Combined therapy with zaprinast and inhaled nitric oxide abolishes hypoxic pulmonary hypertension.
OBJECTIVE
To determine whether the combination of the phosphodiesterase 5 inhibitor zaprinast and inhaled nitric oxide (NO) decreases hypoxic pulmonary hypertension in the rat.


METHODS
Prospective, experimental study.


METHODS
Animal laboratory of a university medical center.


METHODS
Male Sprague-Dawley rats.


METHODS
Anesthetized rats were mechanically ventilated and instrumented for measurement of mean systemic arterial pressure, pulmonary arterial pressure, and cardiac output. In group 1, four acute hypoxic challenges (FIO2 = 0.17 for 5 mins) were performed: initial, during 40 ppm inhaled NO, immediately after discontinuation of 5 mins of inhaled NO, and final. In group 2 rats, an initial hypoxic challenge was performed and rats then received zaprinast (3 mg/kg bolus followed by 0.3 mg/kg/min infusion). Four hypoxic challenges analogous to group 1 were then performed during zaprinast administration.


RESULTS
Initial hypoxic challenge produced similar increases in pulmonary arterial pressure in both groups. In group 1, inhaled NO either only before or only during hypoxia decreased the pulmonary hypertensive response to hypoxia. In group 2, zaprinast administration did not alter hemodynamics. Zaprinast alone decreased the pulmonary hypertensive response to hypoxia. The combination of zaprinast and inhaled NO (either before or during hypoxia) abolished the pulmonary hypertensive response to hypoxia.


CONCLUSIONS
Treatment with inhaled NO for 5 mins before but not during hypoxia is as effective as inhaled NO during hypoxia. Inhaled NO and zaprinast both decrease the pulmonary hypertensive response to hypoxia, and the combination abolishes the response. The combination of a phosphodiesterase 5 inhibitor and inhaled NO may have clinical applicability in the treatment of pulmonary hypertension.
Nagamine
J
J
Department of Anesthesia, Stanford University Medical Center, CA 94305-5117, USA.
Hill
L L
LL
Pearl
R G
RG
D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000860:Hypoxia / Q000188:drug therapy; D007262:Infusions, Intravenous; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011688:Purinones / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001993:Bronchodilator Agents; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D009569:Nitric Oxide; C011145:zaprinast