Infusion of graded concentrations of somatostatin in man: pharmacokinetics and differential inhibitory effects on pituitary and islet hormones.

Abstract

The present study was undertaken to determine the plasma levels of somatostatin-like immunoreactivity (SLI) during constant infusion of graded concentrations of synthetic somatostatin-14 (S-14); to determine the half-life (t1/2) and metabolic clearance rate (MCR) of SLI; to correlate the plasma SLI levels with the degree of inhibition of pituitary and islet hormone secretion and to establish whether the plasma SLI levels capable of inhibiting pituitary and islet hormone secretion fall into the physiological range. Four normal subjects on separate occasions were each infused with saline or S-14 (25,50 and 75 micrograms/h) at a constant rate for 2 1/2 h. Thirty min following the infusions, TRH (200 micrograms) and arginine (0.5 g/kg) were given i.v. Blood samples were drawn every 15 min for measurement of GH, TSH, insulin, glucagon and SLI (by RIA of acid-ethanol extracted plasma) and at rapid intervals for 10 min after stopping the infusions for measurement of SLI disappearance. During S-14 infusions, plasma SLI rose rapidly, reached a plateau from 15-150 min and declined rapidly on cessation of the infusions with a mean t 1/2 of 2.72 +/- 0.45 min. Mean plateau SLI levels were: 149 +/- 3 pg/ml (25 micrograms/h), 465 +/- 35 pg/ml (50 micrograms/h), and 1244 +/- 71 pg/ml (75 micrograms/h). SLI was cleared rapidly but the MCR exhibited a dose-dependent decrease from 3225 +/- 699 ml/min for the 25 micrograms infusion to 1249 +/- 241 ml/min for the 75 micrograms/h infusion (P less than 0.05). The 25 micrograms/h infusion dose produced near-maximal suppression of GH secretion and inhibited insulin secretion but not TSH or glucagon secretion. The intermediate dose significantly inhibited GH, TSH, and insulin but not glucagon whereas the 75 micrograms/h infusion suppressed all four hormones. In six normal subjects endogenous plasma SLI rose from a basal value of 32.5 +/- 4.9 pg/ml to 75.5 +/- 9.0 pg/ml following ingestion of a mixed meal. This level was 50% of that resulting from the 25 micrograms/h infusion and which suppressed GH almost completely. We concluded that: Infused S-14 is cleared rapidly and decays with a short t 1/2; S-14 inhibits its own MCR; The somatotrophs are the most sensitive to S-14 inhibition, followed by the thyrotrophs and the B-cells (approximately equally) followed by the A-cells; Fluctuations in plasma SLI occurring physiologically may influence GH and possibly other S-14 sensitive cells by an endocrine mechanism.