Structure-Activity Relationships for the Hypertensinogenic Activity of Ouabain

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Abstract
Elevated levels of an endogenous ouabain circulate in many patients with essential hypertension. However, in contrast to ouabain, digoxin does not induce hypertension. This study investigated the hypothesis that within a single cardiac glycoside, the structural elements that induce hypertension differ from those responsible for high potency as a sodium pump inhibitor. Normal male Sprague-Dawley rats received infusions of vehicle (VEH), rhamnose (RHA), ouabain (OUA), ouabagenin (OGN), dihydro-ouabain (DHO), iso-ouabain (ISO), and a lactone ring opened analog (ORO) at 30 microgram. kg(-1). 24 h(-1) for 5 weeks via subcutaneous osmotic pumps. Cuff pressures were taken weekly. At the end of the study, trunk blood was harvested, extracted by C18 column, and subjected to high-performance liquid chromatography. Fractions were analyzed for OUA, OGN, and DHO by immunoassay. In OUA-, OGN-, and DHO-infused rats, 1 main peak of immunoreactivity corresponding to the infused agent was found. No evidence of in vivo conversion to OUA or DHO was found for any analog except ORO. At 5 weeks, systolic blood pressures in VEH, RHA, OUA, OGN, DHO, ISO, and ORO were 132+/-2.5, 133+/-1.5, 159+/-2.6,* 154+/-4,* 167+/-4,* 171+/-2.2,* and 169+/-2.4* mm Hg, respectively (*P<0.01 versus VEH and RHA, P<0.05 versus OUA). The hypertensinogenic activity was greater than OUA in 3 analogs (DHO, ISO, and ORO) in which the lactone was saturated, conformationally restrained by linkage with the oxygen at C14, or opened, respectively. These compounds were weak inhibitors of dog kidney Na,K-ATPase. Thus, RHA and the unsaturated lactone ring are crucial to the high potency of OUA as an inhibitor of the sodium pump but appear to be unrelated to its ability to induce hypertension. The conclusion that this form of hypertension is mediated primarily by the steroid nucleus suggests also that OUA may have a mechanism of action independent of the sodium pump.