Endogenous digitalislike circulating substances in spontaneously hypertensive rats.

Abstract

SUMMARY 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 hi 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 /tmol P,/mg/hr; p < 0.01) but did not differ from Wistar plasma extracts. These results strongly suggest that circulating digitalislike compound(s) are present in elevated amounts hi SHR as early as 3 to 4 weeks of age, but their exact participation in blood pressure elevation or maintenance remains to be clarified.

Exogenous Ouabain Is Accumulated in the Adrenals and Mimics the Kinetics of Endogenous Digitalis-like Factor in Rats.

“…Moreover, the [3Hlouabain levels both in plasma and adrenals were significantly higher in SHR than in WKY from the age of 6 wk, just after the beginning of systolic BP elevation, onward. This observation is also partly compatible with the previous report (16) that the plasma of SHR showed higher inhibition of Na+ efflux from erythrocytes and of Na+,K+-ATPase as well as higher digoxin-like immunoreactivity than did the plasma of WKY. All these observations indicate that [3H]ouabain of dietary origin mimics the kinetics and pathophysiological roles of EDLF.…”

“…Moreover, reversephase HPLC showed that orally ingested [3H] ouabain was not metabolized and was present in the plasma and various organs, including the adrenal glands. These results are partly compatible with those of a previous pharmacokinetic study in which intravenously administered ouabain was not metabolized in the mammalian body (16).…”

Pathogenesis of hypertension in the sinoaortic-denervated spontaneously hypertensive rat.

“…Chronic increases in arterial pressure may result from primary defects in renal function 36 " 39 or increased plasma levels of circulating hormones or as yet unidentified circulating factors. 40 …”

Arterial Responses in vitro and Plasma Digoxin Immunoreactivity after Losartan and Enalapril Treatments in Experimental Hypertension

“…Several investigations have provided evidence for elevated levels of circulating sodium pump inhibitors in hypertensive subjects (Hamlyn & Manunta 1992) and experimental animals (Wauquier et al 1988;Doris 1994). This digitalis-like factor augments natriuresis, but it also depolarizes smooth muscle via Na π ,K π -ATPase inhibition, and increases calcium influx through voltage-dependent channels.…”

“…The altered function of Na π ,K π -ATPase may play a role in the pathogenesis of hypertension, and elevated levels of circulating sodium pump inhibitors have been found in hypertensive patients (Hamlyn & Manunta 1992) and experimental animals (Wauquier et al 1988;Doris 1994). This digitalis-like factor is a natriuretic agent, but it depolarizes arterial smooth muscle via Na π ,K π -ATPase inhibition, and thus elevates peripheral resistance (Zhu et al 1994).…”