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Pulmonary responses to selective phosphodiesterase-5 and phosphodiesterase-3 inhibitors.

AbstractOBJECTIVE:
To compare the direct pulmonary vasodilating activity and specificity of phosphodiesterase-5 (zaprinast) and phosphodiesterase-3 (milrinone) inhibitors on the pulmonary vascular (PV) bed of the spontaneously breathing cat with an intact chest.
DESIGN:
Prospective, randomized animal study.
SETTING:
Laboratory of university hospital.
SUBJECTS:
Experiments were performed in vivo in intact-chest, spontaneously breathing cats with controlled pulmonary blood flow and constant left atrial pressure.
INTERVENTIONS:
The responses to intralobar injections of zaprinast and milrinone were investigated at low PV tone. PV tone was then increased by intralobar arterial infusion of a thromboxane A(2) mimic, U46619. Animals received intralobar bolus injections of zaprinast or milrinone, followed by continuous IV infusion of the drug, which was administered in incremental doses titrated to produce a 20% reduction in mean systemic arterial pressure.
MEASUREMENTS AND MAIN RESULTS:
At low PV tone, zaprinast, but not milrinone, decreased lobar arterial pressure (LoAP). At elevated PV tone, both drugs caused dose-dependent decreases in LoAP; however, milrinone caused significantly less pulmonary vasodilation. Dose-related decreases in mean systemic arterial pressure were observed with milrinone, but not with zaprinast. When the continuous IV infusion was titrated to produce a 20% reduction in mean systemic arterial pressure, the decreases in lobar arterial pressure with zaprinast infusion were significantly greater than those produced by milrinone.
CONCLUSIONS:
These data show that zaprinast and milrinone exert a direct in vivo vasodilator effect on the PV bed at low (zaprinast) and elevated (zaprinast and milrinone) PV tone; however, at elevated PV tone, the pulmonary vasodilator effect was greater with zaprinast then with milrinone. This suggests that phosphodiesterase-5 inhibitors may potentially offer a therapeutic alternative in the management of acute pulmonary hypertension.
AuthorsIdit Matot, Yaacov Gozal
JournalChest (Chest) Vol. 125 Issue 2 Pg. 644-51 (Feb 2004) ISSN: 0012-3692 [Print] United States
PMID14769749 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Purinones
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • zaprinast
  • Milrinone
Topics
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • 3',5'-Cyclic-AMP Phosphodiesterases (pharmacology)
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Analysis of Variance
  • Animals
  • Cats
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Hypertension, Pulmonary (drug therapy)
  • Infusions, Intravenous
  • Injections, Intralesional
  • Male
  • Milrinone (pharmacology)
  • Phosphoric Diester Hydrolases (pharmacology)
  • Probability
  • Pulmonary Circulation (drug effects, physiology)
  • Purinones (pharmacology)
  • Random Allocation
  • Risk Factors
  • Sensitivity and Specificity
  • Vascular Resistance (drug effects)

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