cyclic-gmp and Ocular-Hypotension

The nitric oxide/soluble guanylate cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. The purpose is to demonstrate that the sGC activator MGV354 lowers IOP in a monkey model of glaucoma and could be considered as a possible new clinical drug candidate.. Changes to cGMP were assessed in primary human trabecular meshwork (hNTM) cells and binding studies were conducted using human sGC full-length protein. Ocular safety tolerability, exposure, and efficacy studies were conducted in rabbit and monkey models following topical ocular dosing of MGV354.. sGC was highly expressed in the human and cynomolgus monkey outflow pathways. MGV354 had a 7-fold greater Bmax to oxidized sGC compared to that of reduced sGC and generated an 8- to 10-fold greater cGMP compared to that of a reduced condition in hTM cells. A single topical ocular dose with MGV354 caused a significant dose-dependent reduction of 20% to 40% (versus vehicle), lasting up to 6 hours in pigmented rabbits and 24 hours postdose in a cynomolgus monkey model of glaucoma. The MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in a monkey model of glaucoma and was greater in magnitude compared to Travatan (travoprost)-induced IOP reduction. Mild to moderate ocular hyperemia was the main adverse effect noted.. MGV354 represents a novel class of sGC activators that can lower IOP in preclinical models of glaucoma. The potential for sGC activators to be used as effective IOP-lowering drugs in glaucoma patients could be further determined in clinical studies.

Topics: Administration, Ophthalmic; Animals; Antihypertensive Agents; Cells, Cultured; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Activators; Glaucoma; Humans; Immunohistochemistry; Intraocular Pressure; Macaca fascicularis; Ocular Hypotension; Ophthalmic Solutions; Piperidines; Pyrazoles; Pyridines; Rabbits; Soluble Guanylyl Cyclase; Trabecular Meshwork

The purpose of the study is to determine if intravitreal injection of c-type natriuretic peptide (CNP) affects intraocular pressure (IOP), aqueous humor dynamics and guanosine 3',5'-cyclic monophosphate (cGMP) concentration in the aqueous humor of the rabbit eye. Also we investigated whether CNP-like immunoreactivities (CNP-LI) were present in porcine aqueous humor and whether CNP-LI were detected in rabbit and porcine ciliary body. The IOP was measured after intravitreal injection of 2 pmol approximately 20 nmol CNP into rabbit eyes. Aqueous humor dynamics (aqueous humor flow, outflow facility, and uveoscleral outflow) and cGMP concentration in the aqueous humor were determined at approximately 6 hr after CNP injection. The CNP concentration in aqueous was measured by radioimmunoassay in porcine eye, and CNP-LI were detected with a monoclonal antibody in porcine and rabbit eyes. Intravitreally injected CNP caused IOP reduction in a dose-dependent manner (P<0.0001) and the maximum effect was observed at 4 approximately 6 hr. CNP increased total outflow facility by approximately 35%, but did not affect aqueous humor flow or uveoscleral outflow. The cGMP concentration in the aqueous of CNP-treated eyes was about 4- to 14-fold higher than that in the contralateral untreated eyes. CNP concentration in aqueous was about 2-fold higher than that in plasma, and CNP-LI were found in non-pigmented epithelium of the ciliary body of both rabbit and porcine eyes. CNP may play an important role in the regulation of IOP.

Topics: Animals; Aqueous Humor; Cyclic GMP; Immunohistochemistry; Intraocular Pressure; Natriuretic Peptide, C-Type; Ocular Hypotension; Proteins; Rabbits; Swine; Time Factors

To determine whether brain natriuretic peptide (BNP) affects intraocular pressure (IOP), aqueous humor dynamics, and cyclic guanosine monophosphate (cGMP) concentration in the aqueous humor of the rabbit eye.. Twenty microliters of 10(-4) M and 10(-5) M (2 nmol, 0.2 nmol) BNP or atrial natriuretic peptide (ANP) were injected intravitreally into rabbit eyes, after which the IOP was measured using a pneumatonometer. Aqueous humor dynamics were studied at approximately 6 hours after the intravitreal injection of 2 nmol BNP. Aqueous humor flow was measured by fluorophotometry, and outflow facility was measured by the two-level constant pressure perfusion method, whereas uveoscleral outflow was measured by the fluorescein isothiocyanate-dextran perfusion method. The concentration of cGMP in the aqueous humor at 6 hours after injection of 2 or 0.2 nmol BNP also was measured by enzyme immunoassay.. Intravitreal administration of BNP or of ANP caused a decrease in IOP, with a maximum effect at approximately 6 hours after the injection. Total outflow facility in eyes treated with 2 nmol BNP increased by 29%, although the aqueous humor flow and uveoscleral outflow did not show significant changes. The concentration of cGMP in the aqueous humor increased significantly in BNP-treated eyes.. Intravitreal injection of BNP into rabbit eyes reduced IOP because of an increase in the outflow facility. Brain natriuretic peptide also increased the concentration of cGMP in the aqueous humor. It is probable that BNP-activated guanylate cyclase induced an upregulation of cGMP in the aqueous humor.

Topics: Animals; Aqueous Humor; Atrial Natriuretic Factor; Cyclic GMP; Fluorescein; Fluoresceins; Fluorescent Dyes; Fluorophotometry; Injections; Intraocular Pressure; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Ocular Hypotension; Rabbits; Tonometry, Ocular; Vitreous Body