Circulating digitalislike compounds have been proposed to be involved in some Na+-dependent types of experimental hypertension and in human essential hypertension. The level of circulating Na+-K+ pump inhibitor(s) was investigated in the spontaneously hypertensive rat of the Okamoto strain (SHR), its normotensive control, Wistar-Kyoto rat (WKY), and the regular Wistar rat using the following criteria: the ability of whole plasma to inhibit the total active Na+ efflux from Wistar rat erythrocytes and to cross-react with digoxin antibodies and the ability of plasma extracts to inhibit Na+,K+-adenosine triphosphatase (ATPase) activity of membranes from rat kidney. SHR plasma inhibited the net Na+ efflux from Wistar erythrocytes by up to 27% compared with WKY or Wistar plasma. For a given number of cells, the inhibition increased with the amount of available plasma. Cross-reactivity with digoxin antibodies was twice as high in SHR as in WKY or Wistar plasma. It was already enhanced in 3- to 4-week-old rats. Plasma extracts from SHR significantly inhibited Na+,K+-ATPase activity when compared with WKY extracts (75.6 +/- 2.6 vs 89.3 +/- 2.4 mumol Pi/mg/hr; p less than 0.01) but did not differ from Wistar plasma extracts. These results strongly suggest that circulating digitalislike compound(s) are present in elevated amounts in SHR as early as 3 to 4 weeks of age, but their exact participation in blood pressure elevation or maintenance remains to be clarified.