Lung vasodilatory response to inhaled iloprost in experimental pulmonary hypertension: amplification by different type phosphodiesterase inhibitors

Abstract

Inhaled prostanoids and phosphodiesterase (PDE) inhibitors have been suggested for treatment of severe pulmonary hypertension. In catheterized rabbits with acute pulmonary hypertension induced by continuous infusion of the stable thromboxane analogue U46619, we asked whether sildenafil (PDE1/5/6 inhibitor), motapizone (PDE3 inhibitor) or 8-Methoxymethyl-IBMX (PDE1 inhibitor) synergize with inhaled iloprost. Inhalation of iloprost caused a transient pulmonary artery pressure decline, levelling off within <20 min, without significant changes in blood gases or systemic hemodynamics. Infusion of 8-Methoxymethyl-IBMX, motapizone and sildenafil caused each a dosedependent decrease in pulmonary artery pressure, with sildenafil possessing the highest efficacy and at the same time selectivity for the pulmonary circulation. When combining a per se ineffective dose of each PDE inhibitor (200 µg/kg × min 8-Methoxymethyl-IBMX, 1 µg/kg × min sildenafil, 5 µg/kg × min motapizone) with subsequent iloprost nebulization, marked amplification of the prostanoid induced pulmonary vasodilatory response was noted and the area under the curve of P PA reduction was nearly threefold increased with all approaches, as compared to sole iloprost administration. Further amplification was achieved with the combination of inhaled iloprost with sildenafil plus motapizone, but not with sildenafil plus 8MM-IBMX. Systemic hemodynamics and gas exchange were not altered for all combinations. We conclude that co-administration of minute systemic doses of selective PDE inhibitors with inhaled iloprost markedly enhances and prolongs the pulmonary vasodilatory response to inhaled iloprost, with maintenance of pulmonary selectivity and ventilation perfusion matching. The prominent effect of sildenafil may be operative via both PDE1 and PDE5, and is further enhanced by co-application of a PDE3 inhibitor.

Phosphodiesterase 1 Upregulation in Pulmonary Arterial Hypertension

“…Along with the first proof of PDE1 upregulation in the pulmonary circulation provided in the present report, a strong rationale to explain potential antiproliferative effects via PDE1 inhibition is provided. Moreover, the present findings may add to the understanding of why certain hemodynamic differences between clinically available PDE5 inhibitors were found 7 and explain the strong synergism between sildenafil and cAMP-increasing compounds, eg, inhaled iloprost, which has been demonstrated experimentally 27 and clinically. [43][44][45] Using another PDE1 inhibitor, PI79, we demonstrated the inhibition of DNA synthesis of pulmonary SMCs in a dose-dependent manner.…”

“…A recent study from Evgenov et al 17 demonstrated that selective inhibition of PDE1 augments the therapeutic efficacy of inhaled NO in an ovine model of acute thromboxane-induced pulmonary hypertension, which demonstrates the contribution of PDE1 to pulmonary vascular tone. On the selectivity of 8MM-IBMX for PDE1 versus other PDEs, previously published data from our own group 27 and from others 16 suggest a 10-to 30-fold more selective inhibition of PDE1 versus PDE3 and PDE4, respectively. Thus, at the currently chosen dose, no relevant inhibition of other PDE isoforms is to be expected to contribute to the findings presented here.…”

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

“…12 Although numerous hypertensive drugs play important roles in hypertension treatment, diets such as the Dietary Approaches to Stop Hypertension (DASH) diet have emerged as effective antihypertensive strategies. 13 Our recent study demonstrated that TRPM8 activation by chronic dietary menthol can prevent high-fat diet-induced obesity in mice via Uncoupling Protein-1-mediated thermogenesis upregulation…”

Phosphodiesterase 5 inhibitors augment UT-15C-stimulated ATP release from erythrocytes of humans with pulmonary arterial hypertension

“…It has been previously shown in isolated perfused lungs and intact rabbits that pulmonary vasodilation is enhanced when PDE inhibitors are administered in combination with inhaled iloprost. 31,32 In studies in humans, reductions in pulmonary vascular resistance produced by the PDE5 inhibitor sildenafil and inhaled iloprost were shown to be additive. 6,33,34 The potential for improved survival in PAH patients treated with this approach is suggested by studies in rats in which pulmonary hypertension was induced by monocrotaline.…”