INFUSION OF GRADED CONCENTRATIONS OF SOMATOSTATIN IN MAN: PHARMACOKINETICS AND DIFFERENTIAL INHIBITORY EFFECTS ON PITUITARY AND ISLET HORMONES

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Abstract
The plasma levels of somatostatin-like immunoreactivity (SLI) were determined during constant infusion of graded concentrations of synthetic somatostatin-14 (S-14); the half-life (t1/2) and metabolic clearance rate (MCR) of SLI were correlated; the plasma SLI levels were correlated with teh degree of inhibition of pituitary and islet hormone secretion and it was established 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 .mu.g/h) at a constant rate for 2 1/2 h. Thirty minutes following the infusions, TRH (200 .mu.g) and arginine (0.5 g/kg) were given i.v. Blood samples were drawn every 15 min for measurement of GH [growth hormone], TSH, insulin, glucagon and SLI (by RIA [radioimmunoassay] of acid-ethanol extracted plasma) and at rapid intervals for 10 min after stopping the infusions for measurement of SLI disapperance. 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 t1/2 of 2.72 .+-. 0.45 min. Mean plateau SLI levels were: 149 .+-. 3 pg/ml (25 .mu.g/h), 465 .+-. 35 pg/ml (50 .mu.g/h) and 1244 .+-. 71 pg/ml (75 .mu.g/h). SLI was cleared rapidly bu tthe MCR exhibited a dose-dependent decrease from 3225 .+-. 699 ml/min for the 25 .mu.g infusion to 1249 .+-. 241 ml/min for the 75 .mu.g/h infusion (P < 0.05). The 25 .mu.g/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 while the 75 .mu.g/h infusion suppressed all 4 hormones. In 6 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 .mu.g/h infusion and which suppressed GH almost completely. Infused S-14 is cleared rapidly and decays with a short t1/2; S-14 inhibits its own MCR; the somatotrophs are the most sensitive to S-14 inhibition, followed by the thyrotrophs and the .beta.-cells (approximately equally) followed by the .alpha.-cells; fluctuations in plasma SLI occurring physiologically may influence GH and possibly other S-14 sensitive cells by an endocrine mechanism.