α₁‐adrenergic stress induces downregulation of Na⁺/Ca²⁺ exchanger in myocardial preparations from rabbits at physiological preload

Abstract

α 1 -adrenergic stimulation and mechanical load are considered crucial for the expression of sarcolemmal Na + /Ca 2+ exchanger (NCX1). However, the interaction between these processes is unknown.We investigated electrically stimulated (1 Hz, 1.75 mmol/L Ca 2+ ) rabbit ventricular trabeculae at physiological preload under stimulation by the selective α 1 -agonist phenylephrine (PE, 10 μmol/L). Using quantitative real-time PCR, downregulation of mRNA to 76.5% ( p b 0.05) was found, while B-type natriuretic peptide (BNP) was increased to 569.5% ( p b 0.05) compared to control. These changes were abolished in the presence of both the α 1 -blocker prazosin (13 μmol/L) and the PKC inhibitor GF109203X (1 μmol/L). Furthermore, no changes in NCX mRNA levels under the influence of PE were found in unstretched trabeculae or in unstretched isolated rabbit myocytes (24 h), while BNP was increased in both preparations. In addition, since the α 1 -adrenergic effect could be Ca 2+ -dependent we tested increased extracellular Ca 2+ (3.0 mmol/L) in stretched trabeculae and found downregulation of NCX1 to 75.2% ( p b 0.05).α 1 -stimulation decreases NCX1 mRNA in rabbit myocardium via PKC. This is critically load-dependent and may be mediated by changes in [Ca 2+ ]. In hypertrophy and heart failure, distinct phenotypes with respect to NCX1 expression may result from the interaction between mechanical load and α 1 -adrenergic stimulation.