VOLUME REFLEX IN DIABETICS

Recently, it has been reported that the natriuretic response to volume
expansion induced by water immersion is diminished in diabetic patients.
This altered sodium excretion in diabetic was not accountable by the
hemodynamic changes or hormonal changes. These studies were unable to
identify a specific mechanism for the altered volume reflex observed in
diabetics. Recently, we have demonstrated that in diabetic rats, the
natriuresis and diuresis produced by acute volume expansion is
significantly blunted compared to control rats. In addition, renal
denervation corrected this blunted natriuresis and diuresis in diabetic
rats. These results suggest that part of the blunted natriuresis to
volume expansion in the diabetic rats is mediated by an altered neural
component of the volume reflex. There are several possible "intermediate
steps" that could be altered in the neural component of the volume reflex.
The present proposal is designed to determine: first, if the afferent limb
of the volume reflex is altered; second, if decrease in norepinephrine
released within the kidney in response to volume expansion is altered;
third, if the end-organ response to renal sympathetic nerve stimulation is
altered; and fourth, if renal alpha-1 adrenergic receptor density and
coupling are altered in diabetic rats. The immediate significance of the
studies proposed in this application is to gain insight into the
mechanisms that cause the altered fluid and electrolyte balance during the
early stage of diabetes. Once we understand the basic mechanisms that are
involved, this information will enhance our ability to treat these
complications in the diabetic state. The long-term significance and
direction of future experiments will be to examine if alleviating this
early sodium retention (e.g., by pharmacological means - blockage of
specific alpha-1 receptor subtype) aids in reducing the later hemodynamic
and cardiovascular problems observed in the diabetic state.