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Influence of diabetes on the α1-Adrenoceptor and associated G-proteins in rat arteries Weber, Lynn Patricia


Abnormal vascular reactivity has been suggested to be a hallmark of impending development of hypertension in arteries from diabetic humans. Previous studies from this laboratory have demonstrated an enhancement in both the contractile and signaling response to ai-adrenoceptor stimulation in arteries from male Wistar rats with 12-14 weeks of streptozotocin-induced diabetes. The purpose of the research in this thesis was to study the basis for the increased signaling in diabetic arteries. Direct stimulation of G-proteins with NaF, in the presence of AlCl3, produced contractile responses in mesenteric and caudal arteries from diabetic rats that were significantly elevated compared to control arteries by a similar magnitude as the noradrenaline (NA) enhancement The larger contractile response of the diabetic arteries was not attributable to a difference between control and diabetic arteries in cAMP or cGMP levels, either basally or in the presence of NaF. Ryanodine which depletes intracellular calcium stores, nifedipine which blocks dihydropyridine-sensitive calcium channels and calphostin C which selectively inhibits proteins kinase C, all significantly inhibited maximum contractile responses of mesenteric arteries from control and diabetic rats to NaF. There were no significant differences between control and diabetic arteries in the relative magnitude of the inhibition produced by the three antagonists. These data suggest that there may be increased activation of the same signaling processes that mediate NA-stimulated vasoconstriction, perhaps contraction-associated G-proteins or the effectors coupled to these G-proteins, in response to NaF in mesenteric arteries from diabetic rats. [More abstract follows]

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