Role of digitalis-like substance in the hypertension of streptozotocin-induced diabetes in reduced renal mass rats

We have previously reported that chronic hypertension develops consistently in Wistar rats with a 25% reduction in renal mass (RRM) following the induction of insulin dependent diabetes mellitus (IDDM) with streptozotocin (STZ, 65 mg/kg body weight, intravenously). In this study, we examined the role of the endogenous digitalis-like substance in the development of hypertension. Four groups of rats were studied: 1) 25% RRM rats with STZ-induced IDDM (25-DM), 2) normal rats with STZ-induced IDDM (2K-DM), 3) 25% RRM rats with vehicle treatment (25-V), and 4) normal rats with vehicle treatment (2K-V). In 25-DM rats, blood pressure progressively increased during the 3 weeks after STZ treatment and was associated with microalbuminuria, low plasma renin activity, and extracellular volume expansion. In contrast, the 2K-DM, 25-V, and 2K-V rats remained normotensive. Furthermore, the plasma and urine levels of digoxin-like immunoreactive factor (DIF), determined by digoxin radioimmunoassay (Baxter), were significantly higher in hypertensive 25-DM rats than in their controls. The same was the case for plasma digitalis-like substance (DLS), determined by exposing canine Na⁺, K⁺-ATPase to plasma fractions and observing the percent inhibition. Increased DIF and DLS in hypertensive 25-DM rats was associated with a significant decrease in Na⁺,K⁺-ATPase activity of microsomes prepared from the left and right ventricles, when compared with microsomes from normotensive 2K-DM animals. Microsomal 5′-nucleotidase, a plasma membrane marker, was unchanged. The DIF and DLS correlated significantly with each other and with myocardial Na⁺,K⁺-ATFase activity and mean blood pressure. These results suggest that increased endogenous digitalis-like substance, which inhibits cardiovascular muscle cell Na⁺-K⁺-pump activity, may be involved in the mechanism of hypertension associated with IDDM in 25% RRM rats.