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 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.
Footnotes
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Send reprint requests to: Evangelos D. Michelakis, M.D., Cardiology, 2C2. 36 WCM Health Sciences Center, University of Alberta, Edmonton, Alberta, Canada T6G 2B7. E-mail: emichela{at}cha.ab.ca
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↵1 S.L.A. and E.D.M. are supported by the Alberta Heritage Foundation for medical research and the Minnesota Affiliate of the American Heart Association (E.D.M.). S.L.A. is also supported by the Alberta Heart and Stroke Foundation and the Medical Research Council. E.K.W. is supported by the Department of Veterans Affairs and the Minnesota Affiliate of the American Heart Association. H.L.R. is supported by National Institutes of Health Grant 59182.
- Abbreviations:
- dex
- dexfenfluramine
- 5-HT
- 5-hydroxytryptamine
- Ik
- outward K+ current
- Kv
- voltage-gated potassium current
- SASMC
- systemic arterial smooth muscle cells
- 4-AP
- 4-aminopyridine
- NO
- nitric oxide
- NOS
- nitric oxide synthase
- L-NAME
- l-NG-nitroarginine methylester
- LVEDP
- left ventricular end diastolic pressure
- CO
- cardiac output
- AII
- angiotensin II
- Received June 3, 1999.
- Accepted August 19, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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