Carbonic anhydrase inhibitors reduce cardiac dysfunction after sustained coronary artery ligation in rats

Background: Two potent carbonic anhydrase (CA) inhibitors with widely differing membrane permeability, poorly diffusible benzolamide (BZ), and highly diffusible ethoxzolamide (ETZ) were assessed to determine whether they can reduce cardiac dysfunction in rats subjected to coronary artery ligation (CAL)-induced myocardial infarction. Methods and results: Rats with evidence of heart failure (HF) at 32 weeks following a permanent left anterior coronary artery occlusion were treated with placebo, BZ, or ETZ (4 mg kg day(-1)) for 4 weeks at which time left ventricular function and structure were evaluated. Lung weight/body weight (LW/BW) ratio increased in CAL rats by 17 +/- 1% vs. control, suggesting pulmonary edema. There was a trend for BZ and ETZ to ameliorate the increase in LW/BW by almost 50% (9 +/- 5% and 9 +/- 8%, respectively, versus CAL) (P=.16, NS). Echocardiographic assessment showed decreased left ventricular midwall shortening in HF rats, 21 +/- 1% vs. control 32 +/- 1%, which was improved by BZ to 29 +/- 1% and ETZ to 27 +/- 1%, and reduced endocardial shortening in HF rats 38 +/- 3% vs. control 62 +/- 1%, partially restored by BZ and ETZ to similar to 50%. Expression of the hypoxia-inducible membrane-associated CAIX isoform increased by similar to 60% in HF rat hearts, and this effect was blocked by ETZ. Conclusions: We conclude that CAL-induced myocardial interstitial fibrosis and associated decline in left ventricular function were diminished with BZ or ETZ treatment. The reductions in cardiac remodeling in HF with both ETZ and BZ CA inhibitors suggest that inhibition of a membrane-bound CA appears to be the critical site for this protection. (C) 2016 Elsevier Inc. All rights reserved.