Abstract-Retinal vasoconstriction and reduced retinal blood flow precede the onset of diabetic retinopathy. The pathophysiological mechanisms that underlie increased retinal arteriolar tone during diabetes remain unclear. Normally, local Ca 2ϩ release events (Ca 2ϩ -sparks), trigger the activation of large-conductance Ca 2ϩ -activated K ϩ (BK)-channels which hyperpolarize and relax vascular smooth muscle cells, thereby causing vasodilatation. In the present study, we examined BK channel function in retinal vascular smooth muscle cells from streptozotocin-induced diabetic rats. The BK channel inhibitor, Penitrem A, constricted nondiabetic retinal arterioles (pressurized to 70mmHg) by 28%. The BK current evoked by caffeine was dramatically reduced in retinal arterioles from diabetic animals even though caffeine-evoked [Ca 2ϩ ] i release was unaffected. Spontaneous BK currents were smaller in diabetic cells, but the amplitude of Ca 2ϩ -sparks was larger. The amplitudes of BK currents elicited by depolarizing voltage steps were similar in control and diabetic arterioles and mRNA expression of the pore-forming BK␣ subunit was unchanged. The Ca 2ϩ -sensitivity of single BK channels from diabetic retinal vascular smooth muscle cells was markedly reduced. The BK␤1 subunit confers Ca 2ϩ -sensitivity to BK channel complexes and both transcript and protein levels for BK␤1 were appreciably lower in diabetic retinal arterioles. The mean open times and the sensitivity of BK channels to tamoxifen were decreased in diabetic cells, consistent with a downregulation of BK␤1 subunits. The potency of blockade by Pen A was lower for BK channels from diabetic animals. Thus, changes in the molecular composition of BK channels could account for retinal hypoperfusion in early diabetes, an idea having wider implications for the pathogenesis of diabetic hypertension. (Circ Res. 2007;100:703-711.)

specialist geriatric assessment and medication review in hospital continuing care resulted in a reduction in medication use, but at a significant cost. No benefits in hard clinical outcomes were demonstrated. However, qualitative benefits and lower costs may become evident over longer periods.

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