RESUMEN

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is a progressive disease in which chronic membrane potential (Em) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative Em is mainly set by two pore domain potassium (K2P) channels, of which the TASK-1 has been extensively investigated. EXPERIMENTAL APPROACH: Ion channel currents and membrane potential of primary cultured human(h) PASMCs were measured using the voltage- and current clamp methods. Intracellular [Ca2+] was monitored using fluorescent microscopy. Pulmonary BP and vascular tone measurements were also performed ex vivo using a rat PAH model. KEY RESULTS: TREK-1 was the most abundantly expressed K2P in hPASMCs of healthy donors and idiopathic(I) PAH patients. Background K+-current was similar in hPASMCs for both groups and significantly enhanced by the TREK activator ML-335. In donor hPASMCs, siRNA silencing or pharmacological inhibition of TREK-1 caused depolarisation, reminiscent of the electrophysiological phenotype of idiopathic PAH. ML-335 hyperpolarised donor hPASMCs and normalised the Em of IPAH hPASMCs. A close link was found between TREK-1 activity and intracellular Ca2+-signalling using a channel activator, ML-335, and an inhibitor, spadin. In the rat, ML-335 relaxed isolated pre-constricted pulmonary arteries and significantly decreased pulmonary arterial pressure in the isolated perfused lung. CONCLUSIONS AND IMPLICATIONS: These data suggest that TREK-1is a key factor in Em setting and Ca2+ homeostasis of hPASMC, and therefore, essential for maintenance of a low resting pulmonary vascular tone. Thus TREK-1 may represent a new therapeutic target for PAH.

Asunto(s)

Hipertensión Pulmonar , Canales de Potasio de Dominio Poro en Tándem , Vasodilatación , Canales de Potasio de Dominio Poro en Tándem/antagonistas & inhibidores , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Animales , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Masculino , Ratas , Vasodilatación/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Células Cultivadas , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Femenino , Ratas Sprague-Dawley , Potenciales de la Membrana/efectos de los fármacos , Ratas Wistar , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Calcio/metabolismo , Persona de Mediana Edad

RESUMEN

Dietary interventions that modulate the brown adipose tissue (BAT) thermogenic activity could represent a promising therapy for metabolic disorders. In order to examine if dietary walnuts intake regulates the expression of BAT thermogenic markers levels in healthy and metabolically challenged (fructose fed) animals, rats were initially divided into the control and fructose-fed groups. After nine weeks, these groups were subdivided into the one kept on the original regimens and the other supplemented with walnuts. High-fructose diet resulted in an increased relative BAT mass and no change in UCP1 content, while the walnut supplementation increased the amount of UCP1 in BAT, but did not affect 5-HT, NA, DHPG content and DHPG/NA ratio regardless of the diet. Moreover, the CD36 levels were increased following the walnut consumption, unlike FATP1, GLUT1, GLUT4, and glycogen content which remained unchanged. Additionally, the BAT levels of activated IR and Akt were not affected by walnut consumption, while ERK signaling was decreased. Overall, we found that walnut consumption increased UCP1 and CD36 content in the BAT of both control and metabolically challenged rats, suggesting that FFAs represent the BAT preferred substrate under the previously described circumstances. This further implies that incorporating walnuts into the everyday diet may help to alleviate some symptoms of the metabolic disorder.

Asunto(s)

Tejido Adiposo Pardo , Antígenos CD36 , Juglans , Proteína Desacopladora 1 , Animales , Proteína Desacopladora 1/metabolismo , Tejido Adiposo Pardo/metabolismo , Antígenos CD36/metabolismo , Antígenos CD36/genética , Ratas , Masculino , Ratas Wistar , Suplementos Dietéticos , Fructosa

RESUMEN

Producing isotactic polypropylene (iPP) homo- and copolymers in a wide composition and property range according to customer demand requires perfect alignment between the process technology, catalyst system and polymer structure. The present review shows this for the Borstar® PP process, a hybrid process employing liquid bulk and gas phase stages, in an exemplary way. It starts with the process design and continues through two generations of Ziegler-Natta catalyst development history to the design of advanced multimodal random and multiphase copolymers. Essential elements of each of the three areas contributing to performance range are highlighted, and an outlook to future development is given.