title: Activation of α1A-adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing.
abstract: A NO-mediated desensitization of vasoconstrictor responses evoked by stimulation of α1-adrenoceptors has been reported in different vessels. We investigated the involvement of each α1-adrenoceptor subtype and constitutive NOS isoforms and the influence of ageing and hypertension on this process.
  
  
  
  Wistar and spontaneously hypertensive rats (SHR), 16, 32, 52 and 72 weeks-old, were used to evaluate the desensitization process. Expression of α1-adrenoceptor subtypes, endothelial NOS (eNOS) and neuronal NOS (nNOS) were determined in rat aorta and left ventricle (LV). Expression levels were also evaluated in LV of a group of heart failure patients with a wide age range.
  
  
  
  Repeated application of phenylephrine decreased subsequent α1-adrenoceptor-mediated vasoconstriction by increasing nNOS protein expression in aorta, but not in tail or mesenteric resistance arteries, where mRNA levels of nNOS were undetectable. This desensitization process disappeared in the absence of endothelium or in the presence of L-NAME (100 μM), nNOS inhibitors, SMTC (1 μM) and TRIM (100 μM), and 5-methylurapidil (100 nM, α1A-antagonist), but not BMY7378 (10 nM, α1D-antagonist). The α1A/nNOS-mediated desensitization was absent in aged SHR and Wistar animals, where the expression of α1A-adrenoceptors was reduced in aorta and LV. In human LV, a negative correlation was found between age and α1A-adrenoceptor expression.
  
  
  
  The α1A-adrenoceptor subtype, through endothelial nNOS-derived NO, may act as a physiological 'brake' against the detrimental effects of excessive α1-adrenoceptor-mediated vasoconstriction. Reduced α1A-adrenoceptor- and nNOS-mediated desensitization in aged patients could be involved in the age-dependent elevation of adrenergic activity.
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universitat de València, Burjassot, Spain.|Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, Burjassot, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Arce
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universitat de València, Burjassot, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Vicente
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universitat de València, Burjassot, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Segura
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universitat de València, Burjassot, Spain.
authors.forename: Nicla
authors.initials: N
authors.lastname: Flacco
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universitat de València, Burjassot, Spain.|Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, Burjassot, Spain.
authors.forename: Fermi
authors.initials: F
authors.lastname: Montó
authors.affiliation: Unidad de Insuficiencia Cardiaca y Trasplantes, Servicio de Cardiología, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Almenar
authors.affiliation: Unidad de Insuficiencia Cardiaca y Trasplantes, Servicio de Cardiología, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Agüero
authors.affiliation: Unidad de Insuficiencia Cardiaca y Trasplantes, Servicio de Cardiología, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Rueda
authors.affiliation: Facultat de Medicina, Departament de Farmacologia, Terapèutica i Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Jiménez-Altayó
authors.affiliation: Facultat de Medicina, Departament de Farmacologia, Terapèutica i Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vila
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universitat de València, Burjassot, Spain.|Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, Burjassot, Spain.
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Noguera
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universitat de València, Burjassot, Spain.|Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, Burjassot, Spain.
authors.forename: Pilar
authors.identifier: 0000-0001-8544-7124
authors.initials: P
authors.lastname: D'Ocon
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universitat de València, Burjassot, Spain.|Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, Burjassot, Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Ivorra
mesh_terms: D000375:Aging; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D052248:Nitric Oxide Synthase Type I