Angiotensin II type 1 receptor inhibition markedly improves the blood perfusion, oxygen tension and first phase of glucose-stimulated insulin secretion in revascularised syngeneic mouse islet grafts.
OBJECTIVE
We recently found evidence of an angiotensin-generating system in pancreatic islets. The present study investigated the effect of endogenously produced angiotensin II on microcirculation and function in transplanted islets.


METHODS
Losartan, an angiotensin II type 1 receptor inhibitor, was administered either acute intravenously to mice with 4-week-old islet renal subcapsular transplants, or added to the drinking water for the final 14 days or throughout the 4-week post-transplantation period. The graft-bearing kidney was, in some cases, dissected out and perfused in vitro to evaluate the effect of angiotensin II and losartan on glucose-stimulated insulin release from the grafts.


RESULTS
Losartan treatment throughout the 4-week post-transplantation period had negative effects on islet revascularisation as well as on islet graft insulin release. However, administration of losartan, either intravenously or orally, after the formation of a new vascular network, improved islet graft blood perfusion. PO2 in the islet transplants was also effectively improved by the losartan treatment. Graft perfusion experiments showed a markedly better first phase of glucose-stimulated insulin release in transplanted islets when exposed to losartan. In contrast, acute administration of angiotensin II decreased islet graft blood flow, PO2 and glucose-stimulated insulin release.


CONCLUSIONS
This study shows that inhibition of the islet reninangiotensin system may be a feasible strategy to increase the blood perfusion, PO2 and function within islet grafts. Such treatment should not be initiated, however, before the islet vascular system has been formed.
Kampf
C
C
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Lau
T
T
Olsson
R
R
Leung
P S
PS
Carlsson
P-O
PO
D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D005947:Glucose / Q000494:pharmacology*; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000098:blood supply*; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D023421:Models, Animal; D011384:Proinsulin / Q000378:metabolism; D013370:Subrenal Capsule Assay; D014185:Transplantation, Isogeneic / Q000502:physiology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007328:Insulin; D011384:Proinsulin; D005947:Glucose; D019808:Losartan