No abstract

Both phosphodiesterase 5 (PDE5) inhibition and endothelin (ET) receptor blockade have been shown to induce pulmonary vasodilation. However, little is known about the effect of combined blockade of these two vasoconstrictor pathways. Since nitric oxide (NO) exerts its pulmonary vasodilator influence via production of cyclic guanosine monophosphate (cGMP) as well as through inhibition of ET, we hypothesized that interaction between the respective signaling pathways precludes an additive vasodilator effect. We tested this hypothesis in chronically instrumented swine exercising on a treadmill by comparing the vasodilator effect of the PDE5 inhibitor EMD360527, the ETA/ETB antagonist tezosentan, and combined EMD360527 and tezosentan. In the systemic circulation, vasodilation by tezosentan and EMD360527 was additive, both at rest and during exercise, resulting in a 17 ± 2% drop in blood pressure. In the pulmonary circulation, both EMD360527 and tezosentan produced vasodilation. However, tezosentan produced no additional pulmonary vasodilation in the presence of EMD360527, either at rest or during exercise. Moreover, in isolated preconstricted porcine pulmonary small arteries (∼300 μm) EMD360527 (1 nM-10 μM) induced dose-dependent vasodilation, whereas tezosentan (1 nM-10 μM) failed to elicit vasodilation irrespective of the presence of EMD360527. However, both PDE5 inhibition and 8Br-cGMP, but not 8Br-cAMP, blunted pulmonary small artery contraction to ET and its precursor Big ET in vitro. In conclusion, in healthy swine, either at rest or during exercise, PDE5 inhibition and the associated increase in cGMP produce pulmonary vasodilation that is mediated in part through inhibition of the ET pathway, thereby precluding an additional vasodilator effect of ETA/ETB receptor blockade in the presence of PDE5 inhibition.

IntroductionFollowing myocardial infarction (MI), left ventricular (LV) remodeling aims to maintain cardiac function. Nevertheless, adverse remodeling results in thinning of the infarct and LV dilation which may subsequently lead to the development of heart failure (HF) with poor prognosis. Wnt/Frizzled signaling plays a key role in cardiac remodeling following MI. We have shown previously that blockade of Wnt/Frizzled signaling with UM206 suppresses adverse remodeling and prevents HF development in mice post‐MI. Here we investigated the effects of UM206 therapy in a clinically relevant large animal model.MethodsTwelve Yorkshire x Landrace swine were subjected to 2h of myocardial ischemia by ligation of the proximal left circumflex artery, followed by reperfusion. Starting 24h post‐MI, 6 animals were treated with UM206 (0.6 μg/kg/day i.v.) for 5 weeks. The 6 control swine were treated with vehicle. Cardiac dimensions and infarct mass (IM) were determined by echocardiography and dedicated markers, respectively.ResultsTreatment with UM206 for 5 weeks resulted in a significant decrease in IM compared to baseline, whereas IM remained unaffected in the control group. This was accompanied by progressive dilation of the LV in the control group between 3 and 5 weeks after MI while adverse remodeling was halted in the UM206 treated group.ConclusionUM206 treatment in a clinically relevant swine model of reperfused myocardial infarction attenuates adverse remodeling.Supported by the Dutch Heart Foundation (2010B196)