title: Dexfenfluramine elevates systemic blood pressure by inhibiting potassium currents in vascular smooth muscle cells.
abstract: Appetite suppressants, such as dexfenfluramine (dex), are associated with primary pulmonary hypertension, valvular heart disease, and systemic vascular complications, such as coronary, cerebral, or mesenteric ischemia. These drugs suppress appetite by enhancing release and inhibiting reuptake of serotonin in the central nervous system. The effects of dex on the systemic circulation have not been studied. K(+) channels regulate vascular tone in most vascular beds. We hypothesized that dex is a systemic vasoconstrictor acting primarily by inhibiting K(+) channels, independent of effects on serotonin. The effects of clinically relevant concentrations of dex (10(-6) to 10(-4) M) on outward K(+) current and membrane potential were studied with whole-cell patch clamping in freshly isolated smooth muscle cells from rat renal, carotid, and basilar arteries. Tone was measured in tissue baths. Blood pressure, cardiac output, and left ventricular end diastolic pressure were assessed in open- and closed-chest anesthetized rats. At 10(-4) M, dex inhibits outward K(+) current (50%) and increases membrane potential (by >35 mV), an effect comparable with 4-aminopyridine (5 mM). Furthermore, dex constricts rings and acutely elevates systemic pressure (+17 +/- 3 mm Hg) and systemic vascular resistance in the presence of ketanserin. Dex vasoconstriction is dose-dependent (threshold dose 10(-6) M; 156 microg/ml) and enhanced in L-NAME-fed rats. We conclude that dex causes acute systemic vasoconstriction, at least in part by inhibition of voltage-gated K(+) channels, independent of effects on serotonin. To our knowledge, this is the first time that a commonly prescribed drug with voltage-gated K(+) channel-blocking properties is shown to have significant hemodynamic effects in vivo.
authors.affiliation: Department of Medicine (Cardiology), Walter C. Mackenzie Health Sciences Center, University of Alberta, Edmonton, Alberta, Canada. emichela@cha.ab.ca
authors.forename: E D
authors.initials: ED
authors.lastname: Michelakis
authors.forename: E K
authors.initials: EK
authors.lastname: Weir
authors.forename: D P
authors.initials: DP
authors.lastname: Nelson
authors.forename: H L
authors.initials: HL
authors.lastname: Reeve
authors.forename: S
authors.initials: S
authors.lastname: Tolarova
authors.forename: S L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020372:Dexfenfluramine / Q000494:pharmacology*; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D015761:4-Aminopyridine; D002118:Calcium; D015220:Calcium Channels; D020372:Dexfenfluramine; D004791:Enzyme Inhibitors; D007650:Ketanserin; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D026902:Potassium Channel Blockers; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C496316:Nos3 protein, rat