IDENTIFICATION OF PDE ISOZYMES IN HUMAN PULMONARY-ARTERY AND EFFECT OF SELECTIVE PDE INHIBITORS

The effects of the nonselective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the selective PDE inhibitors motapizone (type III), rolipram (type IV), zardaverine (type III/IV), and zaprinast (type V and I) on prostaglandin F-2 alpha (PGF(2 alpha))-induced tone in human pulmonary arteries was investigated. Relaxation was achieved by IBMX [concentration eliciting 50% of maximum response (EC(50)): 11.3 mu M, n = 10], motapizone (EC(50): 3.0 mu M, n = 7), zardaverine (EC(50): 3.2 mu M, n = 9), and zaprinast (EC(50): 31.8 mu M, n = 6), whereas rolipram was almost ineffective. The combination of motapizone and zaprinast (10 mu M) was the most effective relaxant with supra-additive relaxation and a motapizone EC(50) of 575 nM. Biochemical studies revealed the presence of the PDE isozymes I, III, IV and V in the cytosolic and particulate phases of arterial homogenates; PDE II was not detectable. Partial inhibition of adenosine 3',5'-cyclic monophosphate (cAMP)-hydrolyzing PDE activity was achieved with rolipram(26 +/- 2.2%) or motapizone (60 +/- 5.4%), whereas there was almost complete inhibition of total PDE activity with zardaverine (81 +/- 2.0%) or the combination of motapizone and rolipram (82 +/- 2.3%). Inhibition of guanosine 3',5'-cyclic monophosphate (cGMP)-hydrolyzing PDE activity was achieved with zaprinast (62 +/- 2.6%) and motapizone (13 +/- 2.3%), indicating the cGMP-hydrolyzing activity of PDE III. We conclude that four out of the five recognized PDE isozyme families are present in human pulmonary artery. PGF(2 alpha)-induced tone in this tissue is effectively relaxed through PDE inhibitors with selectivity for type III, III/IV, and type V PDE.