Nordexfenfluramine causes more severe pulmonary vasoconstriction than dexfenfluramine.
(17/31)
The anorectic agent dexfenfluramine (dex) causes the development of primary pulmonary hypertension in susceptible patients by an unknown mechanism. We compared the effects of dex with those of its major metabolite, nordexfenfluamine (nordex), in the isolated perfused rat lung and in isolated rings of resistance pulmonary arteries. Nordex caused a dose-dependent and more intense vasoconstriction, which can be inhibited by the nonspecific 5-hydroxytryptamine type 2 (5-HT(2)) blocker ketanserin. Similarly a rise in cytosolic calcium concentration ([Ca(2+)](i)) in dispersed pulmonary artery smooth muscle cells (PASMCs) induced by nordex could be prevented by ketanserin. Unlike prior observations with dex, nordex did not inhibit K(+) current or cause depolarization in PASMCs. Removal of Ca(2+) from the tissue bath or addition of nifedipine (1 microM) reduced ring contraction to nordex by 60 +/- 9 and 63 +/- 4%, respectively. The addition of 2-aminoethoxydiphenyl borate (2-APB), a blocker of store-operated channels and the inositol 1,4,5-trisphosphate receptor, caused a dose-dependent decrease in the ring contraction elicited by nordex. The combination of 2-APB (10 microM) and nifedipine (1 microM) completely ablated the nordex contraction. Likewise the release of Ca(2+) from the sarcoplasmic reticulum by cyclopiazonic acid markedly reduced the nordex contraction while leaving the KCl contraction unchanged. We conclude that nordex may be responsible for much of the vasoconstriction stimulated by dex, through the activation of 5-HT(2) receptors and that the [Ca(2+)](i) increase in rat PASMCs caused by dex/nordex is due to both influx of extracellular Ca(2+) and release of Ca(2+) from the sarcoplasmic reticulum. (+info)
Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension.
(18/31)
Dexfenfluramine associated pulmonary arterial hypertension occurring in a patient with hereditary haemorrhagic telangiectasia related to a mutation within the endoglin gene is described. This report highlights the critical role of the TGF-beta signalling pathway in this condition. (+info)
Effects of anorectic drugs on food intake under progressive-ratio and free-access conditions in rats.
(19/31)
The effects of two anorectic drugs, dexfenfluramine and phentermine, on food intake under different food-access conditions were examined. Experiment 1 compared the effects of these drugs on food intake under a progressive-ratio (PR) schedule and free-access conditions. Dexfenfluramine decreased food intake under both conditions, but the doses required to decrease intake under free-access conditions were higher than those required to reduce intake under the PR condition. Intermediate doses of phentermine sometimes increased breaking points, and higher doses decreased them. Phentermine decreased food intake at the same doses under both access conditions. Thus the potency of dexfenfluramine, but not phentermine, to decrease food-maintained behavior depended upon the food-access condition. Experiment 2 used a novel mixed progressive-ratio schedule of food delivery to study the duration of drug effects. Sessions consisted of five components separated by 3-hr timeouts. The ratio requirement reset at the beginning of each component and a new breaking point was obtained. Both dexfenfluramine and phentermine dose-dependently decreased breaking points early in the session. In some rats, compensatory increases in breaking point were observed. That is, breaking points later in the session increased over control levels, resulting in no change in the total number of food pellets earned for the session compared to control. The present findings suggest that the effects of some anorectic drugs depend upon the access conditions for food; increasing the effort to obtain food may enhance their ability to decrease food-maintained behavior. (+info)
Pulmonary hypertension and the serotonin hypothesis: where are we now?
(20/31)
In the 1960s, serotonin (5HT) was associated with pulmonary arterial hypertension (PAH) caused by certain diet pills, but has recently been the subject of renewed interest in the field of PAH. Serotonin can be synthesised in the pulmonary endothelium with the rate-limiting step being the activity of tryptophan hydroxylase1 (Tph1). The serotonin is released and can then: (i) pass into the underlying pulmonary smooth muscle cells through the serotonin transporter (SERT) to initiate proliferation and/or (ii) activate serotonin receptors on pulmonary smooth muscle cells to evoke proliferation and/or contraction. Serotonin may also mediate pulmonary fibroblast proliferation via the SERT and/or serotonin receptors. Here we will unravel, discuss and update the 'serotonin hypothesis' of PAH in light of recent advances in the field. In conclusion, the activity of serotonin receptors, the SERT and Tph1 can all be elevated in clinical and experimental PAH and each offers a potentially unique therapeutic target. (+info)
A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine.
(21/31)