Effects of sildenafil analogue UK 343-664 on a porcine model of acute pulmonary hypertension.
BACKGROUND
Sildenafil (Pfizer Pharmaceuticals, Sandwich, Kent, UK) has been associated with pulmonary vasorelaxation. A more potent Sildenafil analogue (UK 343-664 [Pfizer Pharmaceuticals]) has been developed, but its effects in vivo have not been studied. This study evaluated the effects of UK 343-664 (Pfizer) during acute pulmonary hypertension.


METHODS
Fourteen adult swine were anesthetized with 1 minimum alveolar concentration isoflurane and were mechanically ventilated with an FIO(2) of 50%. End tidal CO(2) was maintained between 32 and 36 mm Hg. 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.


RESULTS
Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue U46619. Animals were randomized into two groups. Group 1 (n = 9) received 500 microg of UK 343-664 (Pfizer) intravenously for more than 2 minutes. Group 2 (n = 5) served as the control group. Data were recorded continuously for 60 minutes. Statistical analyses were performed with the analysis of variance and t tests. A p less than 0.05 was considered significant.Pulmonary hypertension was achieved in all animals. The administration of UK 343-664 (Pfizer) was associated with a significant decrease in pulmonary artery pressure (30.3%; p < 0.05) and pulmonary vascular resistance (42%; p < 0.05) with mild systemic vasodilatation. These effects were partially maintained at 30 minutes (a 17.3% and 39% decrease, respectively; p < 0.05).


CONCLUSIONS
The administration of UK 343-664 (Pfizer) was associated with predominant pulmonary vasodilatation without systemic hypotension. This may represent a significant advance in the treatment of acute pulmonary hypertension. Potential clinical implications for this new phosphodiesterase enzyme type V (PDEV) inhibitor merit further study.
Bonnell
Mark R
MR
Department of Surgery and Anesthesiology, University of Florida, College of Medicine, Gainesville, Florida 32610-0254, USA.
Urdaneta
Felipe
F
Kirby
David S
DS
Valdez
Natalie R
NR
Beaver
Thomas M
TM
Lobato
Emilio B
EB
D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines; D011744:Pyrimidinones / Q000627:therapeutic use*; D011897:Random Allocation; D000068677:Sildenafil Citrate; D013450:Sulfones; D013552:Swine; D014665:Vasodilator Agents
D010879:Piperazines; D011687:Purines; D011744:Pyrimidinones; D013450:Sulfones; C450961:UK 343,664; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate