Structure-activity relationships for the hypertensinogenic activity of ouabain - Role of the sugar and lactone ring

Elevated levels of an endogenous ouabain circulate in many patients with es sential hypertension. However, in contrast to ouabain, digoxin does not ind uce hypertension. This study investigated the hypothesis that within a sing le cardiac glycoside, the structural elements that induce hypertension diff er from those responsible for high potency as a sodium pump inhibitor. Norm al mate 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 mug . kgr(-1) . 24 h(-1) for 5 weeks via subcutaneous osmotic pumps. Cuff pressures were taken week ly. At the end of the study, trunk blood was harvested, extracted by C18 co lumn, and subjected to high-performance liquid chromatography. Fractions we re analyzed for OUA, OGN, and DHO by immunoassay. In OUA-, OGN-, and DHO-in fused rats, 1 main peak of immunoreactivity corresponding to the infused ag ent was found. No evidence of in vivo conversion to OUA or DHO was found fo r 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,*dagger and 169+/-2.4*dagger mm Hg, respectively (*P< 0.01 versus VEH and RHA, <dagger>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 oxy gen at C14, or opened, respectively. These compounds were weak inhibitors o f dog kidney Na,K-ATPase. Thus, RHA and the unsaturated lactone ring are cr ucial to the high potency of OUA as an inhibitor of the sodium pump but app ear to be unrelated to its ability to induce hypertension. The conclusion t hat this form of hypertension is mediated primarily by the steroid nucleus suggests also that OUA may have a mechanism of action independent of the so dium pump.