Prostacyclin and milrinone by aerosolization improve pulmonary hemodynamics in newborn lambs with experimental pulmonary hypertension.
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.
Kumar
Vasanth H
VH
Division of Neonatology, Department of Pediatrics, University at Buffalo, The Women & Children's Hospital of Buffalo, 219 Bryant St., Buffalo, NY 14222-2006, USA. vkumar@upa.chob.edu
Swartz
Daniel D
DD
Rashid
Nasir
N
Lakshminrusimha
Satyan
S
Ma
Changxing
C
Ryan
Rita M
RM
Morin
Frederick C
FC
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D011464:Epoprostenol / Q000008:administration & dosage*; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D007213:Indomethacin; D020105:Milrinone / Q000008:administration & dosage*; D019331:NG-Nitroarginine Methyl Ester; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D011652:Pulmonary Circulation / Q000187:drug effects*; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage*
D000336:Aerosols; D000959:Antihypertensive Agents; D010726:Phosphodiesterase Inhibitors; D014665:Vasodilator Agents; D011464:Epoprostenol; D020105:Milrinone; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin