Relaxation and potentiation of cGMP-mediated response by ibudilast in bovine tracheal smooth muscle

Abstract

The effects of ibudilast, an inhibitor of phosphodiesterases (PDEs), on tension, levels of guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) were investigated in bovine tracheal smooth muscle. We especially examined the combined effect of ibudilast with the cGMP-elevating agents on these parameters. Ibudilast was equipotent to attenuate the precontractions induced by both 0.3 microM methacholine and 40 mM K(+). By contrast, the relaxant effects of sodium nitroprusside and salbutamol on 40 mM K(+)-contracted preparations were smaller than those on 0.3 microM methacholine-contracted ones. Neither N(omega)-nitro-L-arginine (100 microM), an inhibitor of nitric oxide synthase, nor ODQ (1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 5 microM), an inhibitor of soluble guanylyl cyclase, affected the ibudilast-induced relaxation. The relaxations induced by ibudilast and diltiazem on 40 mM K(+)-contracted preparations were significantly attenuated when extracellular CaCl(2) was increased from 2.54 mM to 10 mM. Ibudilast (10 microM), which caused only minor effect by itself, significantly ( P<0.05) shifted the concentration-response curves for the relaxant responses to sodium nitroprusside (SNP), atrial natriuretic peptide (ANP) and salbutamol to the left. On the other hand, ibudilast did not change the relaxant responses to diltiazem. Unlike ibudilast, diltiazem (3 microM) failed to affect the SNP- and salbutamol-induced relaxations. Ibudilast significantly ( P<0.05) increased basal levels of cGMP and cAMP. Furthermore, ibudilast enhanced SNP (0.3 microM)- and ANP (0.3 microM)-induced cGMP accumulation and salbutamol (10 nM)-induced cAMP accumulation. Zaprinast (10 microM), a type 5 PDE inhibitor, enhanced both relaxation and cGMP accumulation induced by SNP and ANP without changing salbutamol-induced responses. These findings suggest that blockade of voltage-gated Ca(2+) channels is involved in the relaxing action of ibudilast in bovine tracheal smooth muscle. However, ibudilast potentiates relaxation responses to ANP and SNP by inhibition of PDE 5, not by blockade of Ca(2+) channels. The enhancement of cGMP-mediated response may contribute to the therapeutic effects of ibudilast.

Platelet-Activating Factor Modulates Activity of Cyclic Nucleotides in Fetal Ovine Pulmonary Vascular Smooth Muscle

“…Endothelium-derived nitric oxide produced under basal conditions or by a stimulus readily diffuses into the contiguous smooth muscle to activate soluble guanylyl cyclase, resulting in increased cGMP synthesis and smooth muscle relaxation (Ignarro, 1990;Nakahara et al, 2002;Gao et al, 2004). Nitric oxide (NO), a potent vasodilator in the pulmonary circulation, is important in the transition of the pulmonary circulation from fetal to postnatal life.…”

“…cAMP production is linked to ␤-adrenergic receptor-mediated activation of adenylyl cyclase (Gilman, 1995;Milligan and Kostenis, 2006). Inhibition of cGMP-and cAMP-dependent phosphodiesterases can also result in high cellular levels of cGMP and cAMP (Nakahara et al, 2002;Hicks et al, 2005). Although 8-Br-cAMP did not significantly alter PAF binding in hypoxia, inhibition of cAMP/PKA with Rp-cAMPS, obliterated the endogenous cAMP effect and significantly increased PAF binding in hypoxia, suggesting that cGMP and cAMP interact with PAFr after activation of their own receptors.…”

Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast

“…This action leads to increased levels of cGMP and inhibition of tracheal smooth muscle contractility (1). Because these increased levels of cGMP result in a potentiating effect on the antiplatelet function of endothelial cell nitric oxide, AV411 also has been used for cerebrovascular disorders, such as poststroke complications (2).…”

The Relaxant Action of Nicorandil in Bovine Tracheal Smooth Muscle

“…To investigate the mechanisms underlying this interaction, we examined the role of Maxi K + channels in nicorandil-induced relaxations of bovine tracheal smooth muscle, since this channel can be activated through NO-cGMP-dependent mechanisms in several smooth muscle tissues, including tracheal smooth muscle [20,21,22,23,24]. In bovine tracheal smooth muscle, sodium nitroprusside-induced relaxations were greatly attenuated when preparations were precontracted with high K + instead of methacholine, as reported in our previous study [25]. In the current study, we found that the Maxi K + channel inhibitor iberiotoxin exhibited an inhibitory effect on NO donor-induced relaxations.…”