Previous work, primarily based on the SHR rat model suggests that there is an interaction of aberrant adrenocortical function with development of hypertension. However, this interaction has not been studied in other hypertension models which lack genetic defects. Preliminary work presented here indicates that in the deoxycorticosterone acetate (DOCA)-hypertensive pig, the adrenal cortex is hypersensitive ACTH (in vivo and in vitro) and angiotensin II (in vitro). These observations were made in animals with established hypertension (16 weeks of DOCA treatment). The preliminary data raise importnat questions: 1) Is there also an altered response to angiotensin II and K+ in vivo? 2) What are the other alterations in adrenocortical cell function? 3) What are the cellular mechanisms causing these cellular alterations? 4) Are these alterations observed in vivo and in vitro primary or secondary to the development of DOCA-hypertension? 5) How do these alterations relate to DOCA-escape and DOCA-dependent and independent phases of hypertension? 6) Does the enhanced sympathetic nervous system affect adrenocortical function during hypertension? 7) Do atrial extracts and atriopeptins modulate adrenocortical function and how is this modulation altered with hypertension? The proposed work is aimed at answering these questions by conducting similar and new experiments in vivo, and in vitro during the development of DOCA- hypertension which has several phases: 1) DOCA-dependent Na+ retaining phase (1-3 days DOCA treatment) b) DOCA-escape phase in which Na+ retention normalizes (after 7 days) c) DOCA-dependent phase in which hypertension is reversible with DOCA removal (up to 21 days treatment) d) DOCA-independent phase in which hypertension is irreversible with DOCA removal (after 4 months treatment). Responses to ACTH angiotensin II, K+ sympathetic nervous system blockers and catecholamine agonists and antagonist, atrial extracts and atriopeptins will be evaluated. Modern techniques will be used to assess adrenocortical function in vivo (Chromatography and radioimmunoassay of plasma corticoids) and in vitro (hormone receptor and steroidogenic pathway analyses). These techniques, already established and validated in the Principal Investigator's laboratory will be used to identify the interactions(s) of aberrant adrenocortical function with both the development and maintenance of hypertension in a model that is closely related to human hypertension.
