Effects of Prostacyclin and Milrinone on Pulmonary Hemodynamics in Newborn Lambs With Persistent Pulmonary Hypertension Induced by Ductal Ligation

Abstract

Prostacyclin (PGI 2 ) stimulates adenyl cyclase to synthesize cAMP within the vascular smooth muscle resulting in vasodilatation. Milrinone inhibits cAMP clearance by phosphodiesterase type III. We studied the dose response of pulmonary and systemic hemodynamics to intratracheal (IT) PGI 2 in newborn lambs with pulmonary hypertension (PH) and whether intravenous milrinone potentiate these effects. IT-PGI 2 at varying doses was administered to lambs with PH induced by prenatal ductal ligation. IT-PGI 2 doses were repeated in the presence of intravenous milrinone (bolus-100 g/kg followed by infusion at 1 g/kg/min). Increasing doses of IT-PGI 2 significantly decreased mean pulmonary arterial pressures (PAP) and pulmonary vascular resistance (PVR) and increased pulmonary blood flow (PBF). Intravenous milrinone by itself produced a significant reduction in PVR and a significant increase in PBF. Intravenous milrinone significantly shortened the onset, prolonged the duration and degree of pulmonary vasodilation produced by PGI 2 . We conclude that intravenous milrinone potentiates the pulmonary vasodilator effects of PGI 2 at lower doses. (Pediatr Res 60: 624-629, 2006) P PHN is a disorder of term and near term infants with significant morbidity and mortality. PPHN results from disruption of the normal decrease in PVR at birth. PGI 2 , the main cyclo-oxygenase product of arachidonic acid in the vascular tissue, is a potent vasodilator and its actions are mediated by cAMP (1,2). It is one of the important mediators of the decrease in PVR at birth (3,4). PGI 2 has been used widely in the treatment of adults with PH. Although there are reports of PGI 2 being used anecdotally in human infants (5,6), systematic studies on the dose response effects of PGI 2 in PPHN are lacking. Milrinone selectively inhibits PDE3, resulting in accumulation of cAMP in myocardium and vascular smooth muscle, improving myocardial performance and producing vasodilation. Milrinone has been used in patients to improve pulmonary hemodynamics in association with systemic hemodynamic dysfunction (7,8). Studies on the use of milrinone in neonates are lacking. Figure 1 shows the PGI 2 -cAMP signal transduction pathway in the vascular smooth muscle. PGI 2 and milrinone in combination can act synergistically in increasing cAMP levels and hence enhance the relaxation of the vascular smooth muscle.The newborn pulmonary circulation is different from the adult pulmonary circulation in its anatomy and physiology (9,10). The response of the infant with PPHN to NO is closer to that of newborn lambs with persistent pulmonary hypertension induced by ligation of the ductus arteriosus (11) than it is to the response of adult humans with PH. Examination of the responses to manipulating cAMP with PGI 2 and milrinone in such lambs seemed warranted in advance of clinical trials. Thus we studied the dose response to IT PGI 2 , the response to intravenous milrinone and enhancement of the effect of PGI 2 by milrinone in newborn lambs with PH induced by ligation o...

Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine*

“…For centers with access to inhaled NO, this is the only selective pulmonary vasodilator reported to be effective in reversal of PPHN (270, 271, 273–278). Milrinone or inamrinone may be added to improve heart function as tolerated (279–281). ECMO remains the therapy of choice for patients with refractory PPHN and sepsis (282–285).…”

Treatment of premature infants with pulmonary hypertension and right ventricular dysfunction with milrinone: a case series

“…19,20 In the newborn lamb model, intravenous milrinone augments the action of PGl 2 (prostaglandins) on pulmonary vasculature by significantly shortening the onset and prolonging the duration and degree of pulmonary vasodilation produced by PGI 2 . 21,22 Milrinone may also exhibit synergistic effects with iNO in lowering PVR. In animal models and clinical pediatric studies, milrinone demonstrates a synergistic effect when used with iNO in Treatment for premature infants with PH and RV dysfunction AT James et al lowering pulmonary vascular resistance.…”

Molecular mechanism of angiotensin II-induced insulin resistance in aortic vascular smooth muscle cells: Roles of Protein Tyrosine Phosphatase-1B

“…Even though we cannot rule out the possibility of cAMP dependent PKA-induced PTP-1B activation in our system, the activation of PKA by Ang II in VSMC has been reported to occur via a cAMP-independent mechanism (Dulin et al, 2001). Since cAMP is known to be a second messenger for vasodilators (Rashid et al, 2006) and inhibits VSMC growth (Zhuplatov et al, 2006), thus antagonizing the Ang II actions in VSMC, the PKA-dependent activation of PTP-1B by Ang II in VSMC most likely occur through a non-cAMP-dependent. An alternative method of PKA activation is through IκB phosphorylation.…”