Endocrine effects of new bombesin/gastrin-releasing peptide antagonists in rats

Four new and specific pseudononapeptide bombesin/gastrin-releasing peptide (GRP) receptor antagonists, containing the D-forms of Trp or Trp analogue (Tpi) at position 6, were studied for their effects on the endocrine pancreas and GRP-(14-27)-induced gastrin release in pentobarbital-anesthetized rats. One of the analogues, D-Tpi⁶,Leu¹³-ψ(CH₂NH)Leu¹⁴-bombesin-(6-14) (RC- 3095), was injected into the lateral brain ventricle just preceding intracerebroventricular administration of GRP-(14-27) to evaluate its antagonistic effect on GRP-induced serum growth hormone (GH) suppression. Analogues RC-3095, D-Trp⁶,Leu¹³-ψ(CH₂NH)Leu¹⁴-bombesin-(6-14) (RC- 3125), and D-Trp⁶,Leu¹³-ψ(CH₂NH)Phe¹⁴-bombesin-(6-14) (RC-3420), but not D-Tpi⁶,Leu¹³-ψ(CH₂NH)Phe¹⁴-bombesin-(6-14) (RC-3105), significantly (P < 0.01) inhibited GRP-(14-27)-stimulated serum gastrin secretion. Analogues RC-3095, RC-3420, and RC-3105, but not RC-3125, demonstrated significant (P < 0.05) antagonistic activities on GRP-(14-27)- stimulated plasma glucagon secretion. Intracerebroventricular injection of RC-3095 (10 μg) immediately before GRP-(14-27) (1 μg) completely prevented the GRP-(14-27)-induced serum GH suppression. These results indicate that 1) marked differences exist in the ability of these analogues to antagonize GRP- (14-27)-induced gastrin or glucagon release, suggesting the existence of different bombesin/GRP receptor subtypes, and 2) the central effect of bombesin/GRP on GH release from the pituitary is probably mediated through specific bombesin/GRP receptors.