RESUMEN
Mitogen-activated protein (MAP) kinases signal to proteins that could modify smooth muscle contraction. Caldesmon is a substrate for extracellular signal-related kinases (ERK) and p38 MAP kinases in vitro and has been suggested to modulate actin-myosin interaction and contraction. Heat shock protein 27 (HSP27) is downstream of p38 MAP kinases presumably participating in the sustained phase of muscle contraction. We tested the role of caldesmon and HSP27 phosphorylation in the contractile response of vascular smooth muscle by using inhibitors of both MAP kinase pathways. In intact smooth muscle, PD-098059 abolished endothelin-1 (ET-1)-stimulated phosphorylation of ERK MAP kinases and caldesmon, but p38 MAP kinase activation and contractile response remained unaffected. SB-203580 reduced muscle contraction and inhibited p38 MAP kinase and HSP27 phosphorylation but had no effect on ERK MAP kinase and caldesmon phosphorylation. In permeabilized muscle fibers, SB-203580 and a polyclonal anti-HSP27 antibody attenuated ET-1-dependent contraction, whereas PD-098059 had no effect. These results suggest that ERK MAP kinases phosphorylate caldesmon in vivo but that activation of this pathway is unnecessary for force development. The generation of maximal force may be modulated by the p38 MAP kinase/HSP27 pathway.
Asunto(s)
Proteínas de Choque Térmico/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso Vascular/fisiología , Animales , Calcio/fisiología , Proteínas de Unión a Calmodulina/genética , Proteínas de Unión a Calmodulina/metabolismo , Secuencia de Consenso , Perros , Endotelina-1/farmacología , Inhibidores Enzimáticos/farmacología , Femenino , Flavonoides/farmacología , Imidazoles/farmacología , Técnicas In Vitro , Masculino , Proteínas Quinasas Activadas por Mitógenos/fisiología , Músculo Liso Vascular/efectos de los fármacos , Fosforilación , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiología , Piridinas/farmacología , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Thirty morbidly obese patients presenting for bariatric surgery were evaluated for symptomatic and objective evidence of gastroesophageal reflux. Sixteen patients had heartburn while 14 were asymptomatic. All underwent esophageal function testing; manometry was performed in all patients, pH monitoring in 28. Patients with esophageal pH < 4 for more than 5% of observed time weighed more than those with normal acid exposure, 165.2 vs 129.8 kg (P < 0.01), and had significantly higher body mass indices, 56.5 vs 48.3 kg/m2 (P < 0.05). Similarly, morbidly obese patients with abnormal reflux scores weighed significantly more and had greater body mass indices than patients with normal scores (P < 0.05). Lower esophageal sphincter pressure was higher in patients with normal esophageal acid exposure than in those with abnormal findings, 15.5 vs 12.5 mm Hg (P < 0.05). This study demonstrates a correlation between both weight and body mass index with gastroesophageal reflux.