Stimulatory effect of PG-KII, an NK 3 tachykinin receptor agonist, on isolated pancreatic acini: species-related differences

Abstract

More information is needed on the physiological role of the tachykinins (TKs), especially neurokinin 3-receptor (NK 3) agonists, in the pancreas. In this paper we investigated and compared the effect of PG-KII (10 −9 to 10 −6 M), a natural NK 3-receptor agonist, with that of the known secretagogues substance P (10 −9 to 10 −6 M), caerulein (10 −11 to 10 −8 M) and carbachol (10 −8 to 10 −5 M), on amylase secretion from dispersed pancreatic acini of the guinea pig and rat. PG-KII (10 −7 M) significantly increased basal amylase release from guinea pig pancreatic acini (from 5.4±0.9% to 11.3±0.5%, P<0.05) but left basal release in the rat unchanged (6.5±0.5%). The stimulant effect of PG-KII on guinea pig acini was significantly reduced by the NK 3-receptor antagonist, SR 142801 (5×10 −7 M), and left unchanged by the NK 1-receptor antagonist, SR 140333 (5×10 −7 M). Conversely, substance P (10 −7 M) significantly stimulated amylase secretion from rat and guinea pig acini (12.6±0.6% and 12.1±0.7%, P<0.05). This stimulated effect of substance P was antagonized by the NK 1-receptor antagonist (5×10 −7 M), but not by the NK 3-receptor antagonist (5×10 −7 M). The PG-KII- and substance P-evoked maximal responses were lower than those evoked by caerulein (10 −9 M) (guinea pig, 19.1±1.3%; rat, 18.2±0.9%, P<0.01) and carbachol (10 −5 M) (guinea pig, 23.3±1.2%; rat, 24.0±1.1%, P<0.01). The inhibitors of phospholipase C U-73122 (10 −5 M), phospholipase A 2 quinacrine (10 −5 M), and protein tyrosine kinase genistein (10 −4 M), partly but significantly inhibited PG-KII, as well as carbachol-stimulated amylase release. Coincubation of PG-KII 10 −7 M with submaximal doses of caerulein (10 −11 to 10 −10 M) and carbachol (10 −7 to 10 −6 M) had an additive effect on amylase release. Pre-incubation with PG-KII (10 −7 M) for 30 min significantly reduced the subsequent amylase response to PG-KII, whereas pre-incubation with caerulein 10 −10 M or carbachol 10 −6 M did not. These findings suggest that PG-KII directly contributes to pancreatic exocrine secretion by interacting with acinar NK 3 receptors of the guinea pig but not of the rat. PG-KII signal transduction involves the intracellular phospholipase C, phospholipase A 2 and protein tyrosine kinase pathways. The NK 3 receptor system cooperates with the other known secretagogues in regulating guinea pig exocrine pancreatic secretion and undergoes rapid homologous desensitization.