Effects of graded LBNP on MSNA and interstitial norepinephrine.

The inotropic and toxic effects of cardiac steroids are thought to result from Na[sup +]-K[sup +]ATPase inhibition, with elevated intracellular Na[sup +](Na[sup +, sub i])causing increased intracellular Ca[sup 2+](Ca[sup 2+, sub i]) via Na-Ca exchange. We studied the effects of ouabain on cat ventricular myocytes in Na[sup +]-free conditions where the exchanger is inhibited. Cell shortening and Ca[sup 2+, sub i] transients (with fluo 4-AM fluorescence) were measured under voltage clamp during exposure to Na[sup +]-free solutions [LiC1 or N-methyl-Dglucamine (NMDG) replacement]. Ouabain enhanced contractility by 121 ± 55% at 1 µmol/1 (n = 11) and 476 ± 159% at 3 µmol/l (n = 8) (means ± SE). Ca[sup 2+, sub i] transient amplitude was also increased. The inotropic effects of ouabain were retained even after pretreatment with saxitoxin (5 µmol/1) or changing the holding potential to -40 mV (to inactivate Na[sup +] current). Similar results were obtained with both Li[sup +] and NMDG replacement and in the absence of external K[sup +], indicating that ouabain produced positive inotropy in the absence of functional Na-Ca exchange and Na[sup +]-K[sup +]-ATPase activity. In contrast, ouabain had no inotropic response in rat ventricular myocytes (10-100 µmol/l). Finally, ouabain reversibly increased Ca[sup 2+] overload toxicity by accelerating the rate of spontaneous after contractions (n = 13). These results suggest that the cellular effects of ouabain on the heart may include actions independent of Na[sup +]-K[sup +]-ATPase inhibition, Na-Ca exchange, and changes in Na[sup +, sub i]. [ABSTRACT FROM AUTHOR]