Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors

Abstract

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 F2 alpha (PFG2 alpha)-induced tone in human pulmonary arteries was investigated. Relaxation was achieved by IBMX [concentration eliciting 50% of maximum response (EC50): 11.3 microM, n = 10], motapizone (EC50:3.0 microM, n = 7), zardaverine (EC50: 3.2 microM, n = 9), and zaprinast (EC50: 31.8 microM, n = 6), whereas rolipram was almost ineffective. The combination of motapizone and zaprinast (10 microM) was the most effective relaxant with supra-additive relaxation and a motapizone EC50 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. PGF2 alpha-induced tone in this tissue is effectively relaxed through PDE inhibitors with selectivity for type III, III/IV, and type V PDE.

Effect of sildenafil on cyclic nucleotide phosphodiesterase activity, vascular tone and calcium signaling in rat pulmonary artery

“…, respectively, for cGMP and cAMP) are much higher than those previously reported in bovine or human pulmonary arteries (Rabe et al, 1994;Pauvert et al, 2002). Sildenafil inhibited the cGMP-PDE activity in both subcellular fractions.…”

“…This pathophysiological adaptation of the pulmonary circulation to maintain hypoxia is a complicated process for which no curative treatment, except heart -lung transplantation, is currently available. Since PDEs are present in the pulmonary artery wall (Rabe et al, 1994;Maclean et al, 1997) and that cGMP-PDE activity is mainly because of the action of PDE5 (Rabe et al, 1994), some PDE5 inhibitors have been administered to counteract PAHT development both in animals and human (Eddahibi et al, 1998;Ziegler et al, 1998;Hanasato et al, 1999). Very recently, pioneer clinical trials with sildenafil have been performed in PAHT (Abrams et al, 2000;Ichinose et al, 2001;Zhao et al, 2001).…”

Therapeutic Potential of Phosphodiesterase 5 Inhibition for Cardiovascular Disease

“…In the human pulmonary circulation, the isoforms 1, 3, 4, and 5 seem to be involved in regulating pulmonary resistance. 10,11 A peculiarity of the cAMP-hydrolyzing PDE 3 is that it can be inhibited by cGMP. 2,12 Therefore, in tissues containing both PDE 3 and 5, sildenafil could indirectly increase cAMP concentrations via inhibition of PDE 3 by cGMP ( Figure 1).…”

“…10,11 Thus, the blood pressure-lowering effects of sildenafil in the pulmonary circulation are of special interest. Zhao et al 48 demonstrated that 100 mg of oral sildenafil markedly reduced the rise in arterial pulmonary pressure in response to breathing 11% inspiratory oxygen in healthy volunteers, which paralleled their findings in a mouse model of hypoxia-induced pulmonary hypertension.…”

Clinical deterioration after sildenafil cessation in patients with pulmonary hypertension

“…This is the predominant phosphodiesterase isoform in the lungs (Rabe et al 1994). Sildenafi l inhibits the breakdown of cGMP, and enhances the ability of endothelial nitric oxide to vasodilate the pulmonary arteries, reducing intravascular calcium, relaxing smooth muscle cells and reducing pulmonary vascular resistance (PVR) (Corbin et al 1999).…”