digitoxin and ouabagenin

Elevated circulating levels of an endogenous ouabain (EO) have been associated with essential hypertension. To investigate structure-activity relationships relevant to blood pressure, we infused either ouabain, ouabagenin, digoxin or digitoxin at 30 microg/kg/day in normal Sprague Dawley rats. After five weeks, the ouabain and ouabagenin infused rats were hypertensive, whereas blood pressures declined below their vehicle controls in rats infused with digoxin or digitoxin. In a second study, mean blood pressures were 118.5+/-1.7 mmHg in rats infused with ouabain (15 microg/kg/day) on day 35 vs. 98.3+/-1.8 and 100.3+/-1.1 mmHg in the digoxin (30 microg/kg/day) and vehicle infused groups (both p<0.005 vs. ouabain), respectively. Plasma and kidney levels of ouabain immunoreactivity were increased 4-8 fold in ouabain infused rats while blood pressure and plasma levels of ouabain returned to normal one week following discontinuation of the steroid infusion. In rats with ouabain-dependent hypertension, secondary infusions of digoxin or digitoxin (30 microg/kg/day) normalized blood pressure even though circulating ouabain remained elevated. In digoxin infused rats, neither blood pressure nor kidney digoxin immunoreactivity was raised whereas plasma digoxin was increased. Collectively, the results show that the hemodynamic effects of these sodium pump inhibitors differ dramatically during prolonged administration and that tissue rather than circulating levels of these agents appear to better explain their effects on blood pressure. These studies suggest that sodium pump inhibition is not the exclusive mediator of the hemodynamic effects of these cardiac glycosides and demonstrate the presence of structure-specific mechanisms that regulate their tissue levels and effects on long-term blood pressure.

Topics: Aldosterone; Animals; Blood Pressure; Cardiotonic Agents; Chronic Disease; Digitoxin; Digoxin; Hypertension, Renal; Kidney; Male; Ouabain; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Tissue Distribution

The mechanism of cardiac oscillatory activity induced by digitalis was studied in the canine ventricular muscle. We determined the role of sarcoplasmic reticulum in the phenomenon of oscillatory afterpotential and mechanical aftercontractions. Additionally we wished to study the interaction between changes in stimulus interval, which are known to affect sarcoplasmic reticulum function and these oscillatory phenomena. Aftercontraction was induced by ouabagenin but it required previous stimulation of the heart. The production of aftercontraction depended on short stimulus interval and bore no relation with the size of the releasable pool of Ca in the sarcoplasmic reticulum as indicated by the size of the driven contraction. Aftercontraction was often seen without an accompanying action potential. When a depolarization was present during aftercontraction, its temporal relation with the contraction often did not show the usual delay, suggesting that electrical activity may not necessarily initiate contraction. This was supported by the finding that Mn, a Ca channel blocker, blocked normal contractions more than aftercontraction. However, inhibition of Ca release from the sarcoplasmic reticulum by ryanodine or of Ca reuptake by caffeine were effective in blocking aftercontraction and when present, oscillatory afterpotential. Abolition of aftercontraction was not due to slowing of relaxation. These studies confirm the role of sarcoplasmic reticulum in causing aftercontraction and oscillatory afterpotential during ouabagenin toxicity and also suggest that there is a relationship between the 'repriming' ability of the sarcoplasmic reticulum and the oscillatory phenomena.

Topics: Animals; Caffeine; Calcium; Cardiac Complexes, Premature; Digitalis; Dogs; Female; Heart Ventricles; Male; Manganese; Myocardial Contraction; Ouabain; Plants, Medicinal; Plants, Toxic; Ryanodine; Sarcoplasmic Reticulum