Aerosolized prostacyclin (PGI2) produces selective pulmonary vasodilation in patients with pulmonary hypertension (PH). The response to PGI2 may be increased by phosphodiesterase type 3 inhibitors such as milrinone. We studied the dose response effects of aerosolized PGI2 and aerosolized milrinone both alone and in combination on pulmonary and systemic hemodynamics in newborn lambs with Nomega-nitro-L-arginine methyl ester (L-NAME)-induced PH. We hypothesized that coaerosolization of PGI2 with milrinone would additively decrease pulmonary vascular resistance (PVR), prolong the duration of action of PGI2, and selectively dilate the pulmonary vasculature. Near-term lambs were delivered by C-section and instrumented and PH was induced by L-NAME (bolus 25 mg/kg; infusion 10 mg.kg(-1).h(-1)) and indomethacin. In the first set of experiments, PGI2 was aerosolized at random doses of 2, 20, 100, 200, 500, and 1,000 ng.kg(-1).min(-1) followed by milrinone at doses of 0.1, 1, and 10 microg.kg(-1).min(-1) over 10 min. In the second set of experiments, milrinone at 1 microg.kg(-1).min(-1) was aerosolized in combination with PGI2 at doses of 20, 100, and 200 ng.kg(-1).min(-1) over 10 min. Pulmonary arterial pressures (PAP) and PVR decreased significantly with increasing doses of aerosolized PGI2 and milrinone. The combination of PGI2 and milrinone significantly reduced PAP and PVR more than either of the drugs aerosolized alone. Addition of milrinone significantly increased the duration of action of PGI2. When aerosolized independently, PGI2 and milrinone selectively dilated the pulmonary vasculature but the combination did not. Milrinone enhances the vasodilatory effects of PGI2 on the pulmonary vasculature but caution must be exercised regarding systemic hypotension.
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...
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