Purchase this article with an account.
B. T. Gabelt, C. A. Rasmussen, P. L. Kaufman, B. Katz; Effect of the Ion Channel Modulator DNB-001 on Ciliary Muscle Contraction. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4856.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The balance between tone of trabecular meshwork (TM) and ciliary muscle (CM) may regulate aqueous humor outflow from the eye. Contractile and relaxation effects of these tissues are at least partially regulated via a calcium-dependent maxi-K+ channel that plays a role in altering membrane potentials of TM and CM. DNB-001, a new in class ion channel modulating compound, has demonstrated biologic activity in lowering IOP in several animal models of glaucoma and in man. To investigate underlying mechanisms of action of DNB-001, we determined the effects of ion modulation on the relaxation and contractile responses in both longitudinal and circular vectors of isolated monkey CM.
A multiple-dose study was performed in 4 monkey CM explants (3 rhesus, 1 cynomolgus, 7-9 yrs) employing concentrations of 0.5 µM, 5.0 µM, and 50.0 µM DNB-001 in 1% DMSO/Krebs solution. Contractile forces in fresh monkey CM strips were monitored in both longitudinal and circular vectors, simultaneously. Responses generated with DNB-001 were compared to those generated by 1 µM carbachol in 1%DMSO/Krebs and to 1% DMSO/Krebs alone.
Resting CM tension after Krebs equilibration was [mean±sem] 88.8±15.4 mg (longitudinal) and 62.8±7.9 mg (circular). Carbachol (1µM) produced a contraction force of 59.4±11.1 mg and 39.7±7.9 mg, in the two vectors respectively. Addition of 1% DMSO to the carbachol solution resulted in a reduction in tension of 11.3±4.8% (longitudinal) and 8.4±1.7% (circular). Carbachol plus DMSO tension was considered as baseline for evaluation of responses to DNB-001 in contracted CM. DNB-001 produced a dose-related relaxation of carbachol pre-contracted CM. 5µM DNB-001 produced a maximum relaxation response of 78.9±26.1% (longitudinal, not significant) and 78.5±17.6% (circular, p<0.05). Following washout with 1% DMSO/Krebs and re-establishing a new baseline, the addition of DNB-001 (5 and 50µM) produced variable but insignificant effects on resting tension.
Results indicate that DNB-001 relaxes pre-contracted CM and possibly resting CM, suggesting, that, at the 5µM dose, DNB-001 might have an effect on aqueous humor outflow in vivo. Further investigation of the mechanism(s) of action in vivo is warranted. Given its neuroprotective profile and its unique physicochemical properties that make it amenable to sustained drug delivery, DNB-001 offers promise for the treatment of glaucoma, with novel therapeutic strategy.
This PDF is available to Subscribers Only