title: Pharmacological characterization of the novel dihydropyridine potassium channel opener, (9R)-9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (A-325100), and the regulation of cardiovascular function in conscious and anesthetized beagle dogs.
abstract: The pharmacological profile of the novel dihydropyridine K channel opener (KCO), (9R)-9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (A-325100), is described in numerous in vitro assays. Furthermore, the cardiovascular effects of A-325100 are characterized in both the anesthetized and conscious dog. In vitro, A-325100 selectively activated KATP currents and potently relaxed vascular smooth muscle (IC50 between 7.69x10 M and 7.78x10 M), an effect that was abolished by glyburide. Moreover, A-325100 did not interact with L-type Ca2+ channels at concentrations up to 30 microM. In anesthetized dogs A-325100 produced a dose-dependent reduction in systemic vascular resistance and mean arterial pressure concomitant with dose-dependent increases in dP/dtmax and heart rate. In conscious telemetry-instrumented dogs oral administration of A-325100 produced a similar response profile, including dose-dependent reductions in MAP and increases in heart rate and dP/dtmax. When concentration-dependent changes in MAP, heart rate, and dP/dtmax were compared relative to circulating plasma concentrations, A-325100 produced similar effects in both the anesthetized and conscious dog. In conclusion, the present study provides the first pharmacological description of the novel and selective tricyclic dihydropyridine KCO, A-325100. When studied in vivo, A-325100 produced similar concentration-dependent cardiovascular effects in both models consistent with its mode of action and independent of route of administration. Thus, these data demonstrate that the hemodynamic effects of vasoactive compounds, such as KCOs, can be effectively profiled in both the conscious and anesthetized dog.
authors.affiliation: Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA. ryan.fryer@abbot.com
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Rakestraw
authors.forename: Lee C
authors.initials: LC
authors.lastname: Preusser
authors.forename: Michael E
authors.initials: ME
authors.lastname: Brune
authors.forename: William A
authors.initials: WA
authors.lastname: Carroll
authors.forename: Steven A
authors.initials: SA
authors.lastname: Buckner
authors.forename: Char-Chang
authors.initials: CC
authors.lastname: Shieh
authors.forename: Linda L
authors.initials: LL
authors.lastname: King
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Cox
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Reinhart
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000758:Anesthesia; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004095:Dihydropyridines / Q000097:blood / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D008024:Ligands; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011169:Portal Vein / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism*; D011753:Pyrones / Q000097:blood / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
chemical_list: C505398:9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo(3,4-b)pyrano(4,3-e)pyridine-1,8(4H,7H)-dione; D004095:Dihydropyridines; D008024:Ligands; D015221:Potassium Channels; D011753:Pyrones; D000255:Adenosine Triphosphate