Vasodilation by cell membrane permeable but not impermeable carbonic anhydrase inhibitors of precontracted retinal arteries

Purpose Carbonic anhydrase inhibitors (CAI's) are used to lower intraocular pressure in glaucoma. Some have also been found to elevate retinal and optic nerve PO2 and cause vasodilation of retinal arteries. But the mechanism causing the vasodilatation is unknown. The aim is to identify which carbonic anhydrase isoenzymes are involved in control of vascular tone, and whether located intracellularly or on the surface of cell membranes. Selective membrane permeable and impermeable CAI's were used for this purpose. Methods Dissected segments of porcine retinal arteries were mounted in a wire myograph for measurement of contractile activity and precontracted with 10 −6  M U‐46619, a prostaglandin analog, added to the organ bath. With the vascular tone stabilized the CAI's tested were applied separately to the bath, and the effects of each on the tone recorded. Results are presented as mean ± SEM percentage of the maximum vasodilation, as compared to the prior vasoconstriction per mm, induced by 10 −6  M U‐46619. Results The membrane permeable CAI dorzolamide (10 −3  M) induced a mean relaxation of porcine retinal arteries by 76 ± 8% (p < 0.02) when precontracted with U‐46619. Benzolamide, considered a membrane impermeable CAI, induced a significant mean relaxation of 85 ± 8% (p < 0.01) at 10 −3  M after U‐46629 induced vasoconstriction; this relaxation was dose‐dependent. The pyridinium derivative FC5‐207A (10 −3  M), a membrane impermeable CAI, had no effects on the vascular tone of retinal arteries precontracted by U‐45519, at any dose tested. Conclusions Membrane permeable carbonic anhydrase inhibitors induce vasodilation in precontracted porcine retinal arteries, while membrane impermeable inhibitors do not, suggesting that cytosolic isoenzymes are involved in mediating the vasodilation. The results indicate that benzolamide is probably a membrane permeable CAI.