RT Journal Article
SR Electronic
T1 Dexfenfluramine Elevates Systemic Blood Pressure by Inhibiting Potassium Currents in Vascular Smooth Muscle Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1143
OP 1149
VO 291
IS 3
A1 Evangelos D. Michelakis
A1 E. Kenneth Weir
A1 Daniel P. Nelson
A1 Helen L. Reeve
A1 Simona Tolarova
A1 Stephen L. Archer
YR 1999
UL http://jpet.aspetjournals.org/content/291/3/1143.abstract
AB 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 μg/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. The American Society for Pharmacology and Experimental Therapeutics