On the fate of centrally administered somatostatin in the rat: massive hypersomatostatinemia resulting from leakage into the peripheral circulation has effects on growth hormone secretion and glucoregulation.

We examined the effects of intracerebroventricular (icv) administration of the somatostatin peptides, S-14 and S-28, and an analog, [D-Trp22]S-28, on spontaneous GH and glucose secretion in freely moving rats bearing chronic icv and intraatrial cannulae. Normal saline icv-treated control rats exhibited the typical pulsatile pattern of GH secretion. Central injection of S-14, S-28, and [D-Trp22]S-28 (each at two different doses, 5 and 10 micrograms) caused an early significant suppression of plasma GH levels which was of longer duration after S-28 or [D-Trp22]S-28 than after S-14 injection. The icv administration of S-28 and [D-Trp22]S-28 (but not S-14) also resulted in significant hyperglycemia, which persisted for periods up to 1 h. In a second study designed to determine whether somatostatin administered via the brain ventricle can reach the peripheral circulation, we measured plasma levels of S-14-like immunoreactivity (S-14 LI) and S-28-(15-28) LI at frequent time intervals after icv injection of S-14 (5 micrograms) and S-28 (10 micrograms). Plasma S-14 LI rose from a basal value of 0.16 +/- 0.02 (+/- SE) ng/ml to a peak of 3.0 +/- 1.0 ng/ml at 1 min, and S-28 icv resulted in a 150-fold increase in plasma S-28-(15-28) LI 1 min after injection. Sephadex G-50 gel chromatography revealed that the plasma immunoreactivity consisted of a single molecular species (either S-14 or S-28) corresponding to the centrally administered counterpart. These results demonstrate that after icv administration at high doses, both forms of somatostatin cause an acute inhibition of spontaneous GH secretion and that the larger form also causes hyperglycemia. We correlate these events with massive hypersomatostatinemia resulting from leakage of the somatostatin peptides from the cerebrospinal fluid into the systemic circulation. The findings indicate that icv injected hypothalamic hormones can reach the peripheral circulation and exert significant biological actions on distant target organs; thus, they have important implications for the design and interpretation of experiments in which peptides are administered via the cerebral ventricles.