Dexfenfluramine elevates systemic blood pressure by inhibiting potassium currents in vascular smooth muscle cells

Appetite suppressants, such as dexfenfluramine (dex), are associated with p rimary pulmonary hypertension, valvular heart disease, and systemic vascula r complications, such as coronary, cerebral, or mesenteric ischemia. These drugs suppress appetite by enhancing release and inhibiting reuptake of ser otonin in the central nervous system. The effects of dex on the systemic ci rculation have not been studied. K+ channels regulate vascular tone in most vascular beds. We hypothesized that dex is a systemic vasoconstrictor acti ng 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-c ell patch clamping in freshly isolated smooth muscle cells from rat renal, carotid, and basilar arteries. Tone was measured in tissue baths. Blood pre ssure, cardiac output, and left ventricular end diastolic pressure were ass essed in open- and closed-chest anesthetized rats. At 10(-4) M, dex inhibit s 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 systemi c vascular resistance in the presence of ketanserin. Dex vasoconstriction i s dose-dependent (threshold dose 10(-6) M; 156 mu g/ml) and enhanced in L-N AME-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 comm only prescribed drug with voltage-gated K+ channel-blocking properties is s hown to have significant hemodynamic effects in vivo.