Angiotensin-converting enzyme inhibitors regulate the Na+-K+ pump via effects on angiotensin metabolism

Treatment of rabbits with angiotensin-converting enzyme (ACE)-inhibiting drugs increases Na+-K+ pump current (I-p) Of isolated cardiac myocytes when intracellular Nai is at near-physiological levels. To examine if effects of ACE inhibitors are related to angiotensin metabolism, we measured I-p in myocytes isolated from rabbits treated with the AT(1) receptor antagonist losartan. I-p was increased to levels similar to those after treatment with ACE inhibitors. Exposure of myocytes from captopril-treated rabbits to 10 nM angiotensin II (ANG II) for 45 min in vitro reduced I-p to levels similar to those of myocytes from untreated control rabbits. This rapid response to ANG II suggests that treatment with captopril had induced a functional change in preexisting pump units rather than synthesis of a new population of pumps. Consistent with this, we could not detect a change in Na+-K+ pump subunit mRNAs during treatment with captopril. The decrease in I-p of myocytes from captopril-treated rabbits induced by ANG II in vitro was blocked by pertussis toxin, bisindolylmaleimide I-p and staurosporine. Exposure of myocytes to phorbol 12-myristate 13-acetate induced a decrease in I-p similar to that induced by ANG II. Thus ACE inhibitors regulate the Na+-K+ pump in myocytes via an effect on angiotensin metabolism. The regulatory mechanism appears to include the AT(1) receptor, a G protein, and protein kinase C.