Effects of raloxifene have been documented in the systemic circulation. However, its impact on the pulmonary circulation is unclear. The present study investigated the role of gender, endothelial modulation, and Ca 2ϩ channel in relaxations evoked by raloxifene in rat pulmonary arteries and veins. Vascular responses were studied on isolated pulmonary blood vessels mounted in a myograph and constricted by U46619 (9,11-dideoxy-11␣,9␣-epoxymethanoprostaglandin F 2␣ ). Constrictions to CaCl 2 were studied in Ca 2ϩ -free, 60 mM K ϩ solution. Changes in the intracellular calcium ion concentration ([Ca 2ϩ ] i ) in vascular smooth muscle were measured using a calcium fluorescence imaging method. Raloxifene was more effective in relaxing U46619-constricted pulmonary arteries from male than female rats. Raloxifene-induced relaxation was unaffected by ICI 182,4,5,5,5,sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17␤-diol], inhibition of the nitric oxide (NO) pathway, or removal of the endothelium. In arteries without endothelium, raloxifene attenuated CaCl 2 -induced constriction and CaCl 2 -stimulated increase in [Ca 2ϩ ] i with similar potencies. Raloxifene caused endothelium-independent relaxations in pulmonary veins, albeit to a lesser degree than in pulmonary arteries. The venous responses showed a gender difference because raloxifene was more potent in male veins. In summary, raloxifene relaxed rat pulmonary arteries, and this effect did not involve the endothelium/NO or ICI 182,780-sensitive estrogen receptors. Raloxifene, like nifedipine, reduced constriction and [Ca 2ϩ ] i increase in response to CaCl 2 in high K ϩ solution. Raloxifene also relaxed high K ϩ -constricted pulmonary veins. Our data indicate that raloxifene acutely relaxes rat pulmonary blood vessels primarily via inhibition of Ca 2ϩ influx through voltage-sensitive Ca 2ϩ channels. Finally, raloxifene induced more relaxation in blood vessels isolated from male than female rats.Despite the favorable effects of hormone replacement therapy (HRT) on established cardiovascular risk factors suggested in early observational studies, the findings from a recent HRT clinical trial have questioned its long-term safety (Rossouw et al., 2002). Designer estrogen or selective estrogen receptor modulators (SERMs) have been developed to avoid the clinical disadvantages of HRT. Raloxifene, the second-generation SERM with antiestrogenic effects on the breast and uterus, represents a promising alternative to HRT because it exerts estrogenic effects on key cardiovascular risk factors (Saitta et al., 2001). Recent clinical studies also support a cardioprotective effect of raloxifene in women at high coronary risk (Barrett-Connor et al

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The present study aimed to investigate the analgesic effect of JCM-16021, a revised traditional Chinese herbal formula, on postinflammatory irritable bowel syndrome (PI-IBS) in rats. The trinitrobenzene sulfonic (TNBS) acid-induced PI-IBS model rats were orally administrated with different doses of JCM-16021 (1.2, 2.4, and 4.8 g/kg/d) for 14 consecutive days. The results showed that JCM-16021 treatment dose-dependently attenuated visceral hyperalgesia in PI-IBS rats. Further, the colonic enterochromaffin (EC) cell number, serotonin (5-HT) content, tryptophan hydroxylase expression, and mechanical-stimuli-induced 5-HT release were significantly ameliorated. Moreover, the decreased levels of mucosal cytokines in PI-IBS, especially the helper T-cell type 1- (Th1-) related cytokine TNF-α, were also elevated after JCM-16021 treatment. These data demonstrate that the analgesic effect of JCM-16021 on TNBS-induced PI-IBS rats may be medicated via reducing colonic EC cell hyperplasia and 5-HT availability.

Selective estrogen receptor modulators (SERMs) reduce vascular tone in the systemic circulation. Their effects on the pulmonary circulation are unknown. The present study examined the effect of oral treatment with raloxifene (a second-generation SERM) on vasomotor reactivity in pulmonary arteries from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Pulmonary arterial rings were suspended in a multi-channel myograph, and changes in isometric tension were measured. WKY rings constricted less to U46619 than SHR rings, and the difference was eliminated after chronic treatment with raloxifene. More contraction to U46619 was obtained after inhibition of nitric oxide synthase (NOS) by L-NAME (as an index of basal NO release) in raloxifene-treated than in control SHR rings. Less U46619-induced contraction after raloxifene treatment occurred only in SHR rings with endothelium, and this effect was abolished upon removal of the endothelium. Raloxifene treatment did not enhance the contribution of basal NO to U46619-induced constriction in WKY rings. Raloxifene treatment did not modify endothelium-dependent relaxation to acetylcholine and endothelium-independent relaxation to nifedipine. The reduced relaxing sensitivity to sodium nitroprusside (SNP) in SHR rings was normalized by raloxifene treatment. Raloxifene treatment reduced CaCl2-induced tone in SHR but not in WKY rings. The results show that chronic treatment with raloxifene could improve pulmonary vascular function in hypertensive animals by (1) increasing basal NO release, (2) reducing vascular smooth muscle tone, and (3) improving the effect of NO on vascular smooth muscle in SHR. In contrast, raloxifene has little effect on vascular reactivity in pulmonary arteries from normotensive WKY rats.

Progress has been made in identifying stem cell aging as a pathological manifestation of a variety of diseases, including obesity. Adipose stem cells (ASCs) play a core role in adipocyte turnover, which maintains tissue homeostasis. Given aberrant lineage determination as a feature of stem cell aging, failure in adipogenesis is a culprit of adipose hypertrophy, resulting in adiposopathy and related complications. In this review, we elucidate how ASC fails in entering adipogenic lineage, with a specific focus on extracellular signaling pathways, epigenetic drift, metabolic reprogramming, and mechanical stretch. Nonetheless, such detrimental alternations can be reversed by guiding ASCs towards adipogenesis. Considering the pathological role of ASC aging in obesity, targeting adipogenesis as an anti-obesity treatment will be a key area of future research, and a strategy to rejuvenate tissue stem cell will be capable of alleviating metabolic syndrome.