Drugs online research references
J Cereb Blood Flow Metab. 2001 Apr;21(4):385-95.
Ionic mechanisms of aglycemic axon injury in mammalian central white matter.
Brown AM, Wender R, Ransom BR.
Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
The authors investigated ionic mechanisms underlying aglycemic axon injury in adult rat optic nerve, a central white matter tract. Axon function was assessed using evoked compound action potentials (CAPs). Glucose withdrawal led to delayed CAP failure, an alkaline extracellular pH shift, and an increase in extracellular [K(+)]. Sixty minutes of glucose withdrawal led to irreversible axon injury. Aglycemic axon injury required extracellular calcium; the extent of injury progressively declined as bath [Ca(2+)] was decreased. To evaluate Ca(2+) movements during aglycemia, the authors recorded extracellular [Ca(2+)] ([Ca(2+)](o)) using Ca(2+)-sensitive microelectrodes. Under control conditions, [Ca(2+)](o) fell with a similar time course to CAP failure, indicating extracellular Ca(2+) moved to an intracellular position during aglycemia. The authors quantified the magnitude of [Ca(2+)]o decrease as the area below baseline [Ca(2+)]o during aglycemia and used this as a qualitative measure of Ca(2+) influx. The authors studied the mechanisms of Ca(2+) influx. Blockade of Na(+) influx reduced Ca(2+) influx and improved CAP recovery, suggesting Na(+)-Ca(2+) exchanger involvement. Consistent with this hypothesis, bepridil reduced axon injury. In addition, diltiazem or nifedipine decreased Ca(2+) influx and increased CAP recovery. The authors conclude aglycemic central white matter injury is caused by Ca(2+) influx into intracellular compartments through reverse Na(+)-Ca(2+) exchange and L-type Ca(2+) channels.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11323524&dopt=Abstract
Mol Pharmacol. 2001 Jun;59(6):1433-40.
Nephrotoxicants induce endothelin release and signaling in renal proximal tubules: effect on drug efflux.
Terlouw SA, Masereeuw R, Russel FG, Miller DS.
Department of Pharmacology/Toxicology, University Medical Centre Nijmegen, 6500 HB Nijmegen, The Netherlands.
We previously used killifish proximal tubules, fluorescent substrates, and confocal microscopy to demonstrate that transport mediated by the multidrug resistance protein (Mrp2) and by P-glycoprotein was reduced by nanomolar concentrations of endothelin-1 (ET), acting through a basolateral B-type ET receptor and protein kinase C (PKC). Here we show that representatives of two classes of nephrotoxicants decrease transport by activating the endothelin-PKC signaling pathway. Exposing tubules to radiocontrast agents (iohexol, diatrizoate) or aminoglycoside antibiotics (gentamicin, amikacin) reduced Mrp2-mediated fluorescein methotrexate (FL-MTX) transport from cell to tubular lumen. Pretreating the tubules with an ET(B)-receptor antagonist or with PKC-selective inhibitors abolished these effects. The nephrotoxicants activated signaling by inducing release of ET from the tubules, because adding of an antibody against ET to the medium abolished the effects. Elevating medium Ca(2+) also reduced FL-MTX transport; this reduction was abolished when tubules were pretreated with an ET antibody, an ET(B)-receptor antagonist, PKC-selective inhibitors, or the Ca(2+) channel blocker, nifedipine. None of these drugs by themselves affected FL-MTX transport. Importantly, nifedipine also blocked the ET(B)-receptor/PKC-dependent reduction in FL-MTX transport caused by gentamicin and diatrizoate. These results for two classes of structurally unrelated nephrotoxicants suggest that Ca(2+)-dependent ET release and subsequent action through an autocrine mechanism may be an early response to tubular injury.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11353803&dopt=Abstract
Acta Physiol Scand. 1990 Dec;140(4):545-55.
Contractile effects of endothelin-1 and localization of endothelin binding sites in rabbit lower urinary tract smooth muscle.
Garcia-Pascual A, Larsson B, Andersson KE.
Department of Clinical Pharmacology, University Hospital of Lund, Sweden.
In isolated rabbit bladder and urethral smooth muscle, endothelin-1 caused concentration-related, slowly developing contractions that were difficult to wash out. Relative to contractions induced by K+ (124 mM), contractions in bladder preparations reached a higher amplitude than in urethral preparations. There was a marked tachyphylaxis to the effects of the peptide. The endothelin-1-induced contractions were not significantly affected by phentolamine or indomethacin in the urethra, or by scopolamine or indomethacin in the bladder. Incubation for 30 min in a Ca2(+)-free solution abolished the endothelin-1-induced contractions. Nifedipine did not affect the actions of endothelin-1 in the urethra but had a marked inhibitory action on its effects in the bladder. In the presence of endothelin-1, Ca2(+)-induced contractions were significantly blocked by nifedipine in the bladder but not in the urethra. Urethral preparations at resting tension responded to electrical stimulation by tetrodotoxin-sensitive, frequency-dependent contractions sensitive to alpha-adrenoceptor blockade. Pretreatment with endothelin-1 (10(-9) M) produced a significant increase in the nerve-induced contractions but had no significant effect on contractions induced by exogenous noradrenaline. Endothelin-1 did not affect spontaneous or stimulation-induced efflux of 3H-labelled noradrenaline in urethral smooth muscle. Preparations contracted by endothelin-1 were frequency-dependently relaxed by electrical stimulation. The peptide had no significant effect on the responses induced by electrical stimulation in the bladder preparations. In both bladder and urethra, [125]endothelin-1 binding sites were found mainly in the outer longitudinal muscle layer, in vessels and in the submucosa. The highest density of binding sites appeared to be in vessels and the outer muscle layer in both types of muscle. The results suggest that in the rabbit both bladder and urethral smooth muscle contain binding sites for endothelin. The peptide has contractant effects dependent on extracellular calcium in both types of tissue, but voltage-operated calcium channels seem to involved in activation only of bladder smooth muscle. The functional importance of endothelin-1 in the rabbit lower urinary tract remains to be elucidated.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2082715&dopt=Abstract
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