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Vol. 291, Issue 3, 1143-1149, December 1999
Department of Medicine (Cardiology), Walter C. Mackenzie Health
Sciences Center, University of Alberta, Edmonton, Alberta, Canada
(E.D.M., S.L.A.); and Department of Medicine (Cardiology), Veterans
Administration Medical Center and the University of Minnesota,
Minneapolis, Minnesota (E.K.W., D.P.N., H.L.R., S.T.)
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 104 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
104 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 106 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.
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