Effects of arginine vasopressin and oxytocin on glucagon release from clonal α-cell line In-R1-G9: Involvement of V1b receptors
Abstract
Receptor antagonists were used to determine which receptor mediates the effect of arginine vasopressin (AVP) and oxytocin (OT) on glucagon release from hamster glucagonoma In-R1-G9 cells. Both AVP (10−9–10−6 M) and OT (10−8–10−5 M) increased glucagon release from In-R1-G9 cells in a concentration-dependent manner and AVP was ~30-fold more potent than OT in this aspect. The antagonists with potent V1b receptor blocking activity, CL-4-84 (10−9–10−6 M), dP[Tyr(Me)2]AVP and AO-2-44 (10−8–10−6 M), antagonized the effect of both AVP and OT in a concentration-dependent manner. Other receptor antagonists at 10−6 M failed to block the effect of AVP and OT; these included a highly selective OT-receptor antagonist, L-366,948 and a receptor antagonist WK-3–6. However, these antagonists at higher concentrations (10−5 and 10−4 M) caused inhibition of AVP- and OT-induced glucagon release. The order of antagonistic potency was estimated as CL-4-84 ≈ dP[Tyr(Me)2]AVP ≈ AO-2-44 > WK 3–6 > L366,948. d[D-3-Pal]VP (10−8–10−5 M), a V1b receptor agonist, also increased glucagon release in a concentration-dependent manner, which was antagonized by dP[Tyr(Me)2]AVP (10−8-10−6 M) and CL-4-84 (10−9–10−6 M), but not by WK-3–6 (10−6 M) or L-366,948 (10−6 M). Therefore, the stimulatory effects of both OT and AVP on glucagon release may be mediated by V1b receptors, but not by V1a, V2 or OT receptors.
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Without the negative feedback system of corticosterone, CRH is highly enhanced and may primarily combine with CRHR1 to stimulate negative feedback through ACTH in the pituitary gland in type 2 diabetic rats with long-term ADX. Although the negative feedback signal was not transmitted appropriately following long-term ADX with type 2 diabetes, a high GR protein level was maintained as in type 2 diabetes. The long-termed lack of corticosterone in the blood stream is a very important factor for normal regulation of the HPA axis even in diabetic animals. From the data, we can conclude that the stimulated HPA axis regulation in the developing type 2 diabetic animals following long-term adrenalectomy has remained elevated rather than diminished. Therefore, the current study may provide useful information to better understand patients suffering from both type 2 diabetes and Addison's disease.
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