Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension.
OBJECTIVE
To evaluate the effects of phosphodiesterase type III and V (PDEIII and PDEV) inhibition on pulmonary and systemic haemodynamics in a porcine model of acute pulmonary hypertension.


METHODS
Twenty-four adult swine were anaesthetized with 1 MAC isoflurane and mechanically ventilated with an FI(O(2)) of 100%. Micromanometer-tipped catheters were placed in the ascending aorta, pulmonary artery and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound. Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue, U46619. The animals were then randomized to four groups: Group 1 (n=6) received 50 mg of sildenafil (PDEV inhibitor) diluted in water via an orogastric tube; Group 2 (n=6) received 50 microg kg(-1) of i.v. milrinone (PDEIII inhibitor); Group 3 (n=6) received sildenafil followed by milrinone; and Group 4 (n=6) received placebo via an orogastric tube.


RESULTS
Pulmonary hypertension was achieved in all animals. Calculated pulmonary vascular resistance decreased by an average of 36% after sildenafil (P<0.05), 41% after milrinone (P<0.05), and 61% with both drugs combined (P<0.05). Systemic vascular resistance decreased by 37% (P<0.05) with milrinone alone, and 36% (P<0.05) with milrinone and sildenafil combined but it was preserved in the sildenafil group. Cardiac output and right ventricular dP/dT were significantly improved after milrinone or both drugs combined, but not with sildenafil.


CONCLUSIONS
Milrinone and sildenafil are effective pulmonary vasodilators, with independent action and additive effect. Both drugs combined achieved a better haemodynamic profile, with greater pulmonary vasodilatation and increased contractility but without additional systemic vasodilatation. The systemic haemodynamic profile (systemic vasodilation, cardiac output, right ventricular dP/dT) is improved with milrinone but not with sildenafil.
Lobato
E B
EB
Department of Anaesthesiology and Department of Surgery, University of Florida College of Medicine, FL 32610-0254, USA.
Beaver
T
T
Muehlschlegel
J
J
Kirby
D S
DS
Klodell
C
C
Sidi
A
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000208:Acute Disease; D000818:Animals; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004195:Disease Models, Animal; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D020105:Milrinone / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents / Q000627:therapeutic use
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000068677:Sildenafil Citrate; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020105:Milrinone