Effects of fluoxetine, phentermine, and venlafaxine on pulmonary arterial pressure and electrophysiology.
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The anorexic agents dexfenfluramine and fenfluramine plus phentermine have been associated with outbreaks of pulmonary hypertension. The fenfluramines release serotonin and reduce serotonin reuptake in neurons. They also inhibit potassium current (IK), causing membrane potential depolarization in pulmonary arterial smooth muscle cells. The recent withdrawal of the fenfluramines has led to the use of fluoxetine and phentermine as an alternative anorexic combination. Because fluoxetine and venlafaxine reduce serotonin reuptake, we compared the effects of these agents with those of phentermine and dexfenfluramine on pulmonary arterial pressure, IK, and membrane potential. Fluoxetine, venlafaxine, and phentermine caused minimal increases in pulmonary arterial pressure at concentrations < 100 microM but did cause a dose-dependent inhibition of IK. The order of potency for inhibition of IK at +50 mV was fluoxetine > dexfenfluramine = venlafaxine > phentermine. Despite the inhibitory effect on IK at more positive membrane potentials, fluoxetine, venlafaxine, and phentermine, in contrast to dexfenfluramine, had minimal effects on the cell resting membrane potential (all at a concentration of 100 microM). However, application of 100 microM fluoxetine to cells that had been depolarized to -30 mV by current injection elicited a further depolarization of >18 mV. These results suggest that fluoxetine, venlafaxine, and phentermine do not inhibit IK at the resting membrane potential. Consequently, they may present less risk of inducing pulmonary hypertension than the fenfluramines, at least by mechanisms involving membrane depolarization. (+info)
Effect of chlorphentermine on the lipids of rat lungs.
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Chronic administration of chlorphentermine to rats resulted in a reduction of body weight compared to a normal control group. The weight of the heart, liver, kidney, and spleen was less in the treated group while the weight of the lungs was increased significantly. There was no change in the ratio of right ventricular to left ventricular weight in the rats treated with chlorphentermine, supporting the views that this drug does not cause pulmonary hypertension. Biochemical analysis showed that the increase in the weight of the lungs was due to the accumulation of phospholipid. All classes of phospholipid were affected, but particularly phosphatidyl choline, the tissue concentration of which increased nine times. Chlorphentermine also increased the proportion of palmitate present in pulmonary phosphatidyl choline. Histological examination of the lung after treatment with chlorphentermine showed evidence of this drug-induced lipidosis. No conclusion can as yet be reached as to the mechanism involved in the accumulation of phospholipid in the lung after chlorphentermine. (+info)