Inhibition of nitric oxide synthase by NG-nitro-L-arginine causes a preferential decrease in pancreatic islet blood flow in normal rats and spontaneously diabetic GK rats

Abstract

To elucidate the effect of nitric oxide (NO) on the blood flow of the pancreatic islets, the NO synthase inhibitor NG-nitro-L-arginine (N-arg; 25 mg/kg BW) was administered iv to rats 10 min before pancreatic blood flow was measured with a nonradioactive microsphere technique. In male Sprague-Dawley rats, N-arg induced a marked decrease in islet blood flow (16 +/- 4 vs. 44 +/- 8 microliters/min.g pancreas; P < 0.001) and a less pronounced decrease in whole pancreatic blood flow (0.27 +/- 0.04 vs. 0.43 +/- 0.06 ml/min.g; P < 0.05), leading to a markedly decreased fractional islet blood flow (5.5 +/- 0.9% vs. 10.3 +/- 1.3%; P < 0.02). In a second experiment, injection of D-glucose (300 mg/kg BW, iv) in male Sprague-Dawley rats induced a selective increase in islet blood flow (P < 0.05). Such an increase has previously been shown to be mediated by a vagal cholinergic mechanism. Administration of N-arg to these rats resulted in decreased pancreatic (P < 0.05), islet (P < 0.001), and fractional (P < 0.001) islet blood flow, which did not differ from those observed in normoglycemic rats after treatment with N-arg. Furthermore, we studied the mechanism behind the previously described increase in islet blood perfusion, mediated by the vagus nerve, in F1-hybrids of the GK (Goto-Kakizaki) rat, a spontaneous animal model of noninsulin-dependent diabetes mellitus. Administration of N-arg to female GK rats resulted in decreases in islet (P < 0.001), pancreatic (P < 0.01), and fractional islet blood flow (P < 0.001) to the levels observed in female Wistar rats treated in parallel. These data are consistent with the possibility that NO is an important physiological regulator of islet blood flow. Furthermore, the vagally dependent high levels of islet blood flow demonstrated in the GK rat appear to be mediated by a mechanism involving NO.

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy

“…We and others previously demonstrated increased islet perfusion in adult GK and hybrid rats compared with Wistar rats (Atef et al 1994, Svensson et al 1994, 2000, Carlsson et al 1997. However, in the present study, no significant differences in islet blood perfusion between sham-operated Wistar and sham-operated hybrid or GK rats were seen.…”

Improved Vascular Engraftment and Graft Function After Inhibition of the Angiostatic Factor Thrombospondin-1 in Mouse Pancreatic Islets

“…It is possible that this reflects higher blood perfusion in individual blood vessels and thereby better oxygen transport capacities of islet blood vessels in the absence of TSP-1, e.g., due to loss of the previously described counteracting effect of TSP-1 on nitric oxide-mediated vasodilation (41). Nitric oxide is the main mediator of high blood perfusion in endogenous and transplanted islets (42,43). It should be noted that an intra-islet vasodilation is not necessarily reflected in increased total graft blood flow, which is measured by laser-Doppler flowmetry, because total graft blood flow represents not only the nutritive blood flow to the endocrine cells but also blood flow in the vast number of stroma capillaries.…”

Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat

“…In addition, the decrease of the alpha-cell mass appears rather late as compared to that of the beta cells. It is conceivable that the decrease of the alphacell mass could be partly due to the disorganization of the normal islet architecture and the development of fibrosis, two parameters which may participate in the perturbation of islet blood flow previously described in the adult GK model [43,44] and in doing so also affecting the alteration of endocrine insular cell growth.…”