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.
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.
Lynch
Joseph
J
Merck Research Laboratories, West Point, PA 19486, USA. joseph_lynch@merck.com
Regan
Christopher
C
Stump
Gary
G
Tannenbaum
Pamela
P
Stevens
Joanne
J
Bone
Ashleigh
A
Gilberto
David
D
Johnson
Colena
C
Fujino
Naoko
N
Takenaga
Norihiro
N
Tokita
Shigeru
S
Nagase
Tsuyoshi
T
Sato
Nagaaki
N
Renger
John
J
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003243:Consciousness / Q000187:drug effects; D003913:Dextroamphetamine / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D017442:Histamine Agonists / Q000494:pharmacology; D008297:Male; D000077408:Modafinil; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D017442:Histamine Agonists; D018377:Neurotransmitter Agents; D052999:Quinazolinones; D000661:Amphetamine; D000077408:Modafinil; D003913:Dextroamphetamine; D009638:Norepinephrine