title: Enhanced endothelium-dependent relaxation of rat pulmonary artery following β-adrenergic overstimulation: involvement of the NO/cGMP/VASP pathway.
abstract: OBJECTIVE
  The aim of this study was to investigate whether β-adrenoceptor (β-AR) overstimulation induced by in vivo treatment with isoproterenol (ISO) alters vascular reactivity and nitric oxide (NO) production and signaling in pulmonary arteries.
  
  
  METHODS
  Vehicle or ISO (0.3mgkg(-1)day(-1)) was administered daily to male Wistar rats. After 7days, the jugular vein was cannulated to assess right ventricular (RV) systolic pressure (SP) and end diastolic pressure (EDP). The extralobar pulmonary arteries were isolated to evaluate the relaxation responses, protein expression (Western blot), NO production (diaminofluorescein-2 fluorescence), and cyclic guanosine 3',5'-monophosphate (cGMP) levels (enzyme immunoassay kit).
  
  
  RESULTS
  ISO treatment induced RV hypertrophy; however, no differences in RV-SP and EDP were observed. The pulmonary arteries from the ISO-treated group showed enhanced relaxation to acetylcholine that was abolished by the NO synthase (NOS) inhibitor N(ω)-nitro-l-arginine methyl ester (l-NAME); whereas relaxation elicited by sodium nitroprusside, ISO, metaproterenol, mirabegron, or KCl was not affected by ISO treatment. ISO-treated rats displayed enhanced endothelial NOS (eNOS) and vasodilator-stimulated phosphoprotein (VASP) expression in the pulmonary arteries, while phosphodiesterase-5 protein expression decreased. ISO treatment increased NO and cGMP levels and did not induce eNOS uncoupling.
  
  
  CONCLUSIONS
  The present data indicate that β-AR overactivation enhances the endothelium-dependent relaxation of pulmonary arteries. This effect was linked to an increase in eNOS-derived NO production, cGMP formation and VASP content and to a decrease in phosphodiesterase-5 expression. Therefore, elevated NO bioactivity through cGMP/VASP signaling could represent a protective mechanism of β-AR overactivation on pulmonary circulation.
authors: Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, SP, Brazil. Electronic address: anadavel@unicamp.br.
authors: Ana P
authors: AP
authors: Davel
authors: Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, SP, Brazil.
authors: Jamaira A
authors: JA
authors: Victorio
authors: Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, SP, Brazil.
authors: Maria A
authors: MA
authors: Delbin
authors: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo - USP, São Paulo, SP, Brazil.
authors: Livia E
authors: LE
authors: Fukuda
authors: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo - USP, São Paulo, SP, Brazil.
authors: Luciana V
authors: LV
authors: Rossoni
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000318:Adrenergic beta-Agonists; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP; D007545:Isoproterenol
keywords: Endothelium; Nitric oxide; Pulmonary artery; Ventricular hypertrophy; β-Adrenoceptor