Blood flow regulation in the transplanted fetal endocrine pancreas. Acquisition of a nitric oxide-dependent glucose-induced increase in blood flow.

Islet-like cell clusters (ICCs) were prepared from the fetal porcine pancreas by a culture technique. The ICCs (approximately 500) were implanted under the left renal capsule of nude (nu/nu) C57BL/6J mice. Six weeks, months, 12 months, or 16-24 months later, the animals were anesthetized and the blood flows to the xenogeneic islet graft and the adjacent kidney parenchyma were measured with laser-Doppler flowmetry. After the blood flow measurements, the graft-bearing kidneys were prepared for enzyme and immunohistochemistry. The blood perfusion of the graft was higher than that of the kidney at all times investigated. Intraperitoneal administration of glucose caused only slight and parallel changes in renal and graft blood flows 6 weeks, 6 months, or 12 months after transplantation. However, in all but 1 animal (n=16) transplanted >16 months before the blood flow measurements, glucose caused a marked increase in graft blood flow but did not affect renal blood flow. Injection of 2-deoxy-glucose also increased graft blood perfusion in animals transplanted > 16 months earlier (n=5). Treatment with NG-monomethyl-L-arginine (n=6), an inhibitor of nitric oxide synthase, prevented this glucose-induced flow increase. Nicotinamide adenine dinucleotide phosphate diaphorase histochemistry revealed nitric oxide synthase only in the endothelium and media of graft arterioles in animals in the oldest age group. Thus, with the passage of time after implantation, the grafted xenogeneic ICCs seem to achieve an autonomous blood flow regulation, different from that of the implantation organ. The reactivity to an increment in blood glucose concentration in the graft is similar to that seen in native islets in the pancreas but is not present until >16 months after implantation. The mechanisms for the glucose-induced blood flow increase are obscure but probably depend on local release of nitric oxide within graft arterioles.