Phosphodiesterase-3 inhibition prevents the increase in pulmonary vascular resistance following inhaled nitric oxide withdrawal in lambs*

Abstract

Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of guanosine-3',5'-cyclic monophosphate. However, alterations in endogenous nitric oxide/guanosine-3',5'-cyclic monophosphate during inhaled nitric oxide have been implicated in the clinically significant increases in pulmonary vascular resistance noted upon its acute withdrawal. Previous in vitro data suggest that exogenous nitric oxide/guanosine-3',5'-cyclic monophosphate can also alter cyclic adenosine monophosphate concentrations via their effect on cyclic adenosine monophosphate production and metabolism. The current in vivo study demonstrates that lung tissue cyclic adenosine monophosphate concentrations are decreased during inhaled nitric oxide and suggests a role for decreased cyclic adenosine monophosphate in the rebound pulmonary hypertension noted upon inhaled nitric oxide withdrawal. Milrinone may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic adenosine monophosphate concentrations and prevent rebound pulmonary hypertension.

Pediatric Pulmonary Hypertension

“…When iNO is stopped abruptly, rebound PH may develop, even if no improvement in oxygenation was observed at the onset of therapy. 207 This phenomenon can lead to life-threatening elevations of PVR and decreased oxygenation (PHCs) 208,209 but can often be overcome by weaning iNO to 1 ppm before its discontinuation. Although not recommended for the prevention of chronic lung disease in preterm infants (BPD), 210 several series have shown improved oxygenation and pulmonary hemodynamics in preterm infants with PPHN physiology, especially in the setting of oligohydramnios and growth restriction.…”

Physiologic responses and plasma endothelin-1 concentrations associated with abrupt cessation of nitric oxide inhalation in isoflurane-anesthetized horses

“…34,39 However, a rebound response has been detected in conscious humans, 19,34-36 anesthetized humans, 19,37 anesthetized pigs, 13,40 conscious sheep, 7 and anesthetized sheep. 15,16,41,42 Thus, because of the wide variety of anesthetics used and the inclusion of conscious subjects in those studies, it is unlikely that the rebound effect or lack of a rebound effect could be wholly attributed to a difference in anesthetic protocol. Nevertheless, it could be argued that the inhalant anesthetic agent used in the present study blunted the HPV response, thereby decreasing the degree of pulmonary vasoconstriction and minimizing the effect of NO inhalation among the study horses.…”

Neonatal Persistent Pulmonary Hypertension Treated with Milrinone: Four Case Reports

“…Milrinone is a PDE III inhibitor which induces pulmonary vasodilation by its actions through a cyclic adenylate monophosphate (cAMP) mediated signaling pathway. In an isolated perfused model of PH, combined iNO and Milrinone therapy act synergistically to produce additional vascular smooth muscle relaxation by cGMP and cAMP pathways, respectively [6,7] . In addition to pulmonary vasodilation, Milrinone is a systemic vasodilator agent with positive inotropic myocardial (contractibility) and lusitropic (myocyte relaxation) properties.…”