K-134

Post-stroke antiplatelet therapy has been proved to reduce the risk of recurrent stroke; however, it may also increase the incidence of intracranial hemorrhage that could offset any benefits. Therefore, the balance between the benefits and risks of antiplatelet drugs is a critical issue to consider. In the present study, we have compared the effects of post-stroke administration of antiplatelet agents on functional outcomes in the stroke-prone spontaneously hypertensive rat (SHRSP), an established animal model that mimics human lacunar stroke and cerebral small vessel disease. We confirmed that a potent phosphodiesterase 3 (PDE3) inhibitor, K-134, significantly improved post-stroke survival rate and survival time, attenuated stroke-induced neurological deficits, and decreased the incidence of cerebral lesion caused by intracerebral hemorrhage and softening. Similarly, cilostazol showed beneficial effects, though to a lower extent with respect to the survival outcome and neurological symptoms. On the other hand, a P2Y12 inhibitor, clopidogrel significantly improved survival outcomes at the higher dose but caused massive bleeding in the brain at both low and high doses. In contrast, no hemorrhagic lesion was observed in K-134-treated SHRSPs despite its antiplatelet activity. Our findings indicate that K-134 may have a superior post-stroke therapeutic outcome in comparison to other antiplatelet drugs.

Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease, which frequently results in fatal rupture; however, no pharmacologic treatment exists to inhibit AAA growth and prevent rupture. In this study, we investigated whether K-134, a novel phosphodiesterase 3 inhibitor, could limit the progression and rupture of AAA using multiple experimental models.

A hypoperfusion-induced AAA rat model was developed by inserting of a small catheter and via tight ligation of the infrarenal aorta. Rats were fed with a 0.15% K-134-containing diet (K-134(+) group) or a normal diet (K-134(-) group) from 7 days before the experiment to 28 days after model creation (pretreatment protocol). After the administration period, elastin fragmentation, macrophage infiltration, reactive oxygen species expression, matrix metalloproteinase levels, aneurysmal tissue hypoxia, and adventitial vasa vasorum (VV) stenosis were assessed. In the delayed treatment protocol, rats with AAA >3 mm were randomly divided to K-134(+) or K-134(-) group 7 days after model creation, and the effect of K-134 on suppressing preexisting AAA was examined. Further, elastase-induced rat model and angiotensin II-infused ApoE^-/- mouse model were also used to examine the ability of K-134 to prevent rupture.

K-134 prevented AAA rupture and significantly improved survival in the pretreatment protocol (P < .01). In the K-134(+) group, elastin degeneration was prevented; macrophage infiltration and reactive oxygen species production were significantly decreased. At 14 days, the enzymatic activity of matrix metalloproteinase-9 was significantly decreased. Further, K-134 inhibited intimal hyperplasia and VV stenosis. Expressions of hypoxic markers, hypoxia-inducible factor-1α, and pimonidazole, in the aneurysmal wall were also attenuated. In the delayed treatment protocol, K-134 also improved survival of rats with preexisting AAA. Similarly, in the elastase-induced rat model and angiotensin II-infused ApoE^-/- mouse model, K-134 inhibited rupture and significantly improved survival (P < .01).

K-134 prevented the rupture of AAA and improved survival through suppressing inflammatory reaction. The inhibition of intimal hyperplasia in the adventitial VV may be associated with reduced hypoxia in the aneurysmal tissue. (JVS-Vascular Science 2020;1:219-32.).

This study shows that K-134, a novel phosphodiesterase 3 inhibitor, suppressed abdominal aortic aneurysm (AAA) rupture. Considering that K-134 had already undergone a phase Ⅱ study in the United States for claudication in peripheral artery occlusive disease patients with good tolerance, K-134 may become a promising new therapeutic option for AAAs and could undergo clinical trials for patients with small AAA.