts (dl-ts, 2nd chromosome) has been studied in D. virilis. The rearing of larvae from the 1st instar at the temperature 31 degrees resulted in the complete or partial arrest of the development of imaginal discs and, consequently, the death of larvae prior to the pupation, at the prepupa stage. The change of temperature from 25 to 31 degrees during the second half of development in the 3rd instar affects the differentiation of imaginal discs. Some organs differentiate completely or partially (eyes, wings, legs) whereas the rest do not develop at all. The sensitive period embraces the whole larval development till the beginning of pupation.

Animals↗
PubMed2000

Inhibitor sensitivity of human serum and vascular semicarbazide-sensitive amine oxidases.

Recent data suggest that elevated serum semicarbazide-sensitive amine oxidase activity (SSAO) may cause endothelial injury. Formation of cytotoxic metabolites (especially formaldehyde) and increased oxidative stress might lead to initiation or progression of atherosclerosis. Effective and selective inhibitors of human SSAO might exert cytoprotective effect on endothelial cells. To compare the inhibitor sensitivity of human serum and vascular tissue SSAO enzyme, the inhibitory effect of semicarbazide and MDL 72974A was investigated. Serum and vascular SSAO activity has been determined using 14C-benzylamine as a substrate. The IC50 values of semicarbazide were estimated to be 5x10(-3) M and 5x10(-4) M for SSAO from human serum and saphenous vein, respectively. MDL 72974A amine oxidase inhibitor was more than thousand times more effective than semicarbazide. The IC50 values were 10(-7) M and 10(-8) M for SSAO from human serum and saphenous vein, respectively. This finding supports the hypothesis that soluble and membrane-bound vascular SSAO enzymes might have similar structure.

Allyl Compounds↗