Inhaled nitric oxide, oxygen, and alkalosis: Dose-response interactions in a lamb model of pulmonary hypertension

Abstract

Inhaled nitric oxide (NO) is currently used as an adjuvant therapy for a variety of pulmonary hypertensive disorders. In both animal and human studies, inhaled NO induces selective, dose‐dependent pulmonary vasodilation. However, its potential interactions with other simultaneously used pulmonary vasodilator therapies have not been studied. Therefore, the objective of this study was to determine the potential dose‐response interactions of inhaled NO, oxygen, and alkalosis therapies. Fourteen newborn lambs (age 1–6 days) were instrumented to measure vascular pressures and left pulmonary artery blood flow. After recovery, the lambs were sedated and mechanically ventilated. During steady‐state pulmonary hypertension induced by U46619 (a thromboxane A2 mimic), the lambs were exposed to the following conditions: Protocol A, inhaled NO (0, 5, 40, and 80 ppm) and inspired oxygen concentrations (FiO2) of 0.21, 0.50, and 1.00; and Protocol B, inhaled NO (0, 5, 40, and 80 ppm) and arterial pH levels of 7.30, 7.40, 7.50, and 7.60. Each condition (in randomly chosen order) was maintained for 10 min, and all variables were allowed to return to baseline between conditions. Inhaled NO, oxygen, and alkalosis produced dose‐dependent decreases in mean pulmonary arterial pressures (P < 0.05). Systemic arterial pressure remained unchanged. At 5 ppm of inhaled NO, alkalosis and oxygen induced further dose‐dependent decreases in mean pulmonary arterial pressures (P<0.05). At inhaled NO doses >5 ppm, alkalosis induced further dose‐independent decreases in mean pulmonary arterial pressure, while oxygen did not. We conclude that in this animal model, oxygen, alkalosis, and inhaled NO induced selective, dose‐dependent pulmonary vasodilation. However, when combined, a systemic arterial pH >7.40 augmented inhaled NO‐induced pulmonary vasodilation, while an FiO2 >0.5 did not. Therefore, weaning high FiO2 during inhaled NO therapy should be considered, since it may not diminish the pulmonary vasodilating effects. Further studies are warranted to guide the clinical weaning strategies of these pulmonary vasodilator therapies. Pediatr Pulmonol. 1999; 28:3–11. © 1999 Wiley‐Liss, Inc.

Endothelium-independent and -dependent vasodilation in alkalotic and acidotic piglet lungs

“…This contrasts with a recent study showing that acute alkalosis enhanced iNO-induced pulmonary vasodilation in intact lambs. 25 Several factors may contribute to the discordant effects of acute and sustained alkalosis on both pulmo-nary vasoconstriction and vasodilation. For example, acute alkalosis-induced pulmonary vasodilation appeared to be mediated by endothelium-derived nitric oxide, 14,23 PGI 2 , 11,13,22 or K + channel activity 24 in various studies, and increases in these modulators might well enhance the vasodilatory effects of exogenous iNO.…”

“…20 However, acidosis increased both baseline and hypoxic PVR in several animal 14,21 and human 15 studies. Thus, vasodilator thelium-derived and endothelium-independent modulator activity 11,13,[22][23][24] and inhaled nitric oxide (iNO)-induced pulmonary vasodilation, 25 suggesting that sustained alkalosis may also potentiate subsequent endotheliumdependent and -independent pulmonary vasodilation. However, alkalosis has also been found to enhance systemic and pulmonary vascular smooth muscle contractility [26][27][28][29] and, in contrast to acute alkalosis, sustained alkalosis failed to attenuate pulmonary vasoconstriction in several preparations.…”

Alterations in cGMP, soluble guanylate cyclase, phosphodiesterase 5, and B‐type natriuretic peptide induced by chronic increased pulmonary blood flow in lambs

“…We have previously demonstrated increased pulmonary vasoconstriction in shunted lambs. 17,26,33,34 Therefore, it is notable that we found persistently elevated cGMP levels at each age point in shunted lambs as compared to normal lambs since cGMP results in pulmonary vascular smooth muscle cell relaxation. Our data suggest that by 4 weeks of age BNP may contribute significantly to cGMP levels in shunted lambs.…”

The Effect of Arterial pH on Oxygenation Persists Even in Infants Treated with Inhaled Nitric Oxide

“…A 1999 study by Heidersbach and colleagues demonstrated dose-dependent pulmonary vasodilation in a lamb model in response to oxygen, alkalosis, and iNO. They proceeded to demonstrate that when the therapies were used in combination, a systemic arterial pH > 7.40 augmented iNO-induced pulmonary vasodilation [10]. The present review was undertaken to examine the validity of the empiric observation that many babies with PPHN continue to exhibit pH-responsiveness when receiving treatment with iNO.…”