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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We tested the hypothesis that relaxation of the carotid artery during hypoxia is mediated by activation of glibenclamide-sensitive potassium channels and that this response is impaired in hyperlipidemic rabbits. In New Zealand White rabbits (plasma cholesterol, 69 +/- 12 mg/dL, mean +/- SEM) and Watanabe heritable hyperlipidemic (WHHL) rabbits (plasma cholesterol, 677 +/- 99 mg/dL), tension of the carotid artery was measured in an organ bath under control conditions and during two levels of hypoxia. In normal rabbits, mild hypoxia produced 21 +/- 2% relaxation in arteries precontracted with phenylephrine. Removal of endothelium or the nitric oxide synthase inhibitor NG-nitro-L-arginine (10(-4) mol/L) almost abolished relaxation in response to mild hypoxia in normal rabbits. Glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive potassium channels, attenuated relaxation during mild hypoxia by almost 60%. In WHHL rabbits mild hypoxia relaxed the carotid artery by only 9 +/- 4% (P < .05 versus normal rabbits). Severe hypoxia produced greater relaxation of the carotid artery in normal than in WHHL rabbits (85 +/- 5% versus 52 +/- 8%, respectively, P < .05). Glibenclamide but not endothelial denudation or NG-nitro-L-arginine attenuated relaxation during severe hypoxia in normal and WHHL rabbits. Relaxation of the carotid artery to sodium nitroprusside was similar in normal and WHHL rabbits. These findings suggest that relaxation of the carotid artery in response to mild and severe hypoxia is impaired in WHHL rabbits and is mediated, in large part, by activation of glibenclamide-sensitive potassium channels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relaxation of the carotid artery to hypoxia is impaired in Watanabe heritable hyperlipidemic rabbits. 758 38

The role of ATP-sensitive potassium channels (KATP) in the mechanism of ischemic preconditioning (PC) is controversial, partly because descriptions of inhibition of PC by KATP blockers in the literature are inconsistent. We sought a reason for the discrepant findings regarding the effects of glibenclamide (Glib), a specific blocker of KATP, in preventing the reduction of infarct size (IS) induced by PC. The effect of Glib pretreatment (0.3 mg/kg i.v.) on PC was examined in three conditions: (a) when PC was performed with 3- and 5-min ischemia (i.e., potency of PC differs), (b) when rabbits were pretreated with prazosin and metoprolol (0.15 mg/kg i.v. each) to reduce myocardial O2 consumption, and (c) when xylazine was added to pentobarbital anesthesia. In rabbits under pentobarbital anesthesia, the left coronary artery was occluded for 30 min and then reperfused. The area at risk (AAR) and IS were determined 72 h after reperfusion in the first series of experiments and 3 h after reperfusion in the second and third series. IS as a percentage of AAR (%IS/AR) were 31.7 +/- 2.8 and 19.6 +/- 2.5% (SEM) after PC with 3- and 5-min ischemia, respectively, values significantly smaller than %IS/AR in the untreated control group (49.2 +/- 3.3%). The limitation of IS observed with 3- or 5-min PC was not prevented by Glib. Glib also failed to block %IS/AR reduction by PC, even when rate-pressure product (RPP) was reduced to approximately 65% by prazosin/metoprolol (Praz/Met) pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glibenclamide, a blocker of ATP-sensitive potassium channels, abolishes infarct size limitation by preconditioning in rabbits anesthetized with xylazine/pentobarbital but not with pentobarbital alone. 759 19

The role of Ca(2+)-dependent potassium channels in mediating vascular responses to activation of adenylate cyclase in vivo is not known. The goal of this study was to examine the hypothesis that dilatation of cerebral arterioles in response to activation of adenylate cyclase is mediated by activation of Ca(2+)-dependent potassium channels. Diameters of cerebral arterioles were measured in vivo in anesthetized rabbits. Topical application of forskolin (1 and 10 mumol/L), a direct activator of adenylate cyclase, dilated cerebral arterioles by 40 +/- 8% (mean +/- SEM) and 71 +/- 9%, respectively, from a control diameter of 85 +/- 4 microns. Iberiotoxin (50 and 100 nmol/L), a selective inhibitor of Ca(2+)-dependent potassium channels, inhibited dilatation in response to both concentrations of forskolin by 45% to 60%. We obtained similar results by using charybdotoxin (50 nmol/L), another inhibitor of Ca(2+)-dependent potassium channels. Vasodilatation in response to dibutyryl cAMP (a cell-permeable cAMP analogue) was also inhibited by iberiotoxin. In contrast, dilatation of cerebral arterioles in response to sodium nitroprusside and acetylcholine (activators of guanylate cyclase) and aprikalim (activator of ATP-sensitive potassium channels) was not inhibited by iberiotoxin. These findings suggest that dilatation of cerebral arterioles in response to forskolin and increases in intracellular concentrations of cAMP are mediated by activation of Ca(2+)-dependent potassium channels. Thus, activation of Ca(2+)-dependent potassium channels may be a major mechanism of cerebral vasodilatation in response to activation of adenylate cyclase in vivo.
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PMID:Dilatation of cerebral arterioles in response to activation of adenylate cyclase is dependent on activation of Ca(2+)-dependent K+ channels. 775 60

We investigated the role of ATP in the active efflux of doxorubicin (DOX) mediated by P-glycoprotein (P-gp), the multidrug-resistance (MDR) gene product, at the blood-brain barrier. In transient brain ischemic rats prepared with 4-vessel occlusion of vertebral and common carotid arteries for 20 min, a procedure that depleted their brain ATP content to 3% that of normal rats, the estimated permeability coefficient of DOX was increased 17-fold (to 243 +/- 2.5 microL/min/g brain). When the ATP content recovered to a normal level by means of 30-min and 24-hr cerebral recirculation of blood, the permeability coefficient recovered to 14.0 +/- 5.0 and 18.4 +/- 2.3 microL/min/g brain (mean +/- SEM, N = 3-6), respectively, very close to the control permeability (14.3 +/- 1.5 microL/min/g brain). The uptake of DOX by primary cultured brain capillary endothelial cells expressing P-gp at the luminal membrane was increased significantly (up to 2-fold), which correlated well with the decrease of cellular ATP contents caused by treating the cells with metabolic inhibitors. Evidence for the ATP-dependent transport of DOX obtained from the present in vivo and in vitro studies strongly indicates that P-gp in the brain capillaries functions actively as an efflux pump in the physiological state, providing a major mechanism to restrict the transfer of DOX into the brain.
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PMID:In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier. 776 97

The injury and recovery processes of complex reactions of liver mitochondrial ATP synthesis during warm ischemia and after reflow were studied separately in terms of the changes in oxidation (electron transfer system) and phosphorylation (H(+)-ATPase). Oxidative activity decreased significantly from the control value of 40 +/- 0.9 (mean +/- SEM, n = 5) to 31.5 +/- 1.13 (nanoatoms oxygen consumed/min/mg protein) after 40 min of warm ischemia, while phosphorylative activity decreased significantly from the control value of 1.06 +/- 0.12 to 0.42 +/- 0.03 (mumole ATP hydrolyzed/min/mg protein) after 20 min of warm ischemia. During 120 min of reflow after 20 min of warm ischemia, the decreased phosphorylation activity recovered to 0.52 +/- 0.01 concomitant with a recovery of intramitochondrial total adenine nucleotide and an increase in the ATP/ADP ratio, while oxidative activity decreased further to 23.9 +/- 0.81. These results indicate that H(+)-ATPase is more vulnerable to warm ischemia than the electron transfer system, but that it is restored concomitant with the recovery of intramitochondrial adenine nucleotide content.
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PMID:Primary and reversible injury of H(+)-ATPase in warm ischemia and reperfusion of rat liver in relation to intramitochondrial adenine nucleotide. 786 69

cAMP is commonly measured using either immunoassay or high-performance liquid chromatography. The current methods are sensitive but may lack versatility and be expensive; also, radioactivity is potentially harmful to the operator and environment. Given these concerns, we developed a highly sensitive enzymatic fluorometric assay for cAMP. The method consists of five steps: (1) destruction of interfering compounds with apyrase, 5' nucleotidase, adenosine deaminase, and alkaline phosphatase; (2) conversion of cAMP to AMP; (3) conversion of AMP to ATP; (4) amplification of ATP by ATP-ADP cycling; and (5) fluorometric measurement of resultant NADPH. cAMP was measured in male Sprague Dawley rats anesthetized with pentobarbital. Stimulated rats (n = 4) received isoproterenol (16 micrograms/kg, s.q.) and aminophylline (20 mg/kg, s.q.), whereas controls (n = 4) received no additional drug. With the enzymatic fluorometric assay, cAMP content in heart, liver, and kidney (pmol/mg wet wt, mean +/- SEM) was 0.34 +/- 0.03, 0.33 +/- 0.03, and 0.92 +/- 0.11 in the control group and 0.77 +/- 0.10, 0.66 +/- 0.04, and 1.53 +/- 0.12 in the stimulated group, respectively. The total assay duration including sample reading procedure varied at 4.5-9.5 hr, depending on its sensitivity. cAMP from the same samples was measured using a commercially available enzyme immunoassay kit and was found to be very similar to the enzymatic fluorometric assay. We conclude that this new assay is sensitive, safe, versatile, and inexpensive and can be used to measure cAMP in multiple types of tissue, including biopsy samples weighing < 200 micrograms.
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PMID:Enzymatic fluorometric assay for tissue cAMP. 786 85

Binding to PTH to its cell surface receptor activates both adenylyl cyclase and phospholipase-C, leading to elevation of cytosolic cAMP and free Ca2+. We have shown previously that extracellular nucleotides interact with P2U and P2Y subtypes of purinoceptor on osteoblastic cells, both linked to Ca2+ mobilization. In the present study, we investigated possible interactions between nucleotide and PTH signaling pathways in osteoblastic cells. The cytosolic free Ca2+ concentration ([Ca2+]i) of UMR-106 osteoblastic cells was monitored by fluorescence spectrophotometry. PTH (0.01-1 microM; bovine 1-84 or human 1-34) induced a small transient elevation of [Ca2+]i, lasting less than 1 min. A number of nucleotides, including ATP, UTP, and UDP, induced transient elevation of [Ca2+]i and potentiated the subsequent Ca2+ response to PTH. Of the nucleotides tested, UDP was the most effective at potentiating the PTH-induced Ca2+ transient. Treatment of cells with UDP (100 microM for 2.5 min), but not inorganic phosphate or uridine, reversibly potentiated the Ca2+ response to PTH (0.1 microM) by 11 +/- 2-fold (mean +/- SEM; n = 39). In contrast, UDP did not affect the cAMP response to PTH, indicating a selective action on Ca2+ signaling. Potentiation of the Ca2+ signal was still observed in the absence of extracellular Ca2+, establishing that nucleotides enhance PTH-induced release of Ca2+ from intracellular stores. Studies using selective purinoceptor agonists suggest that potentiation of PTH signaling is mediated by the P2U receptor subtype. In vivo, nucleotides released during trauma or inflammation may modulate PTH-induced Ca2+ signaling in osteoblasts.
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PMID:Extracellular nucleotides potentiate the cytosolic Ca2+, but not cyclic adenosine 3', 5'-monophosphate response to parathyroid hormone in rat osteoblastic cells. 789 78

The effect of hypoglycaemic, hypoxic, and ischaemic conditions on high-affinity neurotransmitter transport was studied in the human astrocytoma clone D384 and the human neuroblastoma clone SH-SY5Y. Both cell lines expressed a sodium-dependent glutamate/aspartate transporter. Km values for D-[3H]aspartate uptake were 6.1 +/- 0.9 microM for D384 cells and 5.3 +/- 0.3 microM for SH-SY5Y cells (mean +/- SEM of three experiments). In addition, SH-SY5Y, but not D384, expressed a sodium-dependent noradrenaline transporter with Km = 0.6 +/- 0.1 microM (mean +/- SEM of three experiments). Up to 3 h of hypoglycaemic conditions had no effect on neurotransmitter uptake or on ATP levels of each cell line. In sharp contrast, during hypoxic conditions, the uptake of D-[3H]-aspartate and [3H]noradrenaline declined by 43-56% within 5 min. These reduced rates of neurotransmitter uptake were maintained over 30 min of hypoxic conditions. Five minutes of ischaemic conditions caused similar reductions in neurotransmitter uptake rates. A correlation between reductions in rates of neurotransmitter uptake and in ATP levels was observed for each cell line. Results are discussed in relation to other brain preparations, which are used as models of the nervous system to study the effects of ischaemic conditions on neurotransmitter and energy metabolism.
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PMID:Effects of ischaemic conditions on uptake of glutamate, aspartate, and noradrenaline by cell lines derived from the human nervous system. 791 90

To investigate the dynamic control of cardiac ATP synthesis, we simultaneously determined the time course of mitochondrial oxygen consumption with the time course of changes in high-energy phosphates following steps in cardiac energy demand. Isolated isovolumically contracting rabbit hearts were perfused with Tyrode's solution at 28 degrees C (n = 7) or at 37 degrees C (n = 7). Coronary arterial and venous oxygen tensions were monitored with fast-responding oxygen electrodes. A cyclic pacing protocol in which we applied 64 step changes between two different heart rates was used. This enabled nuclear magnetic resonance measurement of the phosphate metabolites with a time resolution of approximately 2 seconds. Oxygen consumption changed after heart-rate steps with time constants of 14 +/- 1 (mean +/- SEM) seconds at 28 degrees C and 11 +/- 1 seconds at 37 degrees C, which are already corrected for diffusion and vascular transport delays. Doubling of the heart rate resulted in a significant decrease in phosphocreatine (PCr) content (11% at 28 degrees C, 8% at 37 degrees C), which was matched by an increase in inorganic phosphate (P(i)) content, although oxygen supply was shown to be nonlimiting. The time constants for the change of both P(i) and PCr content, approximately 5 seconds at 28 degrees C and 2.5 seconds at 37 degrees C, are significantly smaller than the respective time constants for oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardiac high-energy phosphates adapt faster than oxygen consumption to changes in heart rate. 792 20

Several studies of phosphorus 31 (31P) magnetic resonance spectroscopy (MRS) have demonstrated the presence of skeletal muscle metabolic abnormalities during exercise in patients with chronic heart failure (CHF). We studied the contribution of these abnormalities to the limitation of exercise capacity in CHF. In 25 patients (age 57 +/- 2 years, left ventricular ejection fraction [LVEF] 28% +/- 1.6%, peak oxygen consumption (VO2) 16 +/- 1.2 ml/kg/mm) (mean +/- SEM), we studied the calf muscle at rest and during plantar flexion with 31P MRS. The phosphocreatine (PCr) depletion rate was significantly negatively correlated to peak VO2 (r = -0.62, p = 0.001) but not to LVEF. Muscle pH was correlated with the inorganic phosphorus (Pi)/PCr ratio (r = -0.69, p = 0.0001) and with the PCr/adenosine triphosphate beta (ATP beta) ratio (which negatively relates to adenosine diphosphate [ADP] concentration) (r = 0.65, p = 0.00001). Although muscle ATP (ATP/sum of phosphorus [sigma P] remained stable, in 8 patients ATP/sigma P decreased significantly (-15% +/- 4%, p = 0.0002). In this ATP-depleted group, peak VO2 was significantly lower than that of the nondepleted group and PCr depletion more rapid, whereas LVEF did not differ. Skeletal muscle metabolic abnormalities in CHF contribute markedly to the alteration of exercise capacity. Rapid PCr depletion and muscle acidosis are the most relevant abnormalities. ATP depletion and excessive increase in ADP during exercise may contribute further to exercise limitation specifically in patients with more marked CHF.
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PMID:Contribution of specific skeletal muscle metabolic abnormalities to limitation of exercise capacity in patients with chronic heart failure: a phosphorus 31 nuclear magnetic resonance study. 794 49


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