| Hemodynamic and cardiac neurotransmitter-releasing effects in conscious dogs of attention- and wake-promoting agents: a comparison of d-amphetamine, atomoxetine, modafinil, and a novel quinazolinone H3 inverse agonist. | |
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MedLine Citation:
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PMID: 19129736 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Conscious coronary sinus-cannulated dogs were used to assess the hemodynamic effects and local cardiac norepinephrine (NE) and histamine (HA) release of 4 mechanistically diverse agents either clinically approved or representing a potential novel mechanism for the promotion of wakefulness or attention. Dosing regimens were based on reported or concurrently determined wake-promoting activities in canine models. The central nervous system stimulant, d-amphetamine [0.1 mg x kg(-1) x 10 min intravenous (IV)], significantly elevated mean arterial pressure (+30%) and increased coronary sinus and peripheral venous NE concentrations, indicative of cardiac neurotransmitter release. The selective NE reuptake inhibitor atomoxetine (2.0 mg x kg(-1) x 10 min(-1) IV) and modafinil (30.0 mg x kg(-1) x 10 min(-1) IV) also significantly elevated mean arterial pressure (+15% and +30%, respectively), but with no effect on coronary sinus or peripheral NE concentration, suggesting central mechanisms underlying the hemodynamic effects. The preclinical demonstrations of pressor effects with d-amphetamine, atomoxetine, and modafinil are consistent with clinically reported hemodynamic effects with these agents. The quinazolinone HA receptor subtype H3 inverse agonist 5r (0.3 mg x kg(-1) x 10 min(-1) IV) displayed no effect on hemodynamics or on coronary sinus or peripheral NE and HA concentrations. These data suggest the potential for therapeutic effect with the latter mechanism in the absence of peripheral cardiac neurotransmitter release or obvious changes in cardiovascular function. |
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Authors:
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Joseph Lynch; Christopher Regan; Gary Stump; Pamela Tannenbaum; Joanne Stevens; Ashleigh Bone; David Gilberto; Colena Johnson; Naoko Fujino; Norihiro Takenaga; Shigeru Tokita; Tsuyoshi Nagase; Nagaaki Sato; John Renger |
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Publication Detail:
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Type: Comparative Study; Journal Article |
Journal Detail:
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Title: Journal of cardiovascular pharmacology Volume: 53 ISSN: 1533-4023 ISO Abbreviation: J. Cardiovasc. Pharmacol. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2010-06-21 Completed Date: 2010-09-20 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7902492 Medline TA: J Cardiovasc Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 52-9 Citation Subset: IM |
Affiliation:
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Merck Research Laboratories, West Point, PA 19486, USA. joseph_lynch@merck.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amphetamine
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pharmacology* Animals Benzhydryl Compounds Central Nervous System Stimulants / pharmacology Consciousness / drug effects Dextroamphetamine / pharmacology Dogs Female Heart / drug effects Hemodynamics / drug effects* Histamine Agonists / pharmacology Male Neurotransmitter Agents / pharmacology Norepinephrine / pharmacology Quinazolinones / pharmacology Synaptic Transmission / drug effects Wakefulness / drug effects, physiology |
| Chemical | |
Reg. No./Substance:
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0/Benzhydryl Compounds; 0/Central Nervous System Stimulants; 0/Histamine Agonists; 0/Neurotransmitter Agents; 0/Quinazolinones; 300-62-9/Amphetamine; 51-41-2/Norepinephrine; 51-64-9/Dextroamphetamine; 68693-11-8/modafinil |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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