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Calcium Signaling in Cholangiocytes
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Erick Hernandez, Michael H. Nathanson
Gastrin exerts an anti-proliferative effect on cholangiocytes that appears to be mediated by Ca2+. Gastrin increases InsP3 in cholangiocytes, and inhibits DNA synthesis in a fashion that is blocked by Ca2+ chelators or PKC inhibitors.40 Thus it is likely that cholangiocytes express gastrin receptors that link to InsP3 production and Ca2+ signaling. Cholangiocytes also express endothelin-1 receptors.41 Although it has not been determined whether endothelin induces Ca2+ signals in cholangiocytes, such receptors are known to link to Ca2+ signaling pathways in other cells. In addition, stimulation of either gastrin receptors or endothelin receptors in cholangiocytes leads to decreases in secretin receptor expression and secretin-mediated cAMP production.41,42
Therapeutics in pulmonary hypertension
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Maria F. Acosta, Don Hayes, Jeffrey R. Fineman, Jason X.-J. Yuan, Stephen M. Black, Heidi M. Mansour
ET-1 is an endothelially derived peptide that has two receptor subtypes: endothelin A (ETA) and endothelin B (ETB). ETA is expressed exclusively in the smooth muscle cells of pulmonary arteries, while ETB can be found on both smooth muscle cells and endothelial cells. When ET-1 is ligated to the Endothelin A receptor (ETRA), intracellular calcium levels are increased and the protein kinase C pathway is activated. The consequence is that pulmonary vasoconstriction is augmented, accompanied by the stimulation of mitosis of the arterial smooth muscle cells, leading to pulmonary vasculature remodeling. Serotonin levels are elevated in the plasma of PH patients (24), which is thought to contribute to the remodeling of the pulmonary vasculature and the stimulation of vasoconstriction (12).
Impact of Dietary Polyphenols on Arterial Stiffness
Published in Catherina Caballero-George, Natural Products and Cardiovascular Health, 2018
Tess De Bruyne, Lynn Roth, Harry Robberecht, Luc Pieters, Guido De Meyer, Nina Hermans
Several acute and short-term trials have investigated effects of flavonoid-rich foods and beverages on FMD as marker of endothelial function. indicating an increase in FMD of about 20%–30% (Croft, 2016). Phytoestrogens (isoflavonoids (genistein, daidzein), flavonoids (e.g. artemetin), anthocyanins (e.g. delphinidin) induce vasodilation by binding to estrogen receptors in physiologically relevant concentrations, leading to increased endothelial NOS (eNOS) activity and increased NO synthesis (Goszcz et al., 2017). Inhibition of ET-1 release in human umbilical vein endothelial cells (HUVECs), together with increased eNOS expression, has been demonstrated for delphinidin and cyanidin. For delphinidin glycosides, stimulation of endothelin B receptors and inhibition of ACE have also been reported (Goszcz et al., 2017).
Is sotatercept, which traps activins and growth differentiation factors, a new dawn in treating pulmonary arterial hypertension (PAH)?
Published in Expert Opinion on Biological Therapy, 2023
PAH can be idiopathic (of unknown origin), heritable, associated with connective-tissue disease, or drug-induced, e.g. methamphetamines and cocaine. It is a relatively rare condition with a prevalence of ~50 per million [3]. In PAH, the arteries in the lungs are remodeled and so they become thickened or stiff, which increases the pulmonary artery pressure with the extra stress on the right heart causing it to fail, which eventually leads to death. The present treatment consists of vasodilators that target the pulmonary arteries, over the systemic circulation, such as prostacyclin or its analogues and the nitric oxide pathway activators (soluble guanylate cyclase stimulators). Another approach is to antagonize the vasoconstriction medicated by endothelin with receptor antagonists. Although these agents slow the progression of PAH, they do not stop or reverse remodeling. Thus, new treatments that address the remodeling in PAH are required [4]. One agent being developed to prevent the progression of remodeling is sotatercept.
The effects of oral treatment for systemic sclerosis related pulmonary arterial hypertension: A systematic review and meta-analysis
Published in Modern Rheumatology, 2021
Yunxia Lei, Xiao Zhang, Haobo Lin, Yuan Feng, Jieying Wang, Riqiang Luo
In this study, it was shown that ERA monotherapy effectively improved the exercise capacity and hemodynamics parameters, but without significant statistical difference. The reason may be due to patient’s selection or insufficient number of patients, which still needs more investigation. Interestingly, these results are in consistent with the previous meta-analysis published in 2007 [43] and several landmark clinical trials, such as BREATHE-1 study [13]. Long-term blockade of the endothelin A receptor theoretically may be detrimental by promoting vasoconstriction and smooth muscle cell proliferation [44]. Among these studies, exercise capacity is commonly chosen as a primary outcome to assess therapeutic efficacy in PAH clinical trials. Previous studies indicated that the 6-min walk test was shown to be an independent predictor of mortality and a reliable tool for the assessment of exercise capacity in patients with IPAH [15]. However, other studies indicated that myocardial factors, pulmonary fibrosis, osteoarticular/soft tissue involvements made it difficult to know the real exercise capacity of SSc-PAH patients [45–47]. Meanwhile, the baseline difference of 6-min walk test between treated and placebo groups could by itself have influenced the results. Therefore, the validity, reliability and discriminatory capacity of the 6-min walk test may be biased by the co-morbidities of CTD and SSc patients. On the other hand, we demonstrated that combined therapy with ERA and PDE inhibitor could significantly improve the exercise capacity, which provided us with more insights into the therapeutic strategies.
Challenges in pulmonary hypertension associated with left heart disease
Published in Expert Review of Cardiovascular Therapy, 2019
The REACH-1 trial of bosentan in HFrEF suggested a possible improvement in HF symptoms but was stopped for an early elevation in transaminases [88]. The ENABLE-1 and −2 trials studied bosentan in 1613 patients with HFrEF. After a mean follow-up of 1.5 years, there was an increase in hospitalization for HF, liver function test abnormalities and edema but no difference in mortality [86]. The selective endothelin A receptor antagonist darusentan was studied in the HEAT trial [85]. Acute administration resulted in a non-significant increase in cardiac index which became significant after 3 weeks of therapy. Systemic vascular resistance (SVR) was significantly decreased, but pulmonary arterial pressure, pulmonary capillary wedge pressure, right atrial pressure, and pulmonary vascular resistance remained unchanged as did heart rate, systemic blood pressure, and plasma catecholamines. There was a non-significant trend of increased HF exacerbations and death. The subsequent 24-week EARTH study of darusentan found no improvements in endpoints including left ventricular end systolic volume [89]. Results of the ENCOR trial [90] of the dual-receptor ERA enrasentan have never been published; however, treatment with enrasentan was associated with increased hospitalization, higher mortality and progressive LV dysfunction.