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We investigated the three parameters (mu, sigma, tau) of ex-Gaussian distribution of RT derived from the Conners' continuous performance test (CCPT) and examined the moderating effects of the energetic factors (the inter-stimulus intervals (ISIs) and Blocks) among these three parameters, especially tau, an index describing the positive skew of RT distribution. We assessed 195 adolescents with DSM-IV ADHD, and 90 typically developing (TD) adolescents, aged 10-16. Participants and their parents received psychiatric interviews to confirm the diagnosis of ADHD and other psychiatric disorders. Participants also received intelligence (WISC-III) and CCPT assessments. We found that participants with ADHD had a smaller mu, and larger tau. As the ISI/Block increased, the magnitude of group difference in tau increased. Among the three ex-Gaussian parameters, tau was positively associated with omission errors, and mu was negatively associated with commission errors. The moderating effects of ISIs and Blocks on tau parameters suggested that the ex-Gaussian parameters could offer more information about the attention state in vigilance task, especially in ADHD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

BRL 34915 (4-64 X 10(-7) M), isoprenaline (0.5-32 X 10(-8) M) and nicorandil (4-64 X 10(-6) M) produced a slowly-developing relaxation of spontaneous tone of the guinea-pig taenia caeci; with no after-contraction on washout. These inhibitory responses were unaffected by apamin (10(-7) M). Adenosine triphosphate (0.06-2 X 10(-3) M) and noradrenaline (1-16 X 10(-7) M) produced a rapid inhibition of spontaneous tone with a prominent after-contraction, especially on washout. Both the inhibitory effect and the rebound contraction were abolished by apamin (10(-7) M). Exposure to both BRL 34915 (64 X 10(-7) M) and to nicorandil (64 X 10(-6) M) produced an increase in the 86Rb efflux rate coefficient which was unaffected by apamin (10(-7) M). Exposure to isoprenaline (32 X 10(-8) M) had no effect on the 86Rb efflux rate coefficient. Exposure to noradrenaline (16 X 10(-7) M) produced an increase in the 86Rb efflux rate coefficient which was abolished by apamin (10(-7) M). The results confirm that both BRL 34915 and nicorandil are capable of opening potassium channels in smooth muscle but show that the channel is not apamin-sensitive.

1. Contractile responses of rabbit aortic rings elicited by KCl-depolarization, angiotensin II (AII), 5-hydroxytryptamine (5-HT) and noradrenaline (NA) have been investigated in the presence of cromakalim (BRL 34915) and isradipine (PN 200-110). 2. Above 10(-6)M, cromakalim inhibited contractile responses to low (less than or equal to 32 mM) but not to higher KCl concentrations. The 5-HT and AII concentration-response curves were antagonized noncompetitively by cromakalim (10(-7)-10(-5)M) and the maximal responses were inhibited by 40 and 55%, respectively. 3. Isradipine caused less inhibition of AII and 5-HT contractile responses than cromakalim, and in the presence of isradipine (10(-7)M), cromakalim was still able to antagonize further the contractions to AII in this vessel. 4. NA-induced contractions were relatively insensitive to inhibition by cromakalim and isradipine, both drugs causing a small rightward shift of the NA concentration-response curve. This result suggests that NA utilizes different Ca2+ pools from those involved in AII- and 5-HT-induced contractions of this vessel. 5. The sustained (tonic) part of the NA response was inhibited in a concentration-dependent manner by cromakalim (10(-7)-10(-5)M), but not by isradipine. 6. In aortic rings partially depolarized with 3.5 x 10(-2)M KCl, the ability of cromakalim, but not of sodium nitroprusside, atriopeptin III or hydralazine, to inhibit AII- and tonic NA-induced contractions was abolished. 7. Antivasoconstrictor activity of cromakalim on the rabbit aorta appears to involve factors in addition to an indirect inhibition of Ca2+ entry through dihydropyridine-sensitive Ca2+ channels. 8. The ability of cromakalim to open K+ channels and thereby modify the membrane potential would appear to underlie these antivasoconstrictor effects. This mechanism of action of cromakalim clearly differs from that of other vasodilators such as sodium nitroprusside and hydralazine.

Trilostane, a competitive inhibitor of the 3 beta-hydroxysteroid dehydrogenase enzyme system, has adrenal blocking activity and has been used to treat Cushing's syndrome and other disease. To investigate is effect on the normal human hypothalamic-pituitary-testicular axis, trilostane (initially 240 mg/day) was given to ten healthy adult males, the dose increasing at weekly intervals by 240 mg/day up to 960 mg/day. When chromatography was used to remove trilostane and metabolites from the assay system, serum testosterone was found to fall on trilostane therapy (P less than 0.01) and this was accompanied by a rise in LH (P less than 0.01). The responses of FSH and LH to LHRH were unaffected by treatment. It is concluded that trilostane inhibits human testicular 3 beta-hydroxysteroid dehydrogenase and male patients on trilostane should be monitored for sexual dysfunction and impairment of testicular steroidogenesis.

1. The effects of fractionated Leiurus quinquestriatus hebraeus venom on cromakalim-induced 86Rb+ efflux in rabbit aortic smooth muscle were examined. 2. Crude venom (0.1-30 micrograms ml-1) produced a concentration-dependent decrease of 1 microM cromakalim-induced 86Rb+ response. The maximum blocking activity attainable was approximately 60%. 3. Fractionation of crude venom by gel permeation chromatography and subsequent chromatography on a cation ion-exchange column, produced two fractions (X and XI), active in the 86Rb+ blocking assay. 4. Fraction XII contained charybdotoxin (approximately 85% pure). After a final high performance liquid chromatography (h.p.l.c.) purification step, the purified toxin failed to inhibit the cromakalim-stimulated 86Rb+ efflux although it was a potent inhibitor of A23187-induced K+ flux in human erythrocytes and the large conductance calcium-activated potassium channel in rabbit portal vein smooth muscle. 5. Subsequent purification of fraction X by h.p.l.c. yielded a minor peak which contained 86Rb+ blocking activity. This subfraction was also capable of inhibiting apamin-sensitive, angiotensin II-stimulated K+ flux in guinea-pig hepatocytes. 6. It is concluded that the potassium channel opened by cromakalim in rabbit aortic smooth muscle is not blocked by charybdotoxin but by another distinct toxin in the venom of Leiurus quinquestriatus hebraeus.

A comparison has been made of methods utilizing LaCl3 or EGTA for the determination of changes in Ca2+ influx into vascular smooth muscle. Stimulation of 45Ca2+ influx through voltage-operated channels using KCl and blockade of this effect with verapamil were used as test stimuli. Satisfactory results were obtained using ice-cold, Ca2+-free wash solutions containing LaCl3 (10-80.8 mmole.l-1). To achieve a rate of 45Ca2+ exchange of approximately 1% min-1, a wash duration of 60-90 min, depending on the tissue, was necessary. Using an EGTA wash less 45Ca2+ was retained by the tissue and the rate of 45Ca2+ exchange was greater than when LaCl3 was used. However, the changes in 45Ca2+ influx produced by the test stimuli and detected following an EGTA wash were qualitatively similar to those obtained when LaCl3 was used.

The experiments were undertaken to determine whether the effects of the K+ channel opener BRL 34915 on rat isolated vascular smooth muscle and atria were sensitive to pertussis toxin (PTx). PTx treatment of rats (100 micrograms/kg, infused over 15 min) affected some baseline parameters of the isolated tissues: in the atria, heart rate was increased, contractile force was decreased and the basal efflux of 86Rb+ was increased; in portal veins, the spontaneous activity was decreased but the contractility of aortic rings was unaffected. In the isolated atria removed from saline-treated rats, carbamylcholine decreased heart rate and contractile force, shortened the action potential duration by increasing the maximum rate of repolarization and increased 86Rb+ efflux. These effects of carbamylcholine were completely abolished in the atria from PTx-treated rats, demonstrating the efficacy of the toxin. The ability of 300 microM BRL 34915 and of 55 mM KCl to increase atrial 86Rb+ permeability was, however, only slightly affected by PTx treatment. In portal veins from PTx-treated rats, the efficacy of BRL 34915 to inhibit spontaneous activity and to increase 86Rb+ efflux was the same as in control organs. Similarly, in aortic rings, the ability of BRL 34915 to inhibit contractions to low concentrations of KCl or to noradrenaline was unaffected by PTx treatment as was the 86Rb+ efflux response to BRL 34915 in this tissue. It is concluded that PTx treatment does not inhibit the effects of BRL 34915 in the tissues investigated. The results are compatible with the notion that BRL 34915 does not open K+ channels by acting through a PTx-sensitive G-protein.

The effects of the novel anti-hypertensive agent BRL 34915, (+/-) 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl)-2H-b enzo[b]pyran-3-ol, have been compared with those of verapamil on rat isolated portal vein. BRL 34915 produced a concentration-dependent reduction in mechanical responses to noradrenaline but had relatively little inhibitory effect on K+-induced contractions. Verapamil reduced the magnitude of both noradrenaline and K+-induced mechanical responses. BRL 34915 delayed the appearance of the reduced noradrenaline contractions, a property not shared by verapamil. BRL 34915 abolished spontaneous electrical and mechanical discharges and hyperpolarized the portal vein cells close to their calculated potassium equilibrium potential. Verapamil inhibited spontaneous electrical and mechanical discharges, effects associated with a small depolarization. BRL 34915 produced a significant increase in the 86Rb efflux rate coefficient whilst verapamil was without effect on this parameter. The inhibitory effects of BRL 34915 were rapid in onset and readily reversible by washing, whilst those of verapamil were slower in onset and only slowly reversible. It is concluded that the inhibitory effects of BRL 34915 in rat portal vein are produced by the opening of potassium channels in the smooth muscle cells. This inhibits spike activity and in sufficient concentration holds the membrane potential at or close to the potassium equilibrium potential, thereby reducing the effects of excitatory agents.

The effects of the antihypertensive agent BRL 34915 on a variety of responses of the aorta and portal vein of the rat have been compared with those of nicorandil. On portal vein, BRL 34915 (0.01-50 X 10(-6) M) and nicorandil (0.1-500 X 10(-6) M) abolished spontaneous mechanical activity and reduced mechanical responses to noradrenaline (0.1-100 X 10(-6) M) and K+ (5-20 X 10(-3) M) but had little inhibitory effect on responses to K+ (40-80 X 10(-3) M). The onset of the reduced responses to noradrenaline was delayed by both agents. On portal vein, BRL 34915 (0.1-50 X 10(-6) M) and nicorandil (0.5-500 X 10(-6) M) abolished spontaneous electrical and mechanical activity, hyperpolarized the smooth muscle cells to a value close to their calculated potassium equilibrium potential and increased the 86Rb efflux rate coefficient. On aorta, BRL 34915 (0.2-0.8 X 10(-6) M) and nicorandil (8-32 X 10(-6) M) reduced mechanical responses to noradrenaline (0.001-1 X 10(-6) M) and K+ (5-20 X 10(-3) M) but had little inhibitory effect on responses to K+ (40-80 X 10(-3) M). On aorta, BRL 34915 (0.2-0.8 X 10(-6) M) increased the 86Rb efflux rate coefficient whereas nicorandil (8-32 X 10(-6) M) was without effect. It is concluded that the inhibitory actions of BRL 34915 on both aorta and portal vein result from the opening of membrane potassium channels. The resulting membrane shunt inhibits the effects of excitatory agents. The inhibitory effects of nicorandil result from a combination of the opening of potassium channels together with an additional, undefined action.

The effects of pinacidil have been compared with those of glyceryl trinitrate (GTN) using the aorta and portal vein of the rat and the trachealis and taenia caeci of the guinea-pig. In aorta, both pinacidil and GTN inhibited responses to noradrenaline and showed some selective inhibition of contractions to 20 mM K+. Responses to 80 mM K+ were little affected. In trachealis, both pinacidil and GTN inhibited spontaneous tone and selectively relaxed spasms to 20 mM K+. Responses to 80 mM K+ were unaffected. In portal vein, pinacidil completely inhibited spontaneous electrical and mechanical activity. GTN reduced the amplitude of tension waves and extracellularly-recorded discharges, but increased the frequency of spontaneous electrical and mechanical activity. In portal vein, pinacidil inhibited contractions to noradrenaline and selectively inhibited responses to 20 mM K+. GTN had little inhibitory effect on responses to either noradrenaline or K+. In portal veins loaded with 86Rb as a K+-marker, pinacidil significantly increased the 86Rb efflux rate coefficient whilst GTN had no effect on 86Rb exchange. In taenia caeci, both pinacidil and GTN inhibited the spontaneous tone of the preparation. These inhibitory effects were not antagonized by apamin. It is concluded that pinacidil and GTN do not share a common relaxant mechanism. Evidence has been obtained that pinacidil exerts its inhibitory effects by the opening of apamin-insensitive, 86Rb-permeable K+ channels.

The effects of noradrenaline (NA, 10(-5) M) and [arginine8]vasopressin (AVP, 10(-7) M) on tension in Ca2+-free medium and on membrane potential, and the inhibition of NA- and AVP-induced contractions by isradipine, have been compared in mesenteric resistance vessels (MRVs) from Wistar-Kyoto (WKY) rats. The release of intracellular Ca2+ by AVP contributed significantly less to its tension development than does that by NA. Nonetheless, the concentration-response curves for inhibition by isradipine of NA- and AVP-induced tonic tension were nearly identical. Similarly, these two agonists produced the same degree of membrane depolarization. In addition, both agonists were able to stimulate large contractions in vessels previously depolarized by 80 mM K+. AVP also stimulated 45Ca influx into rat cultured aortic smooth muscle cells. In contrast to the stimulation of 45Ca influx by KCl depolarization, the agonist-stimulated 45Ca influx was insensitive to inhibition by organic Ca2+ antagonists. It is concluded that Ca2+ entry through receptor-operated Ca2+-permeable channels (ROCs) may contribute to agonist-induced activation of rat aortic and MRV smooth muscle.

The effects of noradrenaline (NA) on rat, rabbit, and human mesenteric resistance vessels (MRVs) in Ca2+-free medium have been compared. The maximum tension obtained in the absence of extracellular Ca2+ is least and is lost most rapidly with time in the MRVs from rabbit, followed by those from Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), Sprague-Dawley (SD) rats, and from humans. Hence, it seems that the utilization of intracellular Ca2+ during activation of human MRVs by NA may be more substantial than has been found in the animal models. Nonetheless, in studies of the effects of isradipine on NA-induced tension, the human MRVs are similarly sensitive to the effects of this Ca2+ antagonist as WKY rat MRVs have been shown to be. All these resistance vessels, therefore, present quite a contrast to large vessels from rabbit, such as aorta, wherein the utilization of intracellular Ca2+ for NA-induced contraction is far more substantial, and the sensitivity of NA-induced contractions to Ca2+ antagonists is orders of magnitude less than in the MRVs. The basis for high sensitivity of rat and rabbit MRVs to Ca2+ antagonists may lie, at least in part, in the fact that these vessels (from rabbit and rat) depolarize in response to NA from approximately -50 to -30 mV, while aorta (from rabbit) does not, and the affinities of Ca2+ antagonists for voltage-sensitive Ca2+ channels (VSCs) are known to be voltage-dependent. Finally, the effects of the putative K+ channel opener BRL 34915 in rat MRVs appear to involve two sites of action, one with a lower affinity (K1 approximately 0.1 microM), similar to that shown previously in rat aorta, and a second with a higher affinity (K1 approximately 0.01 nM). In summary, these studies provide further evidence that Ca2+ handling processes controlled by both intracellular organelles and by the plasma membrane differ in mesenteric resistance vessels from those in aorta and in other large arteries.

Experiments were undertaken to examine the ability of selenium to protect against acetaminophen-induced hepatotoxicity and to examine possible mechanisms for this protective effect. Pretreatment of male, Sprague-Dawley rats with sodium selenite (12.5 mumol Se/kg, ip) 24 hr prior to acetaminophen administration produced a significant protection against the hepatotoxic effects of acetaminophen as assessed by a decrease in the plasma appearance of alanine aminotransferase and aspartate aminotransferase activities following acetaminophen. This was accompanied by an increase in the hepatic glutathione levels in selenium-treated animals and an inhibition in the decrease in hepatic glutathione content observed in animals receiving hepatotoxic doses of acetaminophen. Selenium pretreatment decreased the in vivo covalent binding of acetaminophen metabolites to hepatic protein, but did not alter hepatic microsomal cytochrome P-450 content or NADPH cytochrome c reductase activity, suggesting that selenium does not significantly alter the metabolism of acetaminophen to reactive electrophilic metabolites by the cytochrome P-450-dependent mixed-function oxidase enzyme system. Selenium produced an increase in the activity of gamma-glutamylcysteine synthetase which may account for the increased glutathione availability in selenium-treated animals and increased the activities of glutathione S-transferase and glucose-6-phosphate dehydrogenase. Examination of the urinary metabolite profile in selenium-treated animals revealed that the urinary excretion of acetaminophen and its metabolites was significantly increased over a 72-hr period. The increase occurred in the AAP-glucuronide metabolite while parent AAP and AAP-sulfate were actually decreased in selenium-treated rats. No change in recovery was observed in the AAP-glutathione or AAP-mercapturate urinary metabolites. While the glutathione conjugating system is enhanced by selenium treatment, amelioration of acetaminophen toxicity is most likely the result of enhanced glucuronidation which effectively diverts the amount of acetaminophen to be converted by the cytochrome P-450 system to the toxic metabolite.