ELEVATED MYOCARDIAL INTERSTITIAL NOREPINEPHRINE CONCENTRATION CONTRIBUTES TO THE REGULATION OF NA-ATPASE IN HEART-FAILURE(K+)

Myocardial Na+,K+-ATPase is reduced in congestive heart failure. To st udy the regulation of Na+,K+-ATPase in congestive heart failure, we pe rformed Western and Northern blot analyses of ventricular myocardium o f dogs with pacing-induced congestive heart failure and chronic norepi nephrine infusion, using isoform-specific antibodies and cDNA probes. Congestive heart failure and norepinephrine infusion caused similar in creases in myocardial interstitial norepinephrine concentration and re ductions of myocardial Na+,K+-ATPase alpha(3)-subunit protein, but dif fered in their effects on myocardial Na+,K+-ATPase alpha(3)-subunit ge ne expression. Chronic norepinephrine infusion produced no changes in the steady-state mRNA level for the alpha(3)-subunit of Na+,K+-ATPase, suggesting that the changes in Na+,K+-ATPase protein were induced via a post-transcriptional mechanism. In contrast, down-regulation of the Na+,K+-ATPase alpha(3)-subunit in the failing heart was accompanied b y a decreased alpha(3)-subunit mRNA level, indicating the presence of a transcriptional event. The alpha(3)-subunit protein content and mRNA level were not affected by either norepinephrine infusion or rapid ve ntricular pacing. We conclude that, while elevated myocardial intersti tial norepinephrine levels may contribute substantially to the down-re gulation of the Na+,K+-ATPase alpha(3)-subunit in the failing myocardi um, additional regulatory factors are responsible for the decreased my ocardial alpha(3)-subunit mRNA expression in congestive heart failure.