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Our previous study demonstrated the longer duration of action potential in ventricular myocytes from genetically diabetic WBN/Kob rats without change in calcium channel density compared with age-matched controls [Tsuchida, K., H. Watajima, and S. Otamo. Am. J. Physiol. 267 ( Heart Circ. Physiol. 36): H2280–H2289, 1994]. In the present study we examined the alteration of potassium currents, especially transient outward current, in ventricular myocytes of genetically diabetic WBN/Kob rats. WBN/Kob rats gradually develop hyperglycemia with aging and show some similarity to non-insulin-dependent diabetes mellitus models, which differ from the insulin-dependent streptozotocin-treated rat model. The density of the intracellular calcium ion-independent transient outward current ( I to) from 17- to 19-mo diabetic rat myocytes was significantly smaller than that from age-matched control rat myocytes. In addition, the density of I to from 17- to 19-mo rat myocytes was significantly less than that from 2-mo rat myocytes, suggesting that aging-induced alteration of I to was accelerated by the diabetic state. The steady-state inactivation curves of I to, the recovery from I toinactivation, and the other outward currents were not significantly altered between diabetic myocytes and age-matched control myocytes. In conclusion, the prolonged duration of action potential from genetically diabetic rat myocytes is mainly due to the depressed I to.

Experiments were designed to investigate the effects of aging and hyperglycemia on relaxation of the aorta for both endothelium-dependent and -independent agents in Wistar (control) and WBN/Kob (genetically diabetic) rats. The concentration of glucose in serum was elevated significantly in aged (90-92 wk) but not young (13-15 wk) WBN/Kob rats. Endothelium-dependent relaxations of both control and WBN/Kob rats to acetylcholine were reduced by aging. The relaxations induced by acetylcholine in aortic strips were significantly attenuated in both young (nondiabetic) and aged (diabetic) WBN/Kob rats, compared with those from age-matched control vessels, respectively. The concentration-response curves for sodium nitroprusside in aortic strips from both aged control and aged WBN/Kob rats were shifted to the left when compared with those from young rats, respectively. However, the maximal relaxation responses to sodium nitroprusside showed no difference among all vessels studied. The relaxations induced by sodium nitroprusside in aortic strips from both young and aged WBN/Kob rats were similar to those from age-matched control rats, respectively. The relaxations induced by atrial natriuretic peptide showed no difference among all vessels studied. In genetically diabetic rats, functional changes in endothelium occurred before elevation of the levels of glucose in the serum. Thus impaired endothelium-dependent relaxation may play an important role in the high incidence of vascular complications in diabetes mellitus.

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Donepezil, a therapeutic drug for Alzheimer’s disease, ameliorates cognitive dysfunction through selective inhibition of acetylcholinesterase. However, recent studies have also reported off-target effects of donepezil that likely contribute to its therapeutic effects. In this study, we investigated the (i) role of donepezil in amyloid precursor protein (APP) processing and (ii) involvement of sorting nexin protein 33 (SNX33), a member of the sorting nexin protein family, in this processing. Results showed that donepezil induces an increase in SNX33 expression in primary cortical neurons. The secretion of sAPPα in culture media increased, whereas the expression of full-length APP in the cell lysate remained unchanged. Exposure of cortical cultures to donepezil led to a decrease in amyloid β (Aβ) protein levels in a concentration- and time-dependent manner. This decrease was not affected by concomitant treatment with acetylcholine receptor antagonists. SNX33 knockdown by target-specific morpholino oligos inhibited the effects of donepezil. Donepezil treatment increased cell membrane surface expression of APP in SNX33 expression-dependent manner. These results suggested that donepezil decreases the level of Aβ by increasing SNX33 expression and APP cleavage by α-secretase in cortical neurons.