Vasodilation of Pre-contracted Porcine Retinal Arteries by Carbonic Anhydrase Inhibitors with Enhanced Lipophilicity

Abstract

Purpose

In this study, we investigated the vasodilation properties on pre-contracted retinal arteries of a restricted series of carbonic anhydrase inhibitors (CAIs) of the sulfonamide type with enhanced lipophilicity, to assess if it affects the potency of CAIs as vasodilators.

Methods

Carbonic anhydrase (CA) inhibition and in vitro kinetics of the compounds designed and synthesized for testing in this study were assessed by extracting human CA isoform proteins (hCA) from human cells expressing the isoforms of interest, and then measure the affinity of the novel compound for the hCAs by stopped-flow CO₂ hydrase spectroscopy. Lipophilicity of compounds was measured by obtaining their octanol-water partition coefficient, expressed as calculated logP. Porcine eyes were obtained from a local abattoir, and the wall tension of porcine retinal arteriole segments dissected from the eyes was measured with small wire vessel myography. The effects of the CA compounds on wall tension were assessed by adding them to the myography bath, after pre-contracting the vessel by prostaglandin analog U-46619.

Results

All compounds induced vasodilation but at different concentrations. Among the tested compounds the most potent vasodilators were found to be the seleno-compound 4 and sulfur-ether compound 8 with EC₅₀ values of 7.13 × 10⁻⁵ and 7.93 × 10⁻⁵ M, respectively, whereas the remaining ones induced complete vasodilation at EC₅₀ comprised within the sub millimolar range.

Conclusions

All the data reported in this study (i.e. results from myography, in vitro kinetics and LogPs) confirm the important role played by several CA isoforms in vasodilation, although the precise mechanism of action still remains to be elucidated.

Keywords:

• Carbonic anhydrase inhibitors (CAIs)
• myography
• retinal artery
• stopped-flow inhibition
• lipophilicity

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available from the corresponding author, Dr. Thor Eysteinsson, upon reasonable request.

Additional information

Funding

This study was supported in part by grants from the Helga Jónsdottir and Sigurlidi Kristjansson Memorial Fund (Reykjavik, Iceland); University of Iceland Research Fund (TE). FC is grateful to “Bando di Ateneo per il Finanziamento di Progetti Competitivi per Ricercatori a Tempo Determinato (RTD) dell’Università di Firenze 2020 − 2021,” which partially funded this work.