Ibudilast, a mixed PDE3/4 inhibitor, causes a selective and nitric oxide/cGMP-independent relaxation of the intracranial vertebrobasilar artery

Ibudilast, a mixed phosphodiesterase (PDE) 3/4 inhibitor, is a cerebral vasodilator widely used in Japan for treating post-stroke dizziness. However, little studies have been conducted on the vasorelaxant effects of PDE inhibitors in the vertebrobasilar artery associated with dizziness onset. The in vitro vasorelaxant properties of ibudilast were, therefore, investigated by comparing with known selective PDE inhibitors, using vertebrobasilar arteries. Vasorelaxant activities of PDE3, PDE4, PDE5 inhibitors, and ibudilast were assessed in 5-hydroxytryptamine precontracted ring preparations from rabbit intracranial and extracranial vertebrobasilar arteries. Ibudilast more selectively relaxed the intracranial than extracranial artery. Similarly, selective PDE3 and PDE4 inhibitors showed higher selectivity for intracranial arteries. Furthermore, like selective PDE4 inhibitor, the vasorelaxation by ibudilast accompanied by increase in cAMP levels was inhibited by the adenylyl cyclase inhibitor SQ22536 in intracranial arteries. Next, it was examined whether nitric oxide (NO)/cGMP signaling is involved in this vasorelaxation in intracranial arteries. The suppression of NO/cGMP signaling by an NO synthase inhibitor or a guanylyl cyclase inhibitor potentiated the vasorelaxion by a PDE3 inhibitor and reduced that by a PDE4 inhibitor, while either suppression of the signaling had little influence on that by ibudilast. These results suggest that ibudilast has the high vasoselectivity for intracranial artery based on a mixed PDE3 and PDE4-inhibition, and effectively relaxes intracranial arteries independently of NO/cGMP signaling because of its vasorelaxation compensated by either PDE3- or PDE4-inhibition depending on the state of NO/cGMP signaling change.