Stimulation of Myocardial Na+-Independent Cl−-HCO3− Exchanger by Angiotensin II Is Mediated by Endogenous Endothelin

Abstract

Experiments were performed in isolated cat papillary muscles loaded with the pH-sensitive dye 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein in the esterified form to study the effect of endothelin-1 (ET-1) on the activity of the Na⁺-independent Cl⁻-HCO₃⁻ exchanger. Exposure to ET-1 (10 nmol/L) raised pH_i by 0.13±0.03 U (<i>P</i>&lt;0.05) in papillary muscles superfused with nominally HCO₃⁻-free solution, whereas no significant change was detected under CO₂/HCO₃⁻-buffered medium. However, if ET-1 was applied to muscles pretreated with the anion exchanger inhibitor 4-acetamido-4′-isothiocyanato-stilbene-2,2′-disulfonic acid, pH_i increased by 0.09±0.02 U (<i>P</i>&lt;0.05) in the presence of CO₂/HCO₃⁻ buffer. The rate of pH_i recovery from trimethylamine hydrochloride–induced intracellular alkaline load was enhanced so that net HCO₃ efflux increased about three times in the presence of ET-1 (2.74±0.25 versus 9.66±1.29 mmol · L⁻¹ · min⁻¹ at pH_i 7.55, <i>P</i>&lt;0.05). This effect was canceled by previous exposure to either 50 nmol/L PD 142,893 (nonselective endothelin receptor blocker) or 300 nmol/L BQ 123 (selective blocker of ET_A receptors). BQ 123 also abolished angiotensin II–induced activation of the Na⁺ independent Cl⁻-HCO₃⁻ exchanger. These results show that ET-1 increases the activity of the Na⁺-independent Cl⁻-HCO₃⁻ exchanger in cardiac tissue through the ET_A receptors. Furthermore, our data suggest that the previously described angiotensin II–induced stimulation of the anion exchanger activity is mediated by endogenous ET-1.