Drugs online research references
J Pharmacol Exp Ther. 1998 Apr;285(1):9-15.
Cardiovascular pharmacology of the A2A adenosine receptor antagonist, SCH 58261, in the rat.
Monopoli A, Casati C, Lozza G, Forlani A, Ongini E.
Schering-Plough Research Institute, San Raffaele Science Park, I-20132, Milan, Italy.
We characterized the in vivo cardiovascular profile of SCH 58261, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2, 4-triazolo[1,5-c] pyrimidine, a selective A2A adenosine receptor antagonist, in conscious, freely moving rats by use of the telemetry system. In normotensive rats, SCH 58261, at 10 mg/kg i.p., significantly (P < .05) inhibited hypotension and tachycardia induced by the A2A receptor agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (0.01 mg/kg i.p.), but not the bradycardic effect caused by the A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (0.03 mg/kg i.p.). SCH 58261, when administered alone, at 0.1 and 1 mg/kg i.p., did not induce significant hemodynamic changes, but at 10 mg/kg i.p., it slightly increased both systolic blood pressure (SBP) and diastolic blood pressure (DBP) (+19 +/- 3 and +16 +/- 2 mm Hg, respectively; P < . 01) and heart rate (HR) (+85 +/- 5 beats/min; P < .01). These effects were inhibited by adrenergic blockade with propranolol (30 mg/kg i.p.) and phentolamine (10 mg/kg i.p.): -5 +/- 3 mm Hg on DBP and -12 +/- 11 beats/min on HR (P < .01). In spontaneously hypertensive rats, SCH 58261, at 3 and 10 mg/kg i.p., increased weakly both SBP (+19 +/- 5 mm Hg and +25 +/- 4 mm Hg) and DBP (+14 +/- 4 mm Hg and +23 +/- 4 mm Hg) vs. vehicle (P < .01) and HR (+45 +/- 17 and +64 +/- 18 beats/min vs. vehicle, respectively; P < .01). The data indicate that SCH 58261 retains A2A selective receptor antagonist properties in vivo. Its effect on cardiovascular sympathetic outflow further suggests that endogenous adenosine exerts a tonic vascular regulation through A2A receptors. Therefore, SCH 58261 can be a useful pharmacological tool for clarifying A2A-mediated cardiovascular actions of adenosine.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9535988&dopt=Abstract
J Immunol. 1994 Sep 15;153(6):2457-69.
Involvement of phospholipase D in the activation of transcription factor AP-1 in human T lymphoid Jurkat cells.
Mollinedo F, Gajate C, Flores I.
Center for Biological Research, Superior Council of Scientific Research, Madrid, Spain.
The induction of the AP-1 transcription factor has been ascribed to the early events leading to T lymphocyte activation. We have examined the possibility that stimulation of phospholipase D (PLD) may regulate activation of transcription factor AP-1 in human T cells by transfecting human T lymphocyte Jurkat cells with a plasmid containing an AP-1 enhancer element and a chloramphenicol acetyltransferase reporter gene. We have detected activatable PLD in Jurkat cells, and we have found that addition of phosphatidic acid (PA), the physiologic product of PLD action on phospholipids, is rapidly incorporated into Jurkat cells and leads to activation of transcription factor AP-1. Treatment of Jurkat cells with anti-CD3 mAb activated both PLD and transcription factor AP-1. Wortmannin, an inhibitor of receptor-coupled PLD activation, blocked the anti-CD3-induced increases in both PLD activity and AP-1 enhancer activity. We found a good correlation in the transfected cells between PLD activation and induction of AP-1 enhancer activity under different experimental conditions. Furthermore, ethanol, an inhibitor of the PLD pathway, blocked the anti-CD3-stimulated AP-1 enhancer activity. However, this anti-CD3-mediated response was not inhibited by neomycin, an inhibitor of phosphoinositide hydrolysis. The increases in AP-1 enhancer activity induced by PA or anti-CD3 mAb were efficiently abrogated by the presence of propranolol, an inhibitor of PA phosphohydrolase and protein kinase C (PKC). Furthermore, the PA- and the anti-CD3-induced increases in AP-1 enhancer activity were blocked by the presence of PKC inhibitors or by PKC down-regulation. These data indicate that PLD stimulation can activate the transcription factor AP-1 in T lymphocytes, and suggest that the induction of AP-1 enhancer factor activity by PA is mediated via PKC stimulation, either through a direct activating effect of PA or through PA-derived diacylglycerol formation. These data also provide evidence for a role of PLD-derived lipids in the induction of AP-1 enhancer activity resulting from stimulation of the TCR/CD3 complex, suggesting that increased PLD activity can play an important role in T lymphocyte activation.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8077660&dopt=Abstract
Eur J Pharmacol. 1994 May 12;257(1-2):79-85.
K+ channel activators, acute glucose tolerance and glibenclamide-induced hypoglycaemia in the hypertensive rat.
Clapham JC, Trail BK, Hamilton TC.
SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
The effects of the K+ channel activators, levcromakalim, pinacidil and diazoxide, at comparable antihypertensive doses, on acute glucose tolerance and glibenclamide-induced hypoglycaemia were examined in conscious spontaneously hypertensive rats (SHR). Levcromakalim (0.15 mg.kg-1 p.o.) and pinacidil (1.0 mg.kg-1 p.o.) caused a slight, but short-lived, impairment of glucose tolerance following oral or s.c. administration of glucose (2.0 g.kg-1). This effect, although small, was abolished by the beta-adrenoceptor blocker, propranolol (2.0 mg.kg-1 p.o.). Diazoxide (30.0 mg.kg-1 p.o.) caused a marked and sustained impairment of oral glucose tolerance and s.c. glucose tolerance, the profile of which was quantitatively and qualitatively different from levcromakalim or pinacidil and was not significantly affected by propranolol. Glibenclamide (1.0-10. mg.kg-1 p.o.) elicited a dose-related hypoglycaemic response. Levcromakalim or pinacidil had little or no significant effect on the hypoglycaemic response elicited by glibenclamide (3.0 mg.kg-1). Conversely, diazoxide both abolished and reversed glibenclamide-induced hypoglycaemia. We conclude that levcromakalim and pinacidil have only marginal and transient effects on glycaemic control in conscious SHR and that these disturbances are probably mediated indirectly via reflex activation of the sympathetic nervous system in response to blood pressure lowering. In addition, at active antihypertensive doses neither levcromakalim nor pinacidil significantly interfered with the ability of glibenclamide to reduce blood glucose concentration. Diazoxide's impairment of oral glucose tolerance, s.c. glucose tolerance and glibenclamide response confirms this drug's well known ability to activate pancreatic KATP channels.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8082711&dopt=Abstract
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