Pulmonary vasoconstrictor influence of endothelin in exercising swine depends critically on phosphodiesterase 5 activity

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.

Surgical Placement of Catheters for Long-term Cardiovascular Exercise Testing in Swine

“…When all points as mentioned above are taken into account, the combination of hemodynamic measurements and blood samples allows for interpretation of the exercise response in terms of whole body and myocardial oxygen consumption, which are better measures for exercise intensity than treadmill speed alone 7,[12][13][14] .…”

“…However, in our research group, we advocate the use of conductance although conductance and resistance are mathematically related, with conductance being flow normalized for pressure, and resistance equaling pressure divided by flow. Although conductance and resistance are interchangeable if one investigates the effect of only a single stimulus (i.e., exercise) 7,17 , interpretation of the two parameters can differ when combining exercise with pharmacological interventions, to investigate the contributions of various vasoactive systems to regulation of vascular tone 4,5,7,14,18 . During exercise, the systemic circulation transforms from a system at rest that is characterized by a low flow and a high resistance (i.e., low conductance) into a system with high flow and low resistance, (high conductance).…”

“…Interpretation of the data thus differs when using resistance or conductance. Although the choice between resistance and conductance may seem rather arbitrary, in physics the variable that undergoes the primary change is designated as the numerator of the index for a response 7,17,18 . Since during exercise aortic blood pressure remains fairly constant whereas cardiac output increases markedly, the most appropriate parameter to describe the systemic vascular response to exercise would appear to be systemic vascular conductance (cardiac output / aortic blood pressure), rather than resistance.…”

“…The choice for either resistance or conductance to describe the vascular responses to exercise in the pulmonary bed appears to be less obvious, because exercise produced increases in cardiac output as well as pulmonary artery pressure 7,17 . A choice for either resistance or conductance is also less critical, in view of the relatively minor exercise-induced changes in PVR and PVC as compared to the degree of vasodilation produced by, for example, ET-receptor blockade 7 .…”

“…A choice for either resistance or conductance is also less critical, in view of the relatively minor exercise-induced changes in PVR and PVC as compared to the degree of vasodilation produced by, for example, ET-receptor blockade 7 . As a result, the use of either resistance or conductance to characterize the vascular effects of a pharmacological vasodilator in the pulmonary circulation will yield similar conclusions.…”