Vascular Contractility and Blood Flow

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Hemodynamic abnormalities such as blood flow and vascular contractility have been reported in many organs of diabetic animals or patients, including the kidney, retina, peripheral arteries, and microvessels of peripheral nerves. In the retina of diabetic patients and animals with a short duration and without clinical retinopathy, blood flow has been shown to be decreased (119-123). One possible explanation for the decreased retinal blood flow in early stage of diabetes is as a result of an increase in vascular resistance at the microcirculatory level induced by PKC activation. We have reported that the decreased retinal blood flow can be mimicked by intravitreous injection of phorbol esters, which are PKC activators (78). Furthermore, decreases in retinal blood flow in diabetic rats have been reported to be normalized by PKC inhibitors (90). In addition to the retina, decreases in blood flow have also been reported in the peripheral nerves of diabetic animals by most investigators; these were normalized by PKC inhibitor, an aldose reductase inhibitor, and antioxidants respectively.

One of the possible mechanisms by which PKC activation could be causing vasoconstriction in the retina is by increased expression of endothelin-1 (ET-1). We have reported that the expression of ET-1, potent vasoconstrictor, is increased in the retina of diabetic rats and that intravitreous injection of endothelin-A receptor antagonist BQ123 prevented the decrease in retinal blood flow in diabetic rats (124). The induction of ET-1 expression could also be normalized by LY333531, a PKC-^-selective inhibitor (125). The decrease in blood flow to the retina could lead to local hypoxia, which is a potent inducer of vascular endothelial growth factor (VEGF); this factor can cause increases in permeability and microaneurysms, as observed in diabetic retina (126,127).

Abnormalities in hemodynamic have been documented to precede diabetic nephropa-thy. Elevated renal glomerular filtration rate and modest increases in renal blood flow are characteristic finding in IDDM patients and experimental diabetic animals with poor glycemic control (128-131). Diabetic glomerular filtration is likely to be the result of hyperglycemia-induced decreases in arteriolar resistance, especially at the level of afferent arteriole, resulting in an elevation of glomerular filtration pressure. This effect of hyperglycemia can be mimicked in vitro by incubating renal mesangial cells with elevated glucose levels that reduced cellular response to vasoconstriction. Several reports have suggested that the activation of PKC via the induction of prostaglandins may involve in this adverse effects of hyperglycemia (132,133).

Changes in NO could also alter vascular contractility and blood flow. In the resistant vessels isolated from diabetic patients and animals, the relaxation phase after acetylcho-line stimulation appears to be delayed (134-137). These impaired vascular relaxation can be restored by PKC inhibitors and mimicked by phorbol ester in normal arteries (137). The inhibition of PKC increased mRNA expression of eNOS in aortic endothelial cells (138). We have observed reduced eNOS expression in microvasculature in Zucker fatty rats, which are the model of insulin resistance (33).

Oral administration of effective specific inhibitor for PKC^ isoform LY333531 to diabetic rats for 2 weeks from the onset of the disease can normalize the retinal blood flow and glomerular filtration rate in parallel with inhibition of PKC activity (90). Similarly, the renal albumin excretion rate can be improved after 8 weeks of such treatment. These data support the idea that the activation of PKCP isoform is involved in the development of some aspects of diabetic vascular complications and endothelial dysfunctions.

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