Abstract
Carbonic anhydrase inhibitors (CAIs), such as dorzolamide (DZA), are used as anti-glaucoma drugs to lower intraocular pressure, but it has been found that some of these drugs act as vasodilators of retinal arteries. The exact mechanism behind the vasodilatory effect is not yet clear. Here we have addressed the issue by using small vessel myography to examine the effect of CAIs of the sulfonamide and coumarin type on the wall tension in isolated segments of porcine retinal arteries. Vessels were pre-contracted by the prostaglandin analog U-46619, and CAIs with varying affinity for five different carbonic anhydrase (CA) isoenzymes found in human tissue tested. We found that all compounds tested cause a vasodilation of pre-contracted retinal arteries, but with varying efficacy, as indicated by the calculated mean EC50 of each compound, ranging from 4.12 µM to 0.86 mM. All compounds had a lower mean EC50 compared to DZA. The dilation induced by benzolamide (BZA) and DZA was additive, suggesting that they may act on separate mechanisms. No clear pattern in efficacy and affinity for CA isoenzymes could be discerned from the results, although Compound 5, with a low affinity for all isoenzymes except the human (h) CA isoform IV, had the greatest potency, with the lowest EC50 and inducing the most rapid and profound dilation of the vessels. The results suggest that more than one isozyme of CA is involved in mediating its role in controlling vascular tone in retinal arteries, with a probable crucial role played by the membrane-bound isoform CA IV.
Highlights
Carbonic anhydrases (CAs; EC 4.2.1.1) are a class of ubiquitous zinc enzymes that are present in a wide variety of tissues in living organisms [1]
The present study shows for the first time that BZA causes a vasodilation in isolated porcine retinal arterioles, which is significantly more profound than that induced by DZA, as found previously by some studies [16,18]
It is not clear if these effects are related to the vasodilatory effects of BZA and other Carbonic anhydrase inhibitors (CAIs) shown here, but it has been shown that charybdotoxin, the selective blocker of calcium activated potassium channels (KCa), blocks vasodilation of isolated mesenteric arteries induced by CAIs [35]
Summary
Carbonic anhydrases (CAs; EC 4.2.1.1) are a class of ubiquitous zinc enzymes that are present in a wide variety of tissues in living organisms [1]. The 6-substituted alkyne derivative 4 showed comparable KIs values for hCAs IV and XII, comprised in the medium nanomolar range (69.2 and 56.4 nM, respectively), whereas the tumor associated isoform IX was inhibited at a micromolar concentration (KI of 4747.6 nM). The sulfonamide CAI BZA 1 (Figure 1), in consideration of its enhanced acidic properties at physiological pH, has for a long time been assumed to act primarily on CAs on the extracellular side of cell membranes [27]. A single dose of 10−3 M compound 6 was added and induced a slow vasodilation, which was 96.8% of the maximum contraction of the vessel. The difference in the vasodilation induced by the two compounds at 10−3 M was significant (Two tailed t-test, p < 0.001)
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