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sGC stimulation totally reverses hypoxia-induced pulmonary vasoconstriction alone and combined with dual endothelin-receptor blockade in a porcine model.
Lundgren, J; Kylhammar, D; Hedelin, P; Rådegran, G.
Afiliación
  • Lundgren J; The Öresund Cardiovascular Research Collaboration, The Clinic for Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden.
Acta Physiol (Oxf) ; 206(3): 178-94, 2012 Nov.
Article en En | MEDLINE | ID: mdl-22682645
AIM: Stimulation of soluble guanylate cyclase (sGC) with BAY 41-8543 was hypothesized to attenuate acute hypoxic pulmonary vasoconstriction alone and combined with dual endothelin (ET)-receptor antagonist tezosentan. METHODS: Measurements were taken in 18 anaesthetized pigs with a mean ± SEM weight of 31.1 ± 0.4 kg, in normoxia (FiO(2)~0.21) and hypoxia (FiO(2)~0.10) without (control protocol, n = 6), and with right atrial infusion of BAY 41-8543 at 1, 3, 6, 9 and 12 µg min(-1) per kg (protocol 2, n = 6) or tezosentan at 5 mg kg(-1) followed by BAY 41-8543 at 1, 3 and 6 µg min(-1) per kg (protocol 3, n = 6). RESULTS: Hypoxia (n = 18) increased (P < 0.001) mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR) by 14.2 ± 0.6 mmHg and 2.8 ± 0.3 WU respectively. During sustained hypoxia without treatment, MPAP and PVR remained stable. BAY 41-8543 (n = 6) dose-dependently decreased (P < 0.001) MPAP and PVR by 15.0 ± 1.2 mmHg and 4.7 ± 0.7 WU respectively. Tezosentan (n = 6) decreased (P < 0.001) MPAP and PVR by 11.8 ± 1.2 mmHg and 2.0 ± 0.2 WU, respectively, whereafter BAY 41-8543 (n = 6) further decreased (P < 0.001) MPAP and PVR by 6.6 ± 0.9 mmHg and 1.9 ± 0.4 WU respectively. Both BAY 41-8543 and tezosentan decreased (P < 0.001) systemic arterial pressure and systemic vascular resistance. Blood-O(2) consumption remained unaltered (P = ns) during all interventions. CONCLUSION: BAY 41-8543 totally reverses the effects of acute hypoxia-induced pulmonary vasoconstriction, and enhances the attenuating effects of tezosentan, without affecting oxygenation. Thus, sGC stimulation, alone or combined with dual ET-receptor blockade, could offer a means to treat pulmonary hypertension related to hypoxia and potentially other causes.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Pirimidinas / Tetrazoles / Resistencia Vascular / Morfolinas / Antagonistas de los Receptores de Endotelina / Guanilato Ciclasa / Hipertensión Pulmonar / Hipoxia Tipo de estudio: Guideline / Prognostic_studies Límite: Animals Idioma: En Revista: Acta Physiol (Oxf) Asunto de la revista: FISIOLOGIA Año: 2012 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Pirimidinas / Tetrazoles / Resistencia Vascular / Morfolinas / Antagonistas de los Receptores de Endotelina / Guanilato Ciclasa / Hipertensión Pulmonar / Hipoxia Tipo de estudio: Guideline / Prognostic_studies Límite: Animals Idioma: En Revista: Acta Physiol (Oxf) Asunto de la revista: FISIOLOGIA Año: 2012 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido