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.


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 kgday-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 ~50%. Expression of the hypoxia-inducible membrane-associated CAIX isoform increased by ~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.
Centro de Investigaciones Cardiovasculares, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 1900 La Plata, Buenos Aires, Argentina.
Lorena A
LA
Vargas
Centro de Investigaciones Cardiovasculares, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 1900 La Plata, Buenos Aires, Argentina.
Oscar A
OA
Pinilla
Centro de Investigaciones Cardiovasculares, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 1900 La Plata, Buenos Aires, Argentina.
Romina G
RG
Díaz
Departamento de Patología, Universidad Favaloro, C1078AAJ Ciudad Autónoma de Buenos Aires, Argentina.
Diana E
DE
Sepúlveda
Department of Medicine, Pulmonary and Critical Care Medicine, VA Puget Sound Health Care System, University of Washington, Seattle, WA 98108, USA.
Erik R
ER
Swenson
Centro de Investigaciones Cardiovasculares, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 1900 La Plata, Buenos Aires, Argentina.
Néstor G
NG
Pérez
Centro de Investigaciones Cardiovasculares, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 1900 La Plata, Buenos Aires, Argentina. Electronic address: balvarez@med.unlp.edu.ar.
Bernardo V
BV
Álvarez
D000818:Animals; D001574:Benzolamide / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D003331:Coronary Vessels / Q000601:surgery; D004195:Disease Models, Animal; D005016:Ethoxzolamide / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D015151:Immunoblotting; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
D002257:Carbonic Anhydrase Inhibitors; D001574:Benzolamide; D005016:Ethoxzolamide
Carbonic anhydrase inhibitors; Heart failure; Intracellular pH; Myocardial infarction