The effects of neuropeptide K (NPK) were measured on mean arterial pressure (MAP) and heart rate (HR) after i.v. injection in urethane-anesthetized rats. NPK (6.5 and 32.5 nmol/kg) produced sustained decreases in MAP and elicited increases in HR. Whereas the NPK-induced tachycardia lasted more than 30 min at 32.5 nmol/kg, a latent and long-lasting bradycaria appeared from 20 min after injection of 6.5 nmol/kg. The initial tachycardia was converted to bradycardia by metoprolol but remained unaffected by hexamethonium, atropine and naloxone. These four treatments, however, prevented the bradycardiac response to NPK at 30 min. Whereas phentolamine, idazoxan, bilateral adrenalectomy and chemical sympathectomy with 6-hydroxydopamine (6-OHDA) preserved the initial tachycardia induced by NPK, they converted the decrease in HR to a tachycardiac response at 30 min. The vasodepressor response to NPK was significantly enhanced by bilateral adrenalectomy, chemical sympathectomy and metoprolol but remained unaffected by all other treatments. Neither the MAP nor the HR responses to NPK were affected by indomethacin. These results suggest that NPK can accelerate HR through non-reflex activation of the sympathoadrenal system. The secondary bradycardia induced by NPK may be due to a vagal reflex while the vasodepressor response to NPK is probably attributable to a direct action mediated by specific receptors on arterial blood vessels. Thus, NPK is considered as the most potent biologically active tachykinin so far described on the rat cardiovascular system.
This study was designed 1) to investigate mechanisms of insulin secretion during exercise after transplantation of islets in the spleen and under the kidney capsule, and 2) to compare these organs as transplantation site regarding an adequate portal or systemic delivery of insulin and glucose homeostasis during exercise. Diabetic rats were provided with 5 μL isogenic islet tissue in the spleen or under the kidney capsule, which results in normoglycemia, and were submitted to a swimming test Portal plasma insulin levels were higher than simultaneously sampled systemic insulin levels in the control and in the intrasplenic islet grafted group, but not in the kidney subcapsular islet-grafted group. Plasma portal and systemic insulin levels decreased, and glucose levels increased during exercise in all groups. The exercise-induced increase in levels of catecholamines was larger in systemic than in portal plasma, suggesting catecholamine extraction by the lungs or intestines. The experiments were repeated after removing of adrenal medulla, resulting in nondetectable or very low plasma adrenaline levels. Despite these low adrenaline levels, insulin levels decreased during exercise. The results indicate that 1) the exercise-induced reduction of insulin secretion is not mediated by circulating adrenaline, but is probably under control of the sympathetic nervous system, which could be the result of reinnervation of the transplanted islets. 2) Although a portal-systemic insulin gradient was absent in rats with kidney subcapsular islet grafts, the absence of a difference in glucose homeostasis during exercise between the sites revealed that all investigated sites are preferential to transplant islets.
The peritoneal cavity is of renewed interest for pancreatic islet transplantation, since it is the preferable site for transplantation of immunoisolated islets. In this study we investigated the minimum islet graft volume needed to restore normoglycemia after free intraperitoneal isogenic transplantation in streptozotocin diabetic rats. Furthermore, graft function was tested by measuring glucose and insulin response to an intravenous glucose load and spontaneously ingested carbohydrate-rich meal. Three graft volumes were used: 8.0-10.0 (group A); 4.0-5.0 (group B); and 2.0-2.3 microliters (group C); 1 microliter contained about 300 islets. All 10 rats in group A and 7 out of 9 rats in group B became normoglycemic for at least 6 months posttransplant, with blood glucose levels not significantly different from normal control animals. Only 3 out of 9 animals in group C became normoglycemic and never for longer than 3 months. The insulin responses to IVGTT in group A and group B were proportional to the grafted islet volume and always significantly lower than those of normal control rats. The insulin response to the test meal showed a similar tendency, which was found to be associated with the absence of preabsorptive insulin secretion. Maximum postprandial blood glucose levels in group A and group B were 0.8 and 1.5 mM higher than in normal control rats. We conclude that intraperitoneal transplantation of at least 4.0-5.0-microliters islet tissue is needed to reverse blood glucose in streptozotocin diabetic rats, and that glucose and insulin levels on IVGTT and test meal in rats with islet grafts of 8.0-10.0 microliters are not completely normalized. It is suggested that the impaired glucose tolerance is due to an insufficient beta-cell mass and a lack of parasympathetic innervation of the transplanted islet tissue.
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