Anorectic drugs and vascular disease: the role of voltage-gated K+ channels.
Anorectic drugs are widely used for the treatment of obesity. They are thought to decrease appetite through their effects on catecholamine or 5-hydroxytryptamine (5-HT) levels in the brain. Their use has been associated with epidemics of pulmonary hypertension and the development of valvular heart disease, hypertension, stroke and digital or mesenteric ischemia. Understanding the mechanism of the cardiovascular toxicity of anorectic drugs is important because of the modern epidemic of obesity and the resulting plethora of new anorexigens, many of which share similar mechanisms with those that have previously caused cardiovascular disease. In addition, the mechanism by which anorexigens cause vascular disease has relevance to the etiology and treatment of pulmonary and systemic hypertension. Recent discoveries have clarified how the anorexigens cause vasoconstriction and hypertension. Most anorexigens directly inhibit voltage-gated K+ (KV) channels in vascular smooth muscle cells (SMCs). This reduced K+ efflux leads to depolarization, the opening of voltage-sensitive Ca2+ channels, an increase in intracellular Ca2+ and vasoconstriction. Endothelial dysfunction appears to be a predisposing factor for the development of anorectic-induced vascular complications. Vasoconstriction is weak at clinically relevant doses of anorectic drugs. However, when nitric oxide synthase is inhibited, vasoconstriction is significantly enhanced. Anorexigens are the only drugs in widespread clinical use that have KV-channel-blocking properties and it is probable that much of their cardiovascular toxicity relates to this mechanism. Investigators need to examine new anorexigens and other therapeutic molecules for inhibitory effects on KV channels, as this effect may be a marker of drugs that will elicit vascular complications.
Michelakis
Evangelos
E
Department of Medicine (Cardiology), University of Alberta, 2C2.36 Walter Mackenzie Health Sciences Centre, Edmonton, AB, Canada T6G 2B7. emichela@cha.ab.ca
D000818:Animals; D001067:Appetite Depressants / Q000009:adverse effects* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D009765:Obesity / Q000188:drug therapy; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D014661:Vasoconstriction / Q000187:drug effects*
D001067:Appetite Depressants; D024642:Potassium Channels, Voltage-Gated; D002118:Calcium