The Role of Angiotensin II Receptor-1 Blockade in the Hypoxic Pulmonary Vasoconstriction Response in Newborn Piglets

Abstract

Background: Angiotensin-converting enzyme activity is increased in newborn infants with respiratory distress syndrome and in animals with alveolar hypoxia. Objective: To test whether angiotensin II (Ang II) mediates the pulmonary vasoconstriction induced by acute hypoxia in newborn piglets. Methods: Eight unanesthetized chronically instrumented newborn piglets (mean ± SEM; age 6.6 ± 0.6 days; weight 2,181 ± 174 g) were randomly assigned to receive a saline solution or the Ang II type 1 receptor (AT₁) antagonist, losartan, in a crossover study design, with an interval of at least 48 h between the first and second study. Pulmonary artery (Ppa), wedge, systemic arterial (Psa) and right atrial pressures, cardiac output (CO), pulmonary (PVR) and systemic (SVR) vascular resistances, and arterial blood gases were obtained in room air, before and during the saline or losartan infusion (6 mg/kg followed by 3 mg/kg/h), and during 6 h of hypoxia (FiO₂ = 0.11) and saline or losartan infusion. Data were analyzed by repeated measures analysis of variance. Results: The pulmonary vasoconstriction induced by acute hypoxia was significantly attenuated during losartan infusion, while Psa, SVR, CO, pH, PaCO₂, PaO₂ and base excess did not differ between groups. During room air, Ppa, PVR, Psa, SVR and CO values were not modified by saline or losartan infusion. Conclusion: These data suggest that the pulmonary vasoconstriction induced by acute hypoxia in newborn piglets is partially mediated by Ang II, acting via AT₁.

Hypoxic Pulmonary Vasoconstriction

“…Although an initial study in isolated rat lungs perfused with physiological salt solution concluded that enhancement of HPV by ANG II was specific for both HPV and ANG II (152), this was not confirmed by a subsequent study in the same preparation, which found that increases in normoxic pulmonary vasomotor tone, whether caused by ANG II or other interventions, enhanced vasoconstrictor responses to both hypoxia and KCl (1240). Antagonists of ACE or ANG II receptors did not prevent HPV in dogs (720,823,997), cats (1552), or isolated rat lungs (509, 1242), but attenuated HPV in humans (259, 958) and neonatal piglets (249). Although the explanation for these discrepancies is unknown, the data suggest that ANG II may sometimes facilitate HPV.…”

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction, pulmonary arterial remodelling and pulmonary hypertension

“…), but attenuated in piglets (Camelo et al . ). In addition, studies in chronically hypoxic rats provide evidence that angiotensin II may also contribute to the development of hypoxic pulmonary arterial remodelling and PH (Zakheim et al .…”

Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system

“…These observations were confirmed in adult humans when the RAS was not previously activated by dehydration or sodium depletion (23). In addition, we have demonstrated that pulmonary vasoconstriction induced by acute hypoxia in newborn piglets was significantly attenuated by the AT 1 -R blocker losartan (2). …”

“…The mechanisms of action of Ang II involve binding to AT 1 -R, as demonstrated in different studies reporting attenuation of pulmonary hypertension by AT 1 -R blockers and transient up-regulation of AT 1 -R in adult rats exposed to chronic hypoxia (6,7). Moreover, we have demonstrated that pulmonary vasoconstriction induced by acute hypoxia was significantly attenuated by the AT 1 -R blocker losartan in piglets (2). Therefore, it is possible that the RAS participates in the mechanisms leading to pulmonary hypertension induced by chronic hypoxia (4,5).…”

“…These events have been consistently observed in experimental animal models and in adult humans (1), but in newborns and in neonatal animal models, only one study showed involvement of the renin-angiotensin system (RAS) (2). They are multifactorial processes involving different mediators such as endothelin and angiotensin II (Ang II) and nitric oxide.…”