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1.
Clin Sci (Lond) ; 136(12): 973-987, 2022 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-35678315

RESUMEN

Cigarette smoking remains the leading modifiable risk factor for cardiopulmonary diseases; however, the effects of nicotine alone on cardiopulmonary function remain largely unknown. Previously, we have shown that chronic nicotine vapor inhalation in mice leads to the development of pulmonary hypertension (PH) with right ventricular (RV) remodeling. The present study aims to further examine the cardiopulmonary effects of nicotine and the role of the α7 nicotinic acetylcholine receptor (α7-nAChR), which is widely expressed in the cardiovascular system. Wild-type (WT) and α7-nAChR knockout (α7-nAChR-/-) mice were exposed to room air (control) or nicotine vapor daily for 12 weeks. Consistent with our previous study, echocardiography and RV catheterization reveal that male WT mice developed increased RV systolic pressure with RV hypertrophy and dilatation following 12-week nicotine vapor exposure; in contrast, these changes were not observed in male α7-nAChR-/- mice. In addition, chronic nicotine inhalation failed to induce PH and RV remodeling in female mice regardless of genotype. The effects of nicotine on the vasculature were further examined in male mice. Our results show that chronic nicotine inhalation led to impaired acetylcholine-mediated vasodilatory response in both thoracic aortas and pulmonary arteries, and these effects were accompanied by altered endothelial nitric oxide synthase phosphorylation (enhanced inhibitory phosphorylation at threonine 495) and reduced plasma nitrite levels in WT but not α7-nAChR-/- mice. Finally, RNA sequencing revealed up-regulation of multiple inflammatory pathways in thoracic aortas from WT but not α7-nAChR-/- mice. We conclude that the α7-nAChR mediates chronic nicotine inhalation-induced PH, RV remodeling and vascular dysfunction.


Asunto(s)
Nicotina , Receptor Nicotínico de Acetilcolina alfa 7 , Acetilcolina/metabolismo , Administración por Inhalación , Animales , Aorta Torácica/efectos de los fármacos , Femenino , Masculino , Ratones , Nicotina/administración & dosificación , Arteria Pulmonar/efectos de los fármacos , Regulación hacia Arriba , Vasodilatación/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7/genética , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo
2.
Hypertension ; 75(5): 1305-1314, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32172623

RESUMEN

Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases; however, the role of nicotine in the pathogenesis of these diseases is incompletely understood. The purpose of this study was to examine the effects of chronic nicotine inhalation on the development of cardiovascular and pulmonary disease with a focus on blood pressure and cardiac remodeling. Male C57BL6/J mice were exposed to air (control) or nicotine vapor (daily, 12 hour on/12 hour off) for 8 weeks. Systemic blood pressure was recorded weekly by radio-telemetry, and cardiac remodeling was monitored by echocardiography. At the end of the 8 weeks, mice were subjected to right heart catheterization to measure right ventricular systolic pressure. Nicotine-exposed mice exhibited elevated systemic blood pressure from weeks 1 to 3, which then returned to baseline from weeks 4 to 8, indicating development of tolerance to nicotine. At 8 weeks, significantly increased right ventricular systolic pressure was detected in nicotine-exposed mice compared with the air controls. Echocardiography showed that 8-week nicotine inhalation resulted in right ventricular (RV) hypertrophy with increased RV free wall thickness and a trend of increase in RV internal diameter. In contrast, there were no significant structural or functional changes in the left ventricle following nicotine exposure. Mechanistically, we observed increased expression of angiotensin-converting enzyme and enhanced activation of mitogen-activated protein kinase pathways in the RV but not in the left ventricle. We conclude that chronic nicotine inhalation alters both systemic and pulmonary blood pressure with the latter accompanied by RV remodeling, possibly leading to progressive and persistent pulmonary hypertension.


Asunto(s)
Presión Sanguínea/efectos de los fármacos , Hipertensión Pulmonar/etiología , Nicotina/farmacología , Arteria Pulmonar/efectos de los fármacos , Remodelación Vascular/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Administración por Inhalación , Angiotensina II/farmacología , Animales , Cámaras de Exposición Atmosférica , Cateterismo Cardíaco , Hipertensión Pulmonar/diagnóstico por imagen , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/diagnóstico por imagen , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Nicotina/administración & dosificación , Nicotina/toxicidad , Arteria Pulmonar/fisiología , Resistencia Vascular/efectos de los fármacos
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