Invited Lecture

Abstract

Acquired and Inherited Forms of Ouabain‐Induced Hypertension: Significance and Relationship to Other Models. John M. Hamlyn. Department of Physiology, School of Medicine, University of Maryland, 655 West Baltimore, Baltimore, MD, USA.The etiology of essential hypertension remains an enigma—a mix of multiple environmental and genetic factors. In 1989, we described an endogenous inhibitor of the sodium pump in the human circulation and in 1991 identified the inhibitor as ouabain or a closely related isomer. Clinical studies showed that endogenous “ouabain” (EO) circulated in elevated amounts in a surprisingly large portion of patients with essential hypertension and that the relationship of EO with pressure was as significant as age. Causality was suggested subsequently by two sets of observations. First, blood pressure and plasma EO returned to normal following removal of the adrenal gland in patients with primary aldosteronism and other adrenal adenomas. Second, the prolonged infusion of ouabain in normal outbred rats induced sustained hypertension (OHR). As various animal models have provided insight into the mechanisms of hypertension, we bred rats for their resistance (BOR) or sensitivity (BOS) to the hypertensionogenic effect of ouabain. The strains were initiated simultaneously in 1992 from an F0 generation comprised of 80 normotensive outbred Sprague Dawley rats (40m, 40f, HSD, Indianapolis). Each member of the F0 generation received a maximally pressor dose of ouabain delivered over 5 weeks via osmotic pumps. Blood pressures were measured at baseline, during infusion, and 2 weeks following pump removal (week 7) using tail cuff plethysmography. Among the F0, 64 animals (∼85%) developed sustained hypertension while 12 (15%) showed little or no rise in either SBP or MBP. The increase in BP induced by ouabain was >1 S.D. above the group mean response in 13 animals (6m, 7f) and >1 S.D. below the mean in 16 animals (5m, 11f). BP in all animals was normal by week 7. Two breeding pairs of F0 OS and OR were chosen and, using a similar selection method and selective inbreeding, multiple stable generations were obtained. By the F3 generation, the BOS and BOR phenotypes were completely segregated while further inbreeding resulted in the appearance of spontaneous hypertension in BOS by week 6. This trait could not be selected against and became pronounced with further inbreeding. In OHR, hypertension was reversible, and characterized by elevated ouabain in the circulation, kidney, hypothalamus and anterior pituitary. Tissue levels were strongly correlated with BP. In both BOS and OHR, hypertension could be prevented or reversed by ACE, AT2 antagonists, digoxin, or blockade of brain EO by antibody fragments. As increased sympathetic nerve activity appears to be crucial to ouabain dependent hypertension we studied short‐term (STP) and long‐term potentiation (LTP) in the isolated superior cervical ganglia (SCG). The time constants for the decay of both STP and LTP (tL) were increased in BOS and OHR and correlated with blood pressure. Captopril normalized blood pressure and tL in OHR. Thus, the duration of ganglionic LTP and blood pressure are tightly linked in acquired and inherited forms of ouabain‐dependent hypertension. Enhanced plasticity in sympathetic neurons appears to be a major factor contributing to the increase in peripheral sympathetic nerve activity (SNA) in ouabain‐dependent hypertension. Studies of the contractility of isolated renal arteries showed enhanced force production in OHR in response to depolarization and in kidneys, the autoregulation of glomerular filtration rate and renal blood flow was less efficient, Moreover, a rightward shift in the pressure natriuresis relationship was found in OHR, such that 25–30 mmHg higher renal perfusion pressure was necessary to excrete a sodium load. In the OHR and BOS models, the overall involvement of the central and peripheral nervous system, hormone profiles, renovascular abnormalities and pharmacological sensitivity appear to have striking parallels with the SHR. It is suggested that common overlapping mechanisms are likely to underlie the etiology of hypertension in these models.