Relaxin does not prevent development of hypoxia-induced pulmonary edema in rats

Abstract

Acute hypoxia impairs left ventricular (LV) inotropic function and induces development of pulmonary edema (PE). Enhanced and uneven hypoxic pulmonary vasoconstriction is an important pathogenic factor of hypoxic PE. We hypothesized that the potent vasodilator relaxin might reduce hypoxic pulmonary vasoconstriction and prevent PE formation. Furthermore, as relaxin has shown beneficial effects in acute heart failure, we expected that relaxin might also improve LV inotropic function in hypoxia. Forty-two rats were exposed over 24 h to normoxia or hypoxia (10% N2 in O2). They were infused with either 0.9% NaCl solution (normoxic/hypoxic controls) or relaxin at two doses (15 and 75 μg kg−1 day−1). After 24 h, hemodynamic measurements and bronchoalveolar lavage were performed. Lung tissue was obtained for histological and immunohistochemical analyses. Hypoxic control rats presented significant depression of LV systolic pressure by 19% and of left and right ventricular contractility by about 40%. Relaxin did not prevent the hypoxic decrease in LV inotropic function, but re-increased right ventricular contractility. Moreover, hypoxia induced moderate interstitial PE and inflammation in the lung. Contrasting to our hypothesis, relaxin did not prevent hypoxia-induced pulmonary edema and inflammation. In hypoxic control rats, PE was similarly distributed in the apical and basal lung lobes. In relaxin-treated rats, PE index was 35–40% higher in the apical than in the basal lobe, which is probably due to gravity effects. We suggest that relaxin induced exaggerated vasodilation, and hence pulmonary overperfusion. In conclusion, the results show that relaxin does not prevent but rather may aggravate PE formation.

Hypoxia-Induced Pulmonary Injury—Adrenergic Blockade Attenuates Nitrosative Stress and Inflammation but Not Pulmonary Edema

“…TNF is a potent stimulator of inflammatory responses in many pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), acute lung injury/acute respiratory distress syndrome (ALI/ARDS) but also HAPE and high-altitude pulmonary hypertension (HAPH) [49,50]. In previous studies, we also found increased levels of TNF in the lungs of rats exposed to normobaric hypoxia with an oxygen content of 10% over time intervals between 6 and 24 h [13,28]. The present results show that TNF is still highly expressed after 72 h of hypoxia suggesting that inflammatory processes are still active and can maintain edema formation.…”

“…Isolated -AB had weaker effects on LV function, but reduced TPR indicating a vasodilatory effect. Vasodilation in the pulmonary vasculature in combination with a reduced LV relaxation and slightly elevated LV edP suggest increased congestion in the pulmonary vascular bed [28]. These alterations of cardiovascular functions by adrenergic blockers and the resulting backlog into the lungs may explain the aggravation of PE.…”

“…PE emerged after 6 h of hypoxia and deteriorated with prolonged exposure to hypoxia over 24 h [12]. It was accompanied by inflammation as demonstrated by increased expression of pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF) [13,28]. The inflammation, however, is considered to be rather a consequence than a cause of PE, but may maintain and aggravate edema formation [29].…”