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 (Ip) of isolated cardiac myocytes when intracellular Na+ is at near-physiological levels. To examine if effects of ACE inhibitors are related to angiotensin metabolism, we measured Ip in myocytes isolated from rabbits treated with the AT1 receptor antagonist losartan. Ip 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 Ip 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 Ip of myocytes from captopril-treated rabbits induced by ANG II in vitro was blocked by pertussis toxin, bisindolylmaleimide I, and staurosporine. Exposure of myocytes to phorbol 12-myristate 13-acetate induced a decrease in Ip 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 AT1 receptor, a G protein, and protein kinase C.