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  • 1
    ISSN: 1527-3458
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride salt] is a selective neuronal nicotinic receptor (NNR) modulator with cognitive enhancing properties in animal models of cognitive functioning. Amongst NNR subtypes, ABT-089 shows selectivity for the cytisine binding site on the α4β2 receptor subtype as compared to the α-bungarotoxin (α-BgT) binding sites on the α7 and α1β1δγ receptor subtypes. In functional in vitro electrophysiological and cation flux assays, ABT-089 displays differential activity including agonism, partial agonism and antagonism depending upon the NNR subtype and assay. ABT-089 is as potent and efficacious as (–)-nicotine at evoking acetylcholine (ACh) release from hippocampal synaptosomes. Furthermore, ABT-089 is neuroprotective against excitotoxic glutamate insults, with even greater potency seen after chronic treatment. Similarly, ABT-089 is effective in models of cognitive functioning, including enhancement of baseline functioning as well as improvement of impaired cognitive functioning seen following septal lesioning and natural aging. In neuroprotective assays the compound is most potent by chronic administration. In stark contrast to the positive effects in the cognitive models, ABT-089 shows little propensity to induce adverse
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Pty
    Clinical and experimental pharmacology and physiology 32 (2005), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. Prostaglandin D (DP) receptor agonists have been shown to induce hypotension in rat models, possibly via peripheral vasodilation. However, it is not known which tissues and organs are most responsive.2. In the present study, BW245C, a DP receptor-selective agonist, was administered to Inactin (Sigma, St Louis, MO, USA)-anaesthetized rats. Animals received three serial i.v. infusions (17 min each) of either BW245C (escalating doses of 0.3, 3 and 30 μg/kg; n = 6) or vehicle (6% ethanol in normal saline; n = 6). Mean arterial pressure (MAP) and heart rate were monitored continuously and regional blood flow was determined by the radionuclide-labelled microsphere method at baseline and at the end of each infusion.3. It was found that BW245C dose-dependently reduced MAP; blood flow increased in forelimb skeletal muscle and skin, resulting in decreases in the regional vascular resistance (RVR) of skeletal muscle to −6 ± 13, −53 ± 11 and −68 ± 6% of baseline following 0.3, 3 and 30 μg/kg BW245C, respectively (P 〈 0.05 vs vehicle treatment for the two higher doses), and skin to −29 ± 8, −55 ± 8 (P 〈 0.05) and −30 ± 16% of baseline, respectively. Relative to vehicle, blood flow and RVR for brain, heart, lung, liver, stomach and kidney were not significantly affected by BW245C.4. These results demonstrate that the hypotension resulting from DP receptor activation in the rat is mediated primarily through vasodilation of arterioles of skeletal muscle independent of changes in blood flow to vital organs.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. Activation of dopamine (DA) receptors produces cardiovascular responses such as vasodilation and hypotension. However, knowledge of the role of specific dopamine receptor subtypes (especially D3 and D4) in the cardiovascular system is limited. The objective of the present study was to characterize the haemodynamic and cardiac responses to agonists with selectivity for D1, D2, D3 and D4 receptor subtypes.2. Inactin-anaesthetized rats were instrumented to measure regional haemodynamic and cardiac contractility responses with slow intravenous infusion of agonists.3. Fenoldopam (a D1 receptor agonist) decreased (P 〈 0.05) renal vascular resistance beginning at a dose of 3 µmol/kg. Infusion of PNU-95666E (a D2 receptor agonist) produced dose-dependent decreases (P 〈 0.05) in mean arterial pressure (MAP), heart rate (HR) and hindquarter vascular resistance (HQVR). Administration of BP897 (a partial D3 receptor agonist) decreased (P 〈 0.05) MAP and HQVR at 3 µmol/kg. PD168077 (a D4 receptor agonist) caused significant increases in HQVR at 1 µmol/kg. None of the compounds tested elicited significant changes in cardiac contractility.4. Using selective agonists of dopamine receptor subtypes, the present studies characterize distinct cardiovascular effects in anaesthetized rats. Consistent with its well-defined effects as a D1 receptor agonist, fenoldopam administration resulted in renal vasodilation. Similar to earlier studies using the non-selective D2-like receptor agonist quinpirole, selective agonism at the D2 receptor using PNU-95666E resulted in bradycardia, hindquarter vasodilation and decreases in arterial pressure. Partial agonism at the D3 receptor with BP897 had no effect on heart rate, but did produce depressor responses driven by decreases in HQVR. Conversely, agonism of the D4 receptor using PD168077 resulted in modest hindquarter vasoconstriction that was not dose dependent. Hence, by comparison, agonism of the D4 receptor has little effect in the cardiovascular system of the rat relative to the other dopamine receptor subtype agonists tested.
    Type of Medium: Electronic Resource
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