Macro- and microvascular disease states currently represent the principal causes of morbidity and mortality in patients with type I or type II diabetes mellitus. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in various beds in different animal models of diabetes and in humans with type I or type II diabetes. Several mechanisms leading to endothelial dysfunction have been reported, including changes in substrate avail ability, impaired release of NO, and increased destruction of NO. The principal mediators of diabetes-associated endothelial dysfunction are (a) increases in oxidized low density lipoprotein, endothelin-1, angiotensin II, oxidative stress, and (b) decreases in the actions of insulin or growth factors in endothelial cells. An accumulating body of evidence indicates that abnormal regulation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway may be one of several factors contributing to vascular dysfunction in diabetes. The PI3-K pathway, which activates serine/threonine protein kinase Akt, enhances NO synthase phosphorylation and NO production. Several studies suggest that in diabetes the relative ineffectiveness of insulin and the hyperglycemia act together to reduce activity in the insulin-receptor substrates (IRS)/PI3-K/Akt pathway, resulting in impairments of both IRS/PI3-K/Akt-mediated endothelial function and NO production. This article summarizes the PI3-K/Akt pathway-mediated contraction and relaxation responses induced by various agents in the blood vessels of diabetic animals.

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Focal application of vasodilators such as acetylcholine (ACh), which evoke arterial hyperpolarization, cause coordinated dilatation along the length of an artery with minimal decay with distance from the site of application. This phenomenon is called spreading vasodilatation. In an artery wall, the endothelium is separated from the surrounding smooth muscle cell layers by an internal elastic lamina (IEL). Adjacent endothelial cells are strongly connected via gap junctions, which can allow direct communication between the cells, including the passage of small molecules and electrical current. Direct communication between an endothelial cell and a smooth muscle cell, through a hole in the IEL, has recently been observed in arteries. Spreading vasodilatation is associated with a spread of hyperpolarization which may be a key mechanism responsible for this spreading arterial vasodilatation. Endothelial cells appear to play an important role in such spread, even though the facilitating mechanisms underlying this spread are as yet unclear. These spreading responses are likely to have an important physiological role in the coordination of blood flow within a vascular network.

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In circular smooth muscle bundles isolated from the guinea-pig stomach antrum, the effects of quinidine, Ni²⁺, flufenamic acid, niflumic acid, La³⁺, SKF-96365 and 4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) on acetylcholine (ACh)-induced depolarization were investigated. Recording membrane potentials from smooth muscle cells with intracellular microelectrodes revealed that ACh (1 μM) depolarized the membrane by 5-8 mV and increased the amplitude and frequency of slow potentials. These effects were inhibited by atropine. Quinidine (10 μM) increased the amplitude of ACh-induced depolarization, with no alteration to the properties of slow potentials. Ni²⁺ (50 μM) transiently (5-10 min) depolarized the membrane by about 5 mV, with an associated increase in frequency and amplitude of slow potentials. In the stabilized condition with Ni²⁺, the amplitude of ACh-induced depolarization remained unchanged. Flufenamic acid (10 μM) inhibited the generation of slow potentials, with no change in either the amplitude of ACh-induced depolarization or of the amplitude and frequency of slow potentials generated during ACh stimulation. A high concentration of flufenamic acid (100 μM) depolarized the membrane and increased the amplitude of ACh-induced depolarization. Niflumic acid (10 μM) hyperpolarized the membrane and increased the amplitude and frequency of slow potentials and also the amplitude of ACh-induced depolarization. DIDS (100 μM) hyperpolarized the membrane and inhibited the amplitude and frequency of slow potentials, with no alteration to the amplitude of ACh-induced depolarization. SKF-96365 (3-50 μM) depolarized the membrane in a concentration-dependent manner, but did not change the level of ACh-induced depolarization. La³⁺ (50 μM) did not alter the properties of the slow potentials or the ACh-induced responses. These results provide evidence that ACh-induced depolarization is not inhibited by chemicals known to inhibit non-selective cation channels. We suggest that muscarinic receptor-mediated signal transduction may be different in smooth muscle and interstitial cells.

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