Pulmonary Hemodynamics in Newborn Piglets during Hypoxemia and Reoxygenation: Blocking of the Endothelin-1 Receptors

Abstract

The effects of blocking endothelin (ET) receptors in pulmonary circulation during hypoxemia and reoxygenation were studied in five groups of piglets. Ten minutes before hypoxemia, the Hyp group (n = 10) was given saline and the 1-mg (n = 9) and 5-mg group (n = 9), respectively, were given 1 and 5 mg/kg i.v. SB 217242 (an ET receptor antagonist). Two groups served as normoxic controls. The piglets were ventilated with 8% O2 until base excess was <-20 mmol/L or mean arterial blood pressure was <20 mm Hg. Reoxygenation was performed with air. The increase of mean pulmonary artery pressure was significantly attenuated during hypoxemia and reoxygenation in the 1-mg group (p = 0.006). The pulmonary vascular resistance index increased significantly at the end of hypoxemia in the Hyp and 5-mg groups but was comparable to baseline in the 1-mg group. During the study period, the changes in pulmonary vascular resistance index were significantly attenuated in the 1-mg group compared with the 5-mg group. Stroke volume index was significantly attenuated compared with baseline in the 5-mg group during both hypoxemia and reoxygenation, whereas, in the Hyp and 1-mg group, stroke volume index was attenuated only at the end of hypoxemia. During hypoxemia, plasma ET-1 decreased from 1.9+/-0.2 to 1.3+/-0.3 ng/L (p = 0.008) in the Hyp group, remained unchanged in the 1-mg group, and increased from 1.6+/-0.2 to 6.6+/-1.6 ng/L (p = 0.008) in the 5-mg group. We conclude that blocking ET receptors attenuates pulmonary vasoconstriction during hypoxemia and reoxygenation in piglets.

Endothelin-A Receptor Blockade in Porcine Pulmonary Hypertension

“…As ET A blockade attenuated only pulmonary vascular resistance and did not change systemic vascular resistance significantly, and furthermore did not affect baseline pulmonary or systemic vascular resistance, it is unlikely that ET A receptors played a significant role in modulation of baseline pulmonary or systemic vascular resistances, or of hypoxia-induced changes in systemic vascular resistance in our model. Our results are roughly similar to those of Medbo et al who investigated the effects of SB 217242 (a combined ET A and ET B blocker) when used as prophylaxis in acutely instrumented and mechanically ventilated 1-to 2-d-old hypoxic piglets and showed that ET receptor blockade attenuated pulmonary vasoconstriction during hypoxemia and reoxygenation (17). However, our study differs from that of Medbo et al (17) as we used older chronically instrumented spontaneously breathing piglets that received ET A receptor-specific blockers, after the onset of hypoxia rather than as prophylaxis.…”

“…Inter-species differences also probably exist in the role of ET-1 in hypoxic pulmonary hypertension. Wong et al (35) showed that the ET A receptor antagonist BQ 123 did not reduce acute hypoxic pulmonary vasoconstriction in intact newborn lambs, although this study and others have shown that ET A receptor antagonists are effective in similar rat (14,15) and porcine models (17,36). It is probable that ET-1 is also involved in human neonatal pulmonary hypertension, for it has been observed that circulating ET-1 levels are elevated in newborn infants with PPHN, are positively correlated with disease severity, and decline with resolution of disease in patients who do not require extracorporeal membrane oxygenation (only 2 of the 24 infants in this study had sepsis, the majority had aspiration syndromes) (7).…”

“…However, the pulmonary circulation of the neonate and young infant is structurally and functionally different compared with the adult pulmonary circulation. Animal studies have demonstrated that prophylaxis with a nonselective ET receptor antagonist in the piglet model attenuates pulmonary vasoconstriction during acute hypoxemia and reoxygenation (17). The efficacy of selective ET A receptor antagonists have not been fully investigated when given after the onset of the stimulus (hypoxia-or infection-induced) causing pulmonary hypertension (i.e.…”

Role of Na⁺-K⁺-ATPase in Sodium Nitroprusside-Induced Relaxation of Pulmonary Artery under Hypoxia

“…For example, pulmonary hypertension can be observed under hypoxia in vivo, but in our experiment with isolated pulmonary artery hypoxia did not alter the resting tension or the contractile responses to KCl. One possible reason for this difference would be that mediators in the pulmonary circulation associated with hypoxic vasoconstriction, such as angiotensin II [18], endothelin [19], thromboxane A 2 [20]and leukotrienes [21], were not present in our experimental system.…”

Comparison of Pulmonary and Inflammatory Effects of Lipid- and Water-Soluble Components in Meconium in Newborn Piglets

“…20 mm Hg, or base excess was ! -20 mmol/l [16]. Immediately before the start of 8 h of reoxygenation, the piglets were given intratracheally a bolus of 3 ml/kg of meconium, or water extract or lipid extract of meconium.…”