Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system.
The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT(1) receptor (AT(1)-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO(2) = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT(1)-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT(1)-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT(1)-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT(1)-R staining, but C animals showed weak iNOS and AT(1)-R staining. Macrophages of L and P animals showed moderate and weak AT(2)-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT(1)-R blockade. We suggest that AT(1)-R blockade might act through AT(2)-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.
Departamento de Puericultura e Pediatria, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brasil. jscamelo@fmrp.usp.br
J S
JS
Camelo
A R
AR
Martins
E
E
Rosa
S G
SG
Ramos
D
D
Hehre
E
E
Bancalari
C
C
Suguihara
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002908:Chronic Disease; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000860:Hypoxia / Q000150:complications*; D007093:Imidazoles / Q000627:therapeutic use*; D007150:Immunohistochemistry; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects; D013552:Swine; D013777:Tetrazoles / Q000627:therapeutic use*; D014655:Vascular Resistance / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; C070967:L 158809; D019001:Nitric Oxide Synthase